78 FR 78321 - Early Warning Reporting, Foreign Defect Reporting, and Motor Vehicle and Equipment Recall...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-26

... DEPARTMENT OF TRANSPORTATION National Highway Traffic Safety Administration 49 CFR Parts 573, 577, and 579 [Docket No. NHTSA--2012-0068; Notice 3] RIN 2127-AK72 Early Warning Reporting, Foreign Defect... final rule. Id. Manufacturers with early warning reporting (EWR) accounts may obtain a copy of the VIN...

Pulsed eddy current differential probe to detect the defects in a stainless steel pipe

NASA Astrophysics Data System (ADS)

Angani, C. S.; Park, D. G.; Kim, C. G.; Leela, P.; Kishore, M.; Cheong, Y. M.

2011-04-01

Pulsed eddy current (PEC) is an electromagnetic nondestructive technique widely used to detect and quantify the flaws in conducting materials. In the present study a differential Hall-sensor probe which is used in the PEC system has been fabricated for the detection of defects in stainless steel pipelines. The differential probe has an exciting coil with two Hall-sensors. A stainless steel test sample with electrical discharge machining (EDM) notches under different depths of 1-5 mm was made and the sample was laminated by plastic insulation having uniform thickness to simulate the pipelines in nuclear power plants (NPPs). The driving coil in the probe is excited by a rectangular current pulse and the resultant response, which is the difference of the two Hall-sensors, has been detected as the PEC probe signal. The discriminating time domain features of the detected pulse such as peak value and time to zero are used to interpret the experimental results with the defects in the test sample. A feature extraction technique such as spectral power density has been devised to infer the PEC response.

Antihistamine Use in Early Pregnancy and Risk of Birth Defects

PubMed Central

Li, Qian; Mitchell, Allen A.; Werler, Martha M.; Yau, Wai-Ping; Hernández-Díaz, Sonia

2014-01-01

Background Several studies have reported an association between use of specific antihistamines in early pregnancy and certain specific birth defects. Objective To test 16 previously-hypothesized associations between specific antihistamines and specific birth defects, and identify possible new associations. Methods We used 1998-2010 data from the Slone Epidemiology Center Birth Defects Study, a multicenter case-control surveillance program of birth defects in North America. Mothers were interviewed within six months of delivery about demographic, reproductive, medical, and behavioral factors, and details on use of prescription and non-prescription medications. We compared 1st trimester exposure to specific antihistamines between 13,213 infants with specific malformations and 6,982 non-malformed controls, using conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), with adjustment for potential confounders, including indication for use. Results Overall, 13.7% of controls were exposed to antihistamines during the 1st trimester. The most commonly-used medications were diphenhydramine (4.2%), loratadine (3.1%), doxylamine (1.9%), and chlorpheniramine (1.7%). Where estimates were stable, none supported the previously-hypothesized associations. Among over 100 exploratory comparisons of other specific antihistamine/defect pairs, 14 had ORs ≥1.5 of which 6 had 95% CI bounds excluding 1.0 before but not after adjustment for multiple comparisons. Conclusion Our findings do not provide meaningful support for previously-posited associations between antihistamines and major congenital anomalies; at the same time, we identified associations that had not been previously suggested. We suspect that previous associations may be chance findings in the context of multiple comparisons, a situation which may also apply to our new findings. PMID:24565715

Vision-Based Sensor for Early Detection of Periodical Defects in Web Materials

PubMed Central

Bulnes, Francisco G.; Usamentiaga, Rubén; García, Daniel F.; Molleda, Julio

2012-01-01

During the production of web materials such as plastic, textiles or metal, where there are rolls involved in the production process, periodically generated defects may occur. If one of these rolls has some kind of flaw, it can generate a defect on the material surface each time it completes a full turn. This can cause the generation of a large number of surface defects, greatly degrading the product quality. For this reason, it is necessary to have a system that can detect these situations as soon as possible. This paper presents a vision-based sensor for the early detection of this kind of defects. It can be adapted to be used in the inspection of any web material, even when the input data are very noisy. To assess its performance, the sensor system was used to detect periodical defects in hot steel strips. A total of 36 strips produced in ArcelorMittal Avilés factory were used for this purpose, 18 to determine the optimal configuration of the proposed sensor using a full-factorial experimental design and the other 18 to verify the validity of the results. Next, they were compared with those provided by a commercial system used worldwide, showing a clear improvement. PMID:23112629

Survival and differentiation defects contribute to neutropenia in glucose-6-phosphatase-β (G6PC3) deficiency in a model of mouse neutrophil granulocyte differentiation.

PubMed

Gautam, S; Kirschnek, S; Gentle, I E; Kopiniok, C; Henneke, P; Häcker, H; Malleret, L; Belaaouaj, A; Häcker, G

2013-08-01

Differentiation of neutrophil granulocytes (neutrophils) occurs through several steps in the bone marrow and requires a coordinate regulation of factors determining survival and lineage-specific development. A number of genes are known whose deficiency disrupts neutrophil generation in humans and in mice. One of the proteins encoded by these genes, glucose-6-phosphatase-β (G6PC3), is involved in glucose metabolism. G6PC3 deficiency causes neutropenia in humans and in mice, linked to enhanced apoptosis and ER stress. We used a model of conditional Hoxb8 expression to test molecular and functional differentiation as well as survival defects in neutrophils from G6PC3(-/-) mice. Progenitor lines were established and differentiated into neutrophils when Hoxb8 was turned off. G6PC3(-/-) progenitor cells underwent substantial apoptosis when differentiation was started. Transgenic expression of Bcl-XL rescued survival; however, Bcl-XL-protected differentiated cells showed reduced proliferation, immaturity and functional deficiency such as altered MAP kinase signaling and reduced cytokine secretion. Impaired glucose utilization was found and was associated with ER stress and apoptosis, associated with the upregulation of Bim and Bax; downregulation of Bim protected against apoptosis during differentiation. ER-stress further caused a profound loss of expression and secretion of the main neutrophil product neutrophil elastase during differentiation. Transplantation of wild-type Hoxb8-progenitor cells into irradiated mice allowed differentiation into neutrophils in the bone marrow in vivo. Transplantation of G6PC3(-/-) cells yielded few mature neutrophils in bone marrow and peripheral blood. Transgenic Bcl-XL permitted differentiation of G6PC3(-/-) cells in vivo. However, functional deficiencies and differentiation abnormalities remained. Differentiation of macrophages from Hoxb8-dependent progenitors was only slightly disturbed. A combination of defects in differentiation

Acquired color vision and visual field defects in patients with ocular hypertension and early glaucoma.

PubMed

Papaconstantinou, Dimitris; Georgalas, Ilias; Kalantzis, George; Karmiris, Efthimios; Koutsandrea, Chrysanthi; Diagourtas, Andreas; Ladas, Ioannis; Georgopoulos, Gerasimos

2009-01-01

To study acquired color vision and visual field defects in patients with ocular hypertension (OH) and early glaucoma. In a prospective study we evaluated 99 eyes of 56 patients with OH without visual field defects and no hereditary color deficiencies, followed up for 4 to 6 years (mean = 4.7 +/- 0.6 years). Color vision defects were studied using a special computer program for Farnsworth-Munsell 100 hue test and visual field tests were performed with Humphrey analyzer using program 30-2. Both tests were repeated every six months. In fifty-six eyes, glaucomatous defects were observed during the follow-up period. There was a statistically significant difference in total error score (TES) between eyes that eventually developed glaucoma (157.89 +/- 31.79) and OH eyes (75.51 +/- 31.57) at the first examination (t value 12.816, p < 0.001). At the same time visual field indices were within normal limits in both groups. In the glaucomatous eyes the earliest statistical significant change in TES was identified at the first year of follow-up and was -20.62 +/- 2.75 (t value 9.08, p < 0.001) while in OH eyes was -2.11 +/- 4.36 (t value 1.1, p = 0.276). Pearson's coefficient was high in all examinations and showed a direct correlation between TES and mean deviation and corrected pattern standard deviation in both groups. Quantitative analysis of color vision defects provides the possibility of follow-up and can prove a useful means for detecting early glaucomatous changes in patients with normal visual fields.

XBtg2 is required for notochord differentiation during early Xenopus development.

PubMed

Sugimoto, Kaoru; Hayata, Tadayoshi; Asashima, Makoto

2005-09-01

The notochord is essential for normal vertebrate development, serving as both a structural support for the embryo and a signaling source for the patterning of adjacent tissues. Previous studies on the notochord have mostly focused on its formation and function in early organogenesis but gene regulation in the differentiation of notochord cells itself remains poorly defined. In the course of screening for genes expressed in developing notochord, we have isolated Xenopus homolog of Btg2 (XBtg2). The mammalian Btg2 genes, Btg2/PC3/TIS21, have been reported to have multiple functions in the regulation of cell proliferation and differentiation but their roles in early development are still unclear. Here we characterized XBtg2 in early Xenopus laevis embryogenesis with focus on notochord development. Translational inhibition of XBtg2 resulted in a shortened and bent axis phenotype and the abnormal structures in the notochord tissue, which did not undergo vacuolation. The XBtg2-depleted notochord cells expressed early notochord markers such as chordin and Xnot at the early tailbud stage, but failed to express differentiation markers of notochord such as Tor70 and 5-D-4 antigens in the later stages. These results suggest that XBtg2 is required for the differentiation of notochord cells such as the process of vacuolar formation after determination of notochord cell fate.

TSH Receptor Function Is Required for Normal Thyroid Differentiation in Zebrafish

PubMed Central

Opitz, Robert; Maquet, Emilie; Zoenen, Maxime; Dadhich, Rajesh

2011-01-01

TSH is the primary physiological regulator of thyroid gland function. The effects of TSH on thyroid cells are mediated via activation of its membrane receptor [TSH receptor (TSHR)]. In this study, we examined functional thyroid differentiation in zebrafish and characterized the role of TSHR signaling during thyroid organogenesis. Cloning of a cDNA encoding zebrafish Tshr showed conservation of primary structure and functional properties between zebrafish and mammalian TSHR. In situ hybridization confirmed that the thyroid is the major site of tshr expression during zebrafish development. In addition, we identified tpo, iyd, duox, and duoxa as novel thyroid differentiation markers in zebrafish. Temporal analyses of differentiation marker expression demonstrated the induction of an early thyroid differentiation program along with thyroid budding, followed by a delayed onset of duox and duoxa expression coincident with thyroid hormone synthesis. Furthermore, comparative analyses in mouse and zebrafish revealed for the first time a thyroid-enriched expression of cell death regulators of the B-cell lymphoma 2 family during early thyroid morphogenesis. Knockdown of tshr function by morpholino microinjection into embryos did not affect early thyroid morphogenesis but caused defects in later functional differentiation. The thyroid phenotype observed in tshr morphants at later stages comprised a reduction in number and size of functional follicles, down-regulation of differentiation markers, as well as reduced thyroid transcription factor expression. A comparison of our results with phenotypes observed in mouse models of defective TSHR and cAMP signaling highlights the value of zebrafish as a model to enhance the understanding of functional differentiation in the vertebrate thyroid. PMID:21737742

E2F4 is required for early eye patterning.

PubMed

Ruzhynsky, Vladimir A; Furimsky, Marosh; Park, David S; Wallace, Valerie A; Slack, Ruth S

2009-01-01

Increasingly, studies reveal novel functions for cell cycle proteins during development. Here, we investigated the role of E2F4 in eye development. E2F4-deficient mouse embryos exhibit severe early eye patterning defects, which are evident from embryonic day 11.5 and characterized by aberrant shape of the optic cup, coloboma as well as abnormal eye pigmentation. Loss of E2F4 is associated with proximal-distal patterning defects in the optic vesicle. These defects are characterized by the expansion of optic stalk marker gene expression to the optic cup and reduced expression of ventral optic cup markers. These defects are associated with a split of Shh expression domain at the ventral midline of the forebrain and expansion of the Shh activity into the ventral optic cup. Despite these patterning defects, early neuronal differentiation and Shh expression in the retina are not affected by E2F4 deletion. Overall, the results of our studies show a novel role of E2F4 in the early eye development. 2009 S. Karger AG, Basel.

Dental enamel defects in German medieval and early-modern-age populations.

PubMed

Lang, J; Birkenbeil, S; Bock, S; Heinrich-Weltzien, R; Kromeyer-Hauschild, K

2016-11-01

Aim of this study was to investigate the frequency and type of developmental defects of enamel (DDE) in a medieval and an early-modern-age population from Thuringia, Germany. Sixty-six skeletons subdivided into 31 single burials (12 th /13 th c.) and 35 individuals buried in groups (15 th /16 th c.) were examined. DDE were classified on 1,246 teeth according to the DDE index. Molar-incisor-hypomineralisation (MIH), a special type of DDE, was recorded according to the European Academy of Paediatric Dentistry (EAPD) criteria. DDE was found in 89.4% of the individuals (single burials 90.3% and group burials 88.6%). Hypoplastic pits were the most frequent defect in primary teeth and linear enamel hypoplasia (LEH) in permanent teeth. 13 individuals (24.1%) showed at least one hypomineralised permanent tooth, 12.2% had MIH on at least one first permanent molar and 10.0% in permanent incisors. Second primary molars were affected in 8.0% of the children and juveniles. No individual suffered from affected molars and incisors in combination. Endogenous factors like nutritional deficiencies and health problems in early childhood could have been aetiological reasons of DDE and MIH. The frequency of DDE and MIH might have been masked by extended carious lesions, dental wear and ante-mortem tooth loss.

A nonmagnetic differentiated early planetary body

NASA Astrophysics Data System (ADS)

Weiss, Benjamin P.; Wang, Huapei; Sharp, Thomas G.; Gattacceca, Jérôme; Shuster, David L.; Downey, Brynna; Hu, Jinping; Fu, Roger R.; Kuan, Aaron T.; Suavet, Clément; Irving, Anthony J.; Wang, Jun; Wang, Jiajun

2017-06-01

Paleomagnetic studies of meteorites have shown that the solar nebula was likely magnetized and that many early planetary bodies generated dynamo magnetic fields in their advecting metallic cores. The surface fields on these bodies were recorded by a diversity of chondrites and achondrites, ranging in intensity from several μT to several hundred μT. In fact, an achondrite parent body without evidence for paleomagnetic fields has yet to be confidently identified, hinting that early solar system field generation and the dynamo process in particular may have been common. Here we present paleomagnetic measurements of the ungrouped achondrite NWA 7325 indicating that it last cooled in a near-zero field (<∼1.7 μT), estimated to have occurred at 4563.09 ± 0.26 million years ago (Ma) from Al-Mg chronometry. Because NWA 7325 is highly depleted in siderophile elements, its parent body nevertheless underwent large-scale metal-silicate differentiation and likely formed a metallic core. This makes NWA 7325 the first recognized example of an essentially unmagnetized igneous rock from a differentiated early solar system body. These results indicate that all magnetic fields, including those from any core dynamo on the NWA 7325 parent body, the solar nebula, young Sun, and solar wind, were <1.7 μT at the location of NWA 7325 at 4563 Ma. This supports a recent conclusion that the solar nebula had dissipated by ∼4 million years after solar system formation. NWA 7325 also serves as an experimental control that gives greater confidence in the positive identification of remanent magnetization in other achondrites.

Acquired color vision and visual field defects in patients with ocular hypertension and early glaucoma

PubMed Central

Papaconstantinou, Dimitris; Georgalas, Ilias; Kalantzis, George; Karmiris, Efthimios; Koutsandrea, Chrysanthi; Diagourtas, Andreas; Ladas, Ioannis; Georgopoulos, Gerasimos

2009-01-01

Purpose: To study acquired color vision and visual field defects in patients with ocular hypertension (OH) and early glaucoma. Methods: In a prospective study we evaluated 99 eyes of 56 patients with OH without visual field defects and no hereditary color deficiencies, followed up for 4 to 6 years (mean = 4.7 ± 0.6 years). Color vision defects were studied using a special computer program for Farnsworth–Munsell 100 hue test and visual field tests were performed with Humphrey analyzer using program 30–2. Both tests were repeated every six months. Results: In fifty-six eyes, glaucomatous defects were observed during the follow-up period. There was a statistically significant difference in total error score (TES) between eyes that eventually developed glaucoma (157.89 ± 31.79) and OH eyes (75.51 ± 31.57) at the first examination (t value 12.816, p < 0.001). At the same time visual field indices were within normal limits in both groups. In the glaucomatous eyes the earliest statistical significant change in TES was identified at the first year of follow-up and was −20.62 ± 2.75 (t value 9.08, p < 0.001) while in OH eyes was −2.11 ± 4.36 (t value 1.1, p = 0.276). Pearson’s coefficient was high in all examinations and showed a direct correlation between TES and mean deviation and corrected pattern standard deviation in both groups. Conclusion: Quantitative analysis of color vision defects provides the possibility of follow-up and can prove a useful means for detecting early glaucomatous changes in patients with normal visual fields. PMID:19668575

Inhibition of master transcription factors in pluripotent cells induces early stage differentiation

PubMed Central

De, Debojyoti; Jeong, Myong-Ho; Leem, Young-Eun; Svergun, Dmitri I.; Wemmer, David E.; Kang, Jong-Sun; Kim, Kyeong Kyu; Kim, Sung-Hou

2014-01-01

The potential for pluripotent cells to differentiate into diverse specialized cell types has given much hope to the field of regenerative medicine. Nevertheless, the low efficiency of cell commitment has been a major bottleneck in this field. Here we provide a strategy to enhance the efficiency of early differentiation of pluripotent cells. We hypothesized that the initial phase of differentiation can be enhanced if the transcriptional activity of master regulators of stemness is suppressed, blocking the formation of functional transcriptomes. However, an obstacle is the lack of an efficient strategy to block protein–protein interactions. In this work, we take advantage of the biochemical property of seventeen kilodalton protein (Skp), a bacterial molecular chaperone that binds directly to sex determining region Y-box 2 (Sox2). The small angle X-ray scattering analyses provided a low resolution model of the complex and suggested that the transactivation domain of Sox2 is probably wrapped in a cleft on Skp trimer. Upon the transduction of Skp into pluripotent cells, the transcriptional activity of Sox2 was inhibited and the expression of Sox2 and octamer-binding transcription factor 4 was reduced, which resulted in the expression of early differentiation markers and appearance of early neuronal and cardiac progenitors. These results suggest that the initial stage of differentiation can be accelerated by inhibiting master transcription factors of stemness. This strategy can possibly be applied to increase the efficiency of stem cell differentiation into various cell types and also provides a clue to understanding the mechanism of early differentiation. PMID:24434556

Early postoperative healing following buccal single flap approach to access intraosseous periodontal defects.

PubMed

Farina, Roberto; Simonelli, Anna; Rizzi, Alessandro; Pramstraller, Mattia; Cucchi, Alessandro; Trombelli, Leonardo

2013-07-01

This study aims to evaluate the early postoperative healing of papillary incision wounds and its association with (1) patient/site-related factors and technical (surgical) aspects as well as with (2) 6-month clinical outcomes following buccal single flap approach (SFA) in the treatment of intraosseous periodontal defects. Forty-three intraosseous defects in 35 patients were accessed with a buccal SFA alone or in combination with a reconstructive technology (graft, enamel matrix derivative (EMD), graft + EMD, or graft + membrane). Postoperative healing was evaluated at 2 weeks using the Early Wound-Healing Index (EHI). EHI ranged from score 1 (i.e., complete flap closure and optimal healing) to score 4 (i.e., loss of primary closure and partial tissue necrosis). SFA resulted in a complete wound closure at 2 weeks in the great majority of sites. A significantly more frequent presence of interdental contact point and interdental soft tissue crater, and narrower base of the interdental papilla were observed at sites with either EHI > 1 or EHI = 4 compared to sites with EHI = 1. No association between EHI and the 6-month clinical outcomes was observed. At 2 weeks, buccal SFA may result in highly predictable complete flap closure. Site-specific characteristics may influence the early postoperative healing of the papillary incision following SFA procedure. Two-week soft tissue healing, however, was not associated with the 6-month clinical outcomes.

Role for early-differentiated natural killer cells in infectious mononucleosis

PubMed Central

Azzi, Tarik; Lünemann, Anna; Murer, Anita; Ueda, Seigo; Béziat, Vivien; Malmberg, Karl-Johan; Staubli, Georg; Gysin, Claudine; Berger, Christoph; Münz, Christian

2014-01-01

A growing body of evidence suggests that the human natural killer (NK)-cell compartment is phenotypically and functionally heterogeneous and is composed of several differentiation stages. Moreover, NK-cell subsets have been shown to exhibit adaptive immune features during herpes virus infection in experimental mice and to expand preferentially during viral infections in humans. However, both phenotype and role of NK cells during acute symptomatic Epstein-Barr virus (EBV) infection, termed infectious mononucleosis (IM), remain unclear. Here, we longitudinally assessed the kinetics, the differentiation, and the proliferation of subsets of NK cells in pediatric IM patients. Our results indicate that acute IM is characterized by the preferential proliferation of early-differentiated CD56dim NKG2A+ immunoglobulin-like receptor- NK cells. Moreover, this NK-cell subset exhibits features of terminal differentiation and persists at higher frequency during at least the first 6 months after acute IM. Finally, we demonstrate that this NK-cell subset preferentially degranulates and proliferates on exposure to EBV-infected B cells expressing lytic antigens. Thus, early-differentiated NK cells might play a key role in the immune control of primary infection with this persistent tumor-associated virus. PMID:25205117

A nonmagnetic differentiated early planetary body

DOE PAGES

Weiss, Benjamin P.; Wang, Huapei; Sharp, Thomas G.; ...

2017-06-19

Paleomagnetic studies of meteorites have shown that the solar nebula was likely magnetized and that many early planetary bodies generated dynamo magnetic fields in their advecting metallic cores. The surface fields on these bodies were recorded by a diversity of chondrites and achondrites, ranging in intensity from several μT to several hundred μT. In fact, an achondrite parent body without evidence for paleomagnetic fields has yet to be confidently identified, hinting that early solar system field generation and the dynamo process in particular may have been common. Here we present paleomagnetic measurements of the ungrouped achondrite NWA 7325 indicating thatmore » it last cooled in a near-zero field (<~1.7μT), estimated to have occurred at 4563.09 ± 0.26 million years ago (Ma) from Al–Mg chronometry. Because NWA 7325 is highly depleted in siderophile elements, its parent body nevertheless underwent large-scale metal-silicate differentiation and likely formed a metallic core. This makes NWA 7325 the first recognized example of an essentially unmagnetized igneous rock from a differentiated early solar system body. These results indicate that all magnetic fields, including those from any core dynamo on the NWA 7325 parent body, the solar nebula, young Sun, and solar wind, were <1.7 μT at the location of NWA 7325 at 4563 Ma. Finally, this supports a recent conclusion that the solar nebula had dissipated by ~4 million years after solar system formation. NWA 7325 also serves as an experimental control that gives greater confidence in the positive identification of remanent magnetization in other achondrites.« less

A Nonmagnetic Differentiated Early Planetary Body

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weiss, Benjamin P.; Wang, Jun

2017-06-15

Paleomagnetic studies of meteorites have shown that the solar nebula was likely magnetized and that many early planetary bodies generated dynamo magnetic fields in their advecting metallic cores. The surface fields on these bodies were recorded by a diversity of chondrites and achondrites, ranging in intensity from several μT to several hundred μT. In fact, an achondrite parent body without evidence for paleomagnetic fields has yet to be confidently identified, hinting that early solar system field generation and the dynamo process in particular may have been common. Here we present paleomagnetic measurements of the ungrouped achondrite NWA 7325 indicating thatmore » it last cooled in a near-zero field (<∼1.7μT), estimated to have occurred at 4563.09 ± 0.26 million years ago (Ma) from Al–Mg chronometry. Because NWA 7325 is highly depleted in siderophile elements, its parent body nevertheless underwent large-scale metal-silicate differentiation and likely formed a metallic core. This makes NWA 7325 the first recognized example of an essentially unmagnetized igneous rock from a differentiated early solar system body. These results indicate that all magnetic fields, including those from any core dynamo on the NWA 7325 parent body, the solar nebula, young Sun, and solar wind, were <1.7 μT at the location of NWA 7325 at 4563 Ma. This supports a recent conclusion that the solar nebula had dissipated by ∼4 million years after solar system formation. NWA 7325 also serves as an experimental control that gives greater confidence in the positive identification of remanent magnetization in other achondrites.« less

Malnutrition-related early childhood exposures and enamel defects in the permanent dentition: A longitudinal study from the Bolivian Amazon.

PubMed

Masterson, Erin E; Fitzpatrick, Annette L; Enquobahrie, Daniel A; Mancl, Lloyd A; Conde, Esther; Hujoel, Philippe P

2017-10-01

We investigated the relationship between early childhood malnutrition-related measures and subsequent enamel defects in the permanent dentition. This cohort study included 349 Amerindian adolescents (10-17 years, 52% male) from the Bolivian Amazon. Exposures included: stunted growth (height-for-age z-scores), underweight (weight-for-age z-scores), anemia (hemoglobin), acute inflammation (C-reactive protein) and parasitic infection (hookworm). We measured the occurrence (no/yes) and extent (<1/3, 1/3-2/3, >2/3) of enamel defects. We estimated associations between childhood exposures and enamel defect measures using log-binomial and multinomial logistic regression. The prevalence of an enamel defect characterized by an orange peel texture on a large central depression on the labial surface of the central maxillary incisors was 92.3%. During childhood (1-4 years), participants had a high prevalence of stunted growth (75.2%), anemia (56.9%), acute inflammation (39.1%), and hookworm infection (49.6%). We observed associations between childhood height-for-age (OR = 0.65; P = 0.028 for >2/3 extent vs. no EH) and gastrointestinal hookworm infection (OR = 3.43; P = 0.035 for >2/3 extent vs. no defects or <1/3 extent) with enamel defects. The study describes a possibly novel form of enamel hypoplasia and provides evidence for associations of malnutrition-related measures in early childhood, including stunted growth and parasitic helminth infection, with the observed enamel defects. © 2017 Wiley Periodicals, Inc.

Emergent presentation of decompensated mitral valve prolapse and atrial septal defect.

PubMed

Kang, Jessie; Das, Bijon

2015-05-01

Mitral valve prolapse is not commonly on the list of differential diagnosis when a patient presents in the emergency department (ED) in severe distress, presenting with non-specific features such as abdominal pain, tachycardia and dyspnea. A healthy 55-year-old man without significant past medical history arrived in the ED with a unique presentation of a primary mitral valve prolapse with an atrial septal defect uncommon in cardiology literature. Early recognition of mitral valve prolapse in high-risk patients for severe mitral regurgitation or patients with underlying cardiovascular abnormalities such as an atrial septal defect is crucial to prevent morbid outcomes such as sudden cardiac death.

Role for early-differentiated natural killer cells in infectious mononucleosis.

PubMed

Azzi, Tarik; Lünemann, Anna; Murer, Anita; Ueda, Seigo; Béziat, Vivien; Malmberg, Karl-Johan; Staubli, Georg; Gysin, Claudine; Berger, Christoph; Münz, Christian; Chijioke, Obinna; Nadal, David

2014-10-16

A growing body of evidence suggests that the human natural killer (NK)-cell compartment is phenotypically and functionally heterogeneous and is composed of several differentiation stages. Moreover, NK-cell subsets have been shown to exhibit adaptive immune features during herpes virus infection in experimental mice and to expand preferentially during viral infections in humans. However, both phenotype and role of NK cells during acute symptomatic Epstein-Barr virus (EBV) infection, termed infectious mononucleosis (IM), remain unclear. Here, we longitudinally assessed the kinetics, the differentiation, and the proliferation of subsets of NK cells in pediatric IM patients. Our results indicate that acute IM is characterized by the preferential proliferation of early-differentiated CD56(dim) NKG2A(+) immunoglobulin-like receptor(-) NK cells. Moreover, this NK-cell subset exhibits features of terminal differentiation and persists at higher frequency during at least the first 6 months after acute IM. Finally, we demonstrate that this NK-cell subset preferentially degranulates and proliferates on exposure to EBV-infected B cells expressing lytic antigens. Thus, early-differentiated NK cells might play a key role in the immune control of primary infection with this persistent tumor-associated virus. © 2014 by The American Society of Hematology.

Synchrotron FTIR microspectroscopy reveals early adipogenic differentiation of human mesenchymal stem cells at single-cell level

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Zhixiao; University of Chinese Academy of Science, Beijing 100049; Tang, Yuzhao

Human mesenchymal stem cells (hMSCs) have been used as an ideal in vitro model to study human adipogenesis. However, little knowledge of the early stage differentiation greatly hinders our understanding on the mechanism of the adipogenesis processes. In this study, synchrotron radiation-based Fourier transform infrared (SR-FTIR) microspectroscopy was applied to track the global structural and compositional changes of lipids, proteins and nucleic acids inside individual hMSCs along the time course. The multivariate analysis of the SR-FTIR spectra distinguished the dynamic and significant changes of the lipids and nucleic acid at early differentiation stage. Importantly, changes of lipid structure during early daysmore » (Day 1–3) of differentiation might serve as a potential biomarker in identifying the state in early differentiation at single cell level. These results proved that SR-FTIR is a powerful tool to study the stem cell fate determination and early lipogenesis events. - Highlights: • Molecular events occur in the early adipogenic differentiation stage of hMSCs are studied by SR-FTIR. • SR-FTIR data suggest that lipids may play an important role in hMSCs determination. • As potential biomarkers, lipids peaks can identify the state of cell in early differentiation stage at single-cell level.« less

N-ras couples antigen receptor signaling to Eomesodermin and to functional CD8+ T cell memory but not to effector differentiation

PubMed Central

Iborra, Salvador; Ramos, Manuel; Arana, David M.; Lázaro, Silvia; Aguilar, Francisco; Santos, Eugenio; López, Daniel

2013-01-01

Signals from the TCR that specifically contribute to effector versus memory CD8+ T cell differentiation are poorly understood. Using mice and adoptively transferred T lymphocytes lacking the small GTPase N-ras, we found that N-ras–deficient CD8+ T cells differentiate efficiently into antiviral primary effectors but have a severe defect in generating protective memory cells. This defect was rescued, although only partly, by rapamycin-mediated inhibition of mammalian target of rapamycin (mTOR) in vivo. The memory defect correlated with a marked impairment in vitro and in vivo of the antigen-mediated early induction of T-box transcription factor Eomesodermin (Eomes), whereas T-bet was unaffected. Besides N-ras, early Eomes induction in vitro required phosphoinositide 3-kinase (PI3K)–AKT but not extracellular signal-regulated kinase (ERK) activation, and it was largely insensitive to rapamycin. Consistent with N-ras coupling Eomes to T cell memory, retrovirally enforced expression of Eomes in N-ras–deficient CD8+ T cells effectively rescued their memory differentiation. Thus, our study identifies a critical role for N-ras as a TCR-proximal regulator of Eomes for early determination of the CD8+ T cell memory fate. PMID:23776078

Alkaline Phosphatase Protects Lipopolysaccharide-Induced Early Pregnancy Defects in Mice

PubMed Central

Lei, Wei; Ni, Hua; Herington, Jennifer; Reese, Jeff; Paria, Bibhash C.

2015-01-01

Excessive cytokine inflammatory response due to chronic or superphysiological level of microbial infection during pregnancy leads to pregnancy complications such as early pregnancy defects/loss and preterm birth. Bacterial toxin lipopolysaccharide (LPS), long recognized as a potent proinflammatory mediator, has been identified as a risk factor for pregnancy complications. Alkaline phosphatase (AP) isozymes have been shown to detoxify LPS by dephosphorylation. In this study, we examined the role of alkaline phosphatase (AP) in mitigating LPS-induced early pregnancy complications in mice. We found that 1) the uterus prior to implantation and implantation sites following embryo implantation produce LPS recognition and dephosphorylation molecules TLR4 and tissue non-specific AP (TNAP) isozyme, respectively; 2) uterine TNAP isozyme dephosphorylates LPS at its sites of production; 3) while LPS administration following embryo implantation elicits proinflammatory cytokine mRNA levels at the embryo implantation sites (EISs) and causes early pregnancy loss, dephosphorylated LPS neither triggers proinflammatory cytokine mRNA levels at the EISs nor induces pregnancy complications; 4) AP isozyme supplementation to accelerate LPS detoxification attenuates LPS-induced pregnancy complications following embryo implantation. These findings suggest that a LPS dephosphorylation strategy using AP isozyme may have a unique therapeutic potential to mitigate LPS- or Gram-negative bacteria-induced pregnancy complications in at-risk women. PMID:25910276

Alkaline phosphatase protects lipopolysaccharide-induced early pregnancy defects in mice.

PubMed

Lei, Wei; Ni, Hua; Herington, Jennifer; Reese, Jeff; Paria, Bibhash C

2015-01-01

Excessive cytokine inflammatory response due to chronic or superphysiological level of microbial infection during pregnancy leads to pregnancy complications such as early pregnancy defects/loss and preterm birth. Bacterial toxin lipopolysaccharide (LPS), long recognized as a potent proinflammatory mediator, has been identified as a risk factor for pregnancy complications. Alkaline phosphatase (AP) isozymes have been shown to detoxify LPS by dephosphorylation. In this study, we examined the role of alkaline phosphatase (AP) in mitigating LPS-induced early pregnancy complications in mice. We found that 1) the uterus prior to implantation and implantation sites following embryo implantation produce LPS recognition and dephosphorylation molecules TLR4 and tissue non-specific AP (TNAP) isozyme, respectively; 2) uterine TNAP isozyme dephosphorylates LPS at its sites of production; 3) while LPS administration following embryo implantation elicits proinflammatory cytokine mRNA levels at the embryo implantation sites (EISs) and causes early pregnancy loss, dephosphorylated LPS neither triggers proinflammatory cytokine mRNA levels at the EISs nor induces pregnancy complications; 4) AP isozyme supplementation to accelerate LPS detoxification attenuates LPS-induced pregnancy complications following embryo implantation. These findings suggest that a LPS dephosphorylation strategy using AP isozyme may have a unique therapeutic potential to mitigate LPS- or Gram-negative bacteria-induced pregnancy complications in at-risk women.

Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome.

PubMed

Al Khatib, Shadi; Keles, Sevgi; Garcia-Lloret, Maria; Karakoc-Aydiner, Elif; Reisli, Ismail; Artac, Hasibe; Camcioglu, Yildiz; Cokugras, Haluk; Somer, Ayper; Kutukculer, Necil; Yilmaz, Mustafa; Ikinciogullari, Aydan; Yegin, Olcay; Yüksek, Mutlu; Genel, Ferah; Kucukosmanoglu, Ercan; Baki, Ali; Bahceciler, Nerin N; Rambhatla, Anupama; Nickerson, Derek W; McGhee, Sean; Barlan, Isil B; Chatila, Talal

2009-08-01

The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired T(H)17 differentiation. To elucidate mechanisms underlying different forms of HIES. A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-alpha was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. T(H)17 and T(H)1 cell differentiation was assessed by measuring the production of IL-17 and IFN-gamma, respectively. Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired T(H)17 responses, but whereas STAT3 mutations abrogated early steps in T(H)17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps. In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired T(H)17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome.

Calvarial defect reconstruction.

PubMed

Jimenez, D F; Barone, C M

1994-04-01

The history of skull trepanation is almost as old as that of humanity. For thousands of years it has been performed for the treatment of numerous medical maladies. The Andean Incas, early Asians and South Seas Islanders, are amongst the many people to perform calvarial trepanation. Hippocrates described techniques for the use of the trepan in early Greek times. With the production of a skull opening comes the challenge of developing methods for closing the defect. It is in reality, more challenging to repair the defect than to create it. Man, with his never ending ingenuity, has tried to develop many techniques. We will discuss some of them and present our method of choice for closure of skull defects.

Early Earth differentiation [rapid communication

NASA Astrophysics Data System (ADS)

Walter, Michael J.; Trønnes, Reidar G.

2004-09-01

The birth and infancy of Earth was a time of profound differentiation involving massive internal reorganization into core, mantle and proto-crust, all within a few hundred million years of solar system formation ( t0). Physical and isotopic evidence indicate that the formation of iron-rich cores generally occurred very early in planetesimals, the building blocks of proto-Earth, within about 3 million years of t0. The final stages of terrestrial planetary accretion involved violent and tremendously energetic giant impacts among core-segregated Mercury- to Mars-sized objects and planetary embryos. As a consequence of impact heating, the early Earth was at times partially or wholly molten, increasing the likelihood for high-pressure and high-temperature equilibration among core- and mantle-forming materials. The Earth's silicate mantle harmoniously possesses abundance levels of the siderophile elements Ni and Co that can be reconciled by equilibration between iron alloy and silicate at conditions comparable to those expected for a deep magma ocean. Solidification of a deep magma ocean possibly involved crystal-melt segregation at high pressures, but subsequent convective stirring of the mantle could have largely erased nascent layering. However, primitive upper mantle rocks apparently have some nonchondritic major and trace element refractory lithophile element ratios that can be plausibly linked to early mantle differentiation of ultra-high-pressure mantle phases. The geochemical effects of crystal fractionation in a deep magma ocean are partly constrained by high-pressure experimentation. Comparison between compositional models for the primitive convecting mantle and bulk silicate Earth generally allows, and possibly favors, 10-15% total fractionation of a deep mantle assemblage comprised predominantly of Mg-perovskite and with minor but geochemically important amounts of Ca-perovskite and ferropericlase. Long-term isolation of such a crystal pile is generally

Early differential processing of material images: Evidence from ERP classification.

PubMed

Wiebel, Christiane B; Valsecchi, Matteo; Gegenfurtner, Karl R

2014-06-24

Investigating the temporal dynamics of natural image processing using event-related potentials (ERPs) has a long tradition in object recognition research. In a classical Go-NoGo task two characteristic effects have been emphasized: an early task independent category effect and a later task-dependent target effect. Here, we set out to use this well-established Go-NoGo paradigm to study the time course of material categorization. Material perception has gained more and more interest over the years as its importance in natural viewing conditions has been ignored for a long time. In addition to analyzing standard ERPs, we conducted a single trial ERP pattern analysis. To validate this procedure, we also measured ERPs in two object categories (people and animals). Our linear classification procedure was able to largely capture the overall pattern of results from the canonical analysis of the ERPs and even extend it. We replicate the known target effect (differential Go-NoGo potential at frontal sites) for the material images. Furthermore, we observe task-independent differential activity between the two material categories as early as 140 ms after stimulus onset. Using our linear classification approach, we show that material categories can be differentiated consistently based on the ERP pattern in single trials around 100 ms after stimulus onset, independent of the target-related status. This strengthens the idea of early differential visual processing of material categories independent of the task, probably due to differences in low-level image properties and suggests pattern classification of ERP topographies as a strong instrument for investigating electrophysiological brain activity. © 2014 ARVO.

Eddy current inspection of weld defects in tubing

NASA Technical Reports Server (NTRS)

Katragadda, G.; Lord, W.

1992-01-01

An approach using differential probes for the inspection of weld defects in tubing is studied. Finite element analysis is used to model the weld regions and defects. Impedance plane signals are predicted for different weld defect types and compared wherever possible with signals from actual welds in tubing. Results show that detection and sizing of defects in tubing is possible using differential eddy current techniques. The phase angle of the impedance plane trajectory gives a good indication of the sizing of the crack. Data on the type of defect can be obtained from the shape of the impedance plane trajectory and the phase. Depending on the skin depth, detection of outer wall, inner wall, and subsurface defects is possible.

Peeling skin syndrome: genetic defects in late terminal differentiation of the epidermis.

PubMed

Bowden, Paul E

2011-03-01

In this issue, Israeli and colleagues confirm that homozygous mutations in corneodesmosin (CDSN) cause type B peeling skin syndrome (PSS), an autosomal recessive skin disorder. The deletion mutation described resulted in a frameshift, producing a downstream premature stop codon and early truncation of the protein. The recently described CDSN nonsense mutation in another PSS family also resulted in protein truncation and nonsense-mediated mRNA decay. Type B generalized PSS can now be clearly distinguished from acral PSS, caused by mutations in transglutaminase 5. This directly affects cornified envelope cross-linking rather than corneodesmosome adherence. These observations provide new insight into the molecular defects underlying two closely related forms of PSS.

Bioactive borate glass promotes the repair of radius segmental bone defects by enhancing the osteogenic differentiation of BMSCs.

PubMed

Zhang, Jieyuan; Guan, Junjie; Zhang, Changqing; Wang, Hui; Huang, Wenhai; Guo, Shangchun; Niu, Xin; Xie, Zongping; Wang, Yang

2015-11-20

Bioactive borate glass (BG) has emerged as a promising alternative for bone regeneration due to its high osteoinductivity, osteoconductivity, compressive strength, and biocompatibility. However, the role of BG in large segmental bone repair is unclear and little is known about the underlying mechanism of BG's osteoinductivity. In this study, we demonstrated that BG possessed pro-osteogenic effects in an experimental model of critical-sized radius defects. Transplanting BG to radius defects resulted in better repair of bone defects as compared to widely used β-TCP. Histological and morphological analysis indicated that BG significantly enhanced new bone formation. Furthermore, the degradation rate of the BG was faster than that of β-TCP, which matched the higher bone regeneration rate. In addition, ions from BG enhanced cell viability, ALP activity, and osteogenic-related genes expression. Mechanistically, the critical genes Smad1/5 and Dlx5 in the BMP pathway and p-Smad1/5 proteins were significantly elevated after BG transplantation, and these effects could be blocked by the BMP/Smad specific inhibitor. Taken together, our findings suggest that BG could repair large segmental bone defects through activating the BMP/Smad pathway and osteogenic differentiation in BMSCs.

A Review of Recent Studies on Differential Reinforcement during Skill Acquisition in Early Intervention

ERIC Educational Resources Information Center

Vladescu, Jason C.; Kodak, Tiffany

2010-01-01

Although the use of differential reinforcement has been recommended in previous investigations and in early intervention curriculum manuals, few studies have evaluated the best method for providing differential reinforcement to maximize independent responding. This paper reviews previous research on the effectiveness of differential reinforcement…

Programmed Application of Transforming Growth Factor β3 and Rac1 Inhibitor NSC23766 Committed Hyaline Cartilage Differentiation of Adipose-Derived Stem Cells for Osteochondral Defect Repair.

PubMed

Zhu, Shouan; Chen, Pengfei; Wu, Yan; Xiong, Si; Sun, Heng; Xia, Qingqing; Shi, Libing; Liu, Huanhuan; Ouyang, Hong Wei

2014-10-01

Hyaline cartilage differentiation is always the challenge with application of stem cells for joint repair. Transforming growth factors (TGFs) and bone morphogenetic proteins can initiate cartilage differentiation but often lead to hypertrophy and calcification, related to abnormal Rac1 activity. In this study, we developed a strategy of programmed application of TGFβ3 and Rac1 inhibitor NSC23766 to commit the hyaline cartilage differentiation of adipose-derived stem cells (ADSCs) for joint cartilage repair. ADSCs were isolated and cultured in a micromass and pellet culture model to evaluate chondrogenic and hypertrophic differentiation. The function of Rac1 was investigated with constitutively active Rac1 mutant and dominant negative Rac1 mutant. The efficacy of ADSCs with programmed application of TGFβ3 and Rac1 inhibitor for cartilage repair was studied in a rat model of osteochondral defects. The results showed that TGFβ3 promoted ADSCs chondro-lineage differentiation and that NSC23766 prevented ADSC-derived chondrocytes from hypertrophy in vitro. The combination of ADSCs, TGFβ3, and NSC23766 promoted quality osteochondral defect repair in rats with much less chondrocytes hypertrophy and significantly higher International Cartilage Repair Society macroscopic and microscopic scores. The findings have illustrated that programmed application of TGFβ3 and Rac1 inhibitor NSC23766 can commit ADSCs to chondro-lineage differentiation and improve the efficacy of ADSCs for cartilage defect repair. These findings suggest a promising stem cell-based strategy for articular cartilage repair. ©AlphaMed Press.

Higher O-GlcNAc Levels Are Associated with Defects in Progenitor Proliferation and Premature Neuronal Differentiation during in-Vitro Human Embryonic Cortical Neurogenesis

PubMed Central

Parween, Shama; Varghese, Divya S.; Ardah, Mustafa T.; Prabakaran, Ashok D.; Mensah-Brown, Eric; Emerald, Bright Starling; Ansari, Suraiya A.

2017-01-01

The nutrient responsive O-GlcNAcylation is a dynamic post-translational protein modification found on several nucleocytoplasmic proteins. Previous studies have suggested that hyperglycemia induces the levels of total O-GlcNAcylation inside the cells. Hyperglycemia mediated increase in protein O-GlcNAcylation has been shown to be responsible for various pathologies including insulin resistance and Alzheimer's disease. Since maternal hyperglycemia during pregnancy is associated with adverse neurodevelopmental outcomes in the offspring, it is intriguing to identify the effect of increased protein O-GlcNAcylation on embryonic neurogenesis. Herein using human embryonic stem cells (hESCs) as model, we show that increased levels of total O-GlcNAc is associated with decreased neural progenitor proliferation and premature differentiation of cortical neurons, reduced AKT phosphorylation, increased apoptosis and defects in the expression of various regulators of embryonic corticogenesis. As defects in proliferation and differentiation during neurodevelopment are common features of various neurodevelopmental disorders, increased O-GlcNAcylation could be one mechanism responsible for defective neurodevelopmental outcomes in metabolically compromised pregnancies such as diabetes. PMID:29311838

Early pregnancy exposure to antihistamines and risk of congenital heart defects: results of two case-control studies.

PubMed

Smedts, Huberdina P M; de Jonge, Linda; Bandola, Sarah J G; Baardman, Marlies E; Bakker, Marian K; Stricker, Bruno H C; Steegers-Theunissen, Régine P M

2014-09-01

We aimed to study the association between use of antihistamines in early pregnancy and congenital heart defects (CHD) in the offspring. Two case-control studies. HAVEN study, Erasmus MC, University Medical Centre, Rotterdam, and Eurocat Northern Netherlands (NNL), University Medical Center Groningen, Groningen, the Netherlands. We studied 361 children with CHD and 410 controls without congenital malformations from the HAVEN study and replicated the analyses in 445 children with CHD and 530 controls from the Eurocat NNL registry. Information about antihistamine use in early pregnancy and potential confounders was obtained from questionnaires postpartum. We calculated the association between antihistamines and CHD risk by multivariable logistic regression analysis. Odds ratios (OR) with 95% confidence intervals (CI). In the HAVEN study, 25 of 771 mothers used antihistamines that were associated with an increased CHD risk (OR 3.0, 95% CI 1.2-7.3), particularly atrioventricular septal defects (AVSD) (OR 5.1, 95 % CI 1.3-20.5) and perimembranous ventricular septal defects (pVSD) (OR 5.1, 95% CI 1.8-14.4). Mothers with severe nausea who did not use antihistamines had a reduced risk (OR 0.7, 95% CI 0.5-0.98), whereas nauseous mothers using antihistamines showed an almost fivefold increased risk of pVSD (OR 4.8, 95% CI 1.1-21.8). The association between antihistamines and AVSD was confirmed in the Eurocat cohort (OR 3.5, 95% CI 1.4-8.7), but we could not replicate the association with overall CHD risk. We found a positive association between antihistamine use in early pregnancy and CHD risk, particularly AVSD, which seemed to be independent of nausea/vomiting.

Impairment of Human Immunodeficiency Virus Type-1 Integrase SUMOylation Correlates with an Early Replication Defect*

PubMed Central

Zamborlini, Alessia; Coiffic, Audrey; Beauclair, Guillaume; Delelis, Olivier; Paris, Joris; Koh, Yashuiro; Magne, Fabian; Giron, Marie-Lou; Tobaly-Tapiero, Joelle; Deprez, Eric; Emiliani, Stephane; Engelman, Alan; de Thé, Hugues; Saïb, Ali

2011-01-01

HIV-1 integrase (IN) orchestrates the integration of the reverse transcribed viral cDNA into the host cell genome and participates also in other steps of HIV-1 replication. Cellular and viral factors assist IN in performing its multiple functions, and post-translational modifications contribute to modulate its activities. Here, we show that HIV-1 IN is modified by SUMO proteins and that phylogenetically conserved SUMOylation consensus motifs represent major SUMO acceptor sites. Viruses harboring SUMOylation site IN mutants displayed a replication defect that was mapped during the early stages of infection, before integration but after reverse transcription. Because SUMOylation-defective IN mutants retained WT catalytic activity, we hypothesize that SUMOylation might regulate the affinity of IN for co-factors, contributing to efficient HIV-1 replication. PMID:21454548

A review of recent studies on differential reinforcement during skill acquisition in early intervention.

PubMed

Vladescu, Jason C; Kodak, Tiffany

2010-01-01

Although the use of differential reinforcement has been recommended in previous investigations and in early intervention curriculum manuals, few studies have evaluated the best method for providing differential reinforcement to maximize independent responding. This paper reviews previous research on the effectiveness of differential reinforcement as treatment and describes important areas of future research.

Gene function in early mouse embryonic stem cell differentiation

PubMed Central

Sene, Kagnew Hailesellasse; Porter, Christopher J; Palidwor, Gareth; Perez-Iratxeta, Carolina; Muro, Enrique M; Campbell, Pearl A; Rudnicki, Michael A; Andrade-Navarro, Miguel A

2007-01-01

Background Little is known about the genes that drive embryonic stem cell differentiation. However, such knowledge is necessary if we are to exploit the therapeutic potential of stem cells. To uncover the genetic determinants of mouse embryonic stem cell (mESC) differentiation, we have generated and analyzed 11-point time-series of DNA microarray data for three biologically equivalent but genetically distinct mESC lines (R1, J1, and V6.5) undergoing undirected differentiation into embryoid bodies (EBs) over a period of two weeks. Results We identified the initial 12 hour period as reflecting the early stages of mESC differentiation and studied probe sets showing consistent changes of gene expression in that period. Gene function analysis indicated significant up-regulation of genes related to regulation of transcription and mRNA splicing, and down-regulation of genes related to intracellular signaling. Phylogenetic analysis indicated that the genes showing the largest expression changes were more likely to have originated in metazoans. The probe sets with the most consistent gene changes in the three cell lines represented 24 down-regulated and 12 up-regulated genes, all with closely related human homologues. Whereas some of these genes are known to be involved in embryonic developmental processes (e.g. Klf4, Otx2, Smn1, Socs3, Tagln, Tdgf1), our analysis points to others (such as transcription factor Phf21a, extracellular matrix related Lama1 and Cyr61, or endoplasmic reticulum related Sc4mol and Scd2) that have not been previously related to mESC function. The majority of identified functions were related to transcriptional regulation, intracellular signaling, and cytoskeleton. Genes involved in other cellular functions important in ESC differentiation such as chromatin remodeling and transmembrane receptors were not observed in this set. Conclusion Our analysis profiles for the first time gene expression at a very early stage of mESC differentiation, and

A REVIEW OF RECENT STUDIES ON DIFFERENTIAL REINFORCEMENT DURING SKILL ACQUISITION IN EARLY INTERVENTION

PubMed Central

Vladescu, Jason C; Kodak, Tiffany

2010-01-01

Although the use of differential reinforcement has been recommended in previous investigations and in early intervention curriculum manuals, few studies have evaluated the best method for providing differential reinforcement to maximize independent responding. This paper reviews previous research on the effectiveness of differential reinforcement as treatment and describes important areas of future research. PMID:21119913

Enhancer and Transcription Factor Dynamics during Myeloid Differentiation Reveal an Early Differentiation Block in Cebpa null Progenitors.

PubMed

Pundhir, Sachin; Bratt Lauridsen, Felicia Kathrine; Schuster, Mikkel Bruhn; Jakobsen, Janus Schou; Ge, Ying; Schoof, Erwin Marten; Rapin, Nicolas; Waage, Johannes; Hasemann, Marie Sigurd; Porse, Bo Torben

2018-05-29

Transcription factors PU.1 and CEBPA are required for the proper coordination of enhancer activity during granulocytic-monocytic (GM) lineage differentiation to form myeloid cells. However, precisely how these factors control the chronology of enhancer establishment during differentiation is not known. Through integrated analyses of enhancer dynamics, transcription factor binding, and proximal gene expression during successive stages of murine GM-lineage differentiation, we unravel the distinct kinetics by which PU.1 and CEBPA coordinate GM enhancer activity. We find no evidence of a pioneering function of PU.1 during late GM-lineage differentiation. Instead, we delineate a set of enhancers that gain accessibility in a CEBPA-dependent manner, suggesting a pioneering function of CEBPA. Analyses of Cebpa null bone marrow demonstrate that CEBPA controls PU.1 levels and, unexpectedly, that the loss of CEBPA results in an early differentiation block. Taken together, our data provide insights into how PU.1 and CEBPA functionally interact to drive GM-lineage differentiation. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

MyoD expression restores defective myogenic differentiation of human mesoangioblasts from inclusion-body myositis muscle.

PubMed

Morosetti, Roberta; Mirabella, Massimiliano; Gliubizzi, Carla; Broccolini, Aldobrando; De Angelis, Luciana; Tagliafico, Enrico; Sampaolesi, Maurilio; Gidaro, Teresa; Papacci, Manuela; Roncaglia, Enrica; Rutella, Sergio; Ferrari, Stefano; Tonali, Pietro Attilio; Ricci, Enzo; Cossu, Giulio

2006-11-07

Inflammatory myopathies (IM) are acquired diseases of skeletal muscle comprising dermatomyositis (DM), polymyositis (PM), and inclusion-body myositis (IBM). Immunosuppressive therapies, usually beneficial for DM and PM, are poorly effective in IBM. We report the isolation and characterization of mesoangioblasts, vessel-associated stem cells, from diagnostic muscle biopsies of IM. The number of cells isolated, proliferation rate and lifespan, markers expression, and ability to differentiate into smooth muscle do not differ among normal and IM mesoangioblasts. At variance with normal, DM and PM mesoangioblasts, cells isolated from IBM, fail to differentiate into skeletal myotubes. These data correlate with lack in connective tissue of IBM muscle of alkaline phosphatase (ALP)-positive cells, conversely dramatically increased in PM and DM. A myogenic inhibitory basic helix-loop-helix factor B3 is highly expressed in IBM mesoangioblasts. Indeed, silencing this gene or overexpressing MyoD rescues the myogenic defect of IBM mesoangioblasts, opening novel cell-based therapeutic strategies for this crippling disorder.

MyoD expression restores defective myogenic differentiation of human mesoangioblasts from inclusion-body myositis muscle

PubMed Central

Morosetti, Roberta; Mirabella, Massimiliano; Gliubizzi, Carla; Broccolini, Aldobrando; De Angelis, Luciana; Tagliafico, Enrico; Sampaolesi, Maurilio; Gidaro, Teresa; Papacci, Manuela; Roncaglia, Enrica; Rutella, Sergio; Ferrari, Stefano; Tonali, Pietro Attilio; Ricci, Enzo; Cossu, Giulio

2006-01-01

Inflammatory myopathies (IM) are acquired diseases of skeletal muscle comprising dermatomyositis (DM), polymyositis (PM), and inclusion-body myositis (IBM). Immunosuppressive therapies, usually beneficial for DM and PM, are poorly effective in IBM. We report the isolation and characterization of mesoangioblasts, vessel-associated stem cells, from diagnostic muscle biopsies of IM. The number of cells isolated, proliferation rate and lifespan, markers expression, and ability to differentiate into smooth muscle do not differ among normal and IM mesoangioblasts. At variance with normal, DM and PM mesoangioblasts, cells isolated from IBM, fail to differentiate into skeletal myotubes. These data correlate with lack in connective tissue of IBM muscle of alkaline phosphatase (ALP)-positive cells, conversely dramatically increased in PM and DM. A myogenic inhibitory basic helix–loop–helix factor B3 is highly expressed in IBM mesoangioblasts. Indeed, silencing this gene or overexpressing MyoD rescues the myogenic defect of IBM mesoangioblasts, opening novel cell-based therapeutic strategies for this crippling disorder. PMID:17077152

Early differentiation of the Moon: Experimental and modeling studies

NASA Technical Reports Server (NTRS)

Longhi, J.

1986-01-01

Major accomplishments include the mapping out of liquidus boundaries of lunar and meteoritic basalts at low pressure; the refinement of computer models that simulate low pressure fractional crystallization; the development of a computer model to calculate high pressure partial melting of the lunar and Martian interiors; and the proposal of a hypothesis of early lunar differentiation based upon terrestrial analogs.

A Mutant Receptor Tyrosine Phosphatase, CD148, Causes Defects in Vascular Development

PubMed Central

Takahashi, Takamune; Takahashi, Keiko; St. John, Patricia L.; Fleming, Paul A.; Tomemori, Takuya; Watanabe, Toshio; Abrahamson, Dale R.; Drake, Christopher J.; Shirasawa, Takuji; Daniel, Thomas O.

2003-01-01

Vascularization defects in genetic recombinant mice have defined critical roles for a number of specific receptor tyrosine kinases. Here we evaluated whether an endothelium-expressed receptor tyrosine phosphatase, CD148 (DEP-1/PTPη), participates in developmental vascularization. A mutant allele, CD148ΔCyGFP, was constructed to eliminate CD148 phosphatase activity by in-frame replacement of cytoplasmic sequences with enhanced green fluorescent protein sequences. Homozygous mutant mice died at midgestation, before embryonic day 11.5 (E11.5), with vascularization failure marked by growth retardation and disorganized vascular structures. Structural abnormalities were observed as early as E8.25 in the yolk sac, prior to the appearance of intraembryonic defects. Homozygous mutant mice displayed enlarged vessels comprised of endothelial cells expressing markers of early differentiation, including VEGFR2 (Flk1), Tal1/SCL, CD31, ephrin-B2, and Tie2, with notable lack of endoglin expression. Increased endothelial cell numbers and mitotic activity indices were demonstrated. At E9.5, homozygous mutant embryos showed homogeneously enlarged primitive vessels defective in vascular remodeling and branching, with impaired pericyte investment adjacent to endothelial structures, in similarity to endoglin-deficient embryos. Developing cardiac tissues showed expanded endocardial projections accompanied by defective endocardial cushion formation. These findings implicate a member of the receptor tyrosine phosphatase family, CD148, in developmental vascular organization and provide evidence that it regulates endothelial proliferation and endothelium-pericyte interactions. PMID:12588999

Early molecular events during retinoic acid induced differentiation of neuromesodermal progenitors

PubMed Central

Cunningham, Thomas J.; Colas, Alexandre

2016-01-01

ABSTRACT Bipotent neuromesodermal progenitors (NMPs) residing in the caudal epiblast drive coordinated body axis extension by generating both posterior neuroectoderm and presomitic mesoderm. Retinoic acid (RA) is required for body axis extension, however the early molecular response to RA signaling is poorly defined, as is its relationship to NMP biology. As endogenous RA is first seen near the time when NMPs appear, we used WNT/FGF agonists to differentiate embryonic stem cells to NMPs which were then treated with a short 2-h pulse of 25 nM RA or 1 µM RA followed by RNA-seq transcriptome analysis. Differential expression analysis of this dataset indicated that treatment with 25 nM RA, but not 1 µM RA, provided physiologically relevant findings. The 25 nM RA dataset yielded a cohort of previously known caudal RA target genes including Fgf8 (repressed) and Sox2 (activated), plus novel early RA signaling targets with nearby conserved RA response elements. Importantly, validation of top-ranked genes in vivo using RA-deficient Raldh2−/− embryos identified novel examples of RA activation (Nkx1-2, Zfp503, Zfp703, Gbx2, Fgf15, Nt5e) or RA repression (Id1) of genes expressed in the NMP niche or progeny. These findings provide evidence for early instructive and permissive roles of RA in controlling differentiation of NMPs to neural and mesodermal lineages. PMID:27793834

Peroxy defects in Rocks and H2O2 formation on the early Earth

NASA Astrophysics Data System (ADS)

Gray, A.; Balk, M.; Mason, P.; Freund, F.; Rothschild, L.

2013-12-01

An oxygen-rich atmosphere appears to have been a prerequisite for complex life to evolve on Earth and possibly elsewhere in the Universe. The question is still shrouded in uncertainty how free oxygen became available on the early Earth. Here we study processes of peroxy defects in silicate minerals which, upon weathering, generate mobilized electronic charge carriers resulting in oxygen formation in an initially anoxic subsurface environment. Reactive Oxygen Species (ROS) are precursors to molecular oxygen during this process. Due to their toxicity they may have strongly influenced the evolution of life. ROS are generated during hydrolysis of peroxy defects, which consist of pairs of oxygen anions. A second pathway for formation occurs during (bio) transformations of iron sulphide minerals. ROS are produced and consumed by intracellular and extracellular reactions of Fe, Mn, C, N, and S species. We propose that despite an overall reducing or neutral oxidation state of the macroenvironment and the absence of free O2 in the atmosphere, microorganisms on the early Earth had to cope with ROS in their microenvironments. They were thus under evolutionary pressure to develop enzymatic and other defenses against the potentially dangerous, even lethal effects of ROS and oxygen. We have investigated how oxygen might be released through weathering and test microorganisms in contact with rock surfaces. Our results show how early Life might have adapted to oxygen. Early microorganisms must have "trained" to detoxify ROS prior to the evolution of aerobic metabolism and oxygenic photosynthesis. A possible way out of this dilemma comes from a study of igneous and high-grade metamorphic rocks, whose minerals contain a small but significant fraction of oxygen anions in the valence state 1- , forming peroxy links of the type O3Si-OO-SiO3 [1, 2]. As water hydrolyzes the peroxy links hydrogen peroxide, H2O2, forms. Continued experimental discovery of H2O2 formation at rock

Molecular hierarchy in neurons differentiated from mouse ES cells containing a single human chromosome 21.

PubMed

Wang, Chi Chiu; Kadota, Mitsutaka; Nishigaki, Ryuichi; Kazuki, Yasuhiro; Shirayoshi, Yasuaki; Rogers, Michael Scott; Gojobori, Takashi; Ikeo, Kazuho; Oshimura, Mitsuo

2004-02-06

Defects in neurogenesis and neuronal differentiation in the fetal brain of Down syndrome (DS) patients lead to the apparent neuropathological abnormalities and contribute to the phenotypic characters of mental retardation, and premature development of Alzheimer's disease, those being the most common phenotype in DS. In order to understand the molecular mechanism underlying the cause of phenotypic abnormalities in the DS brain, we have utilized an in vitro model of TT2F mouse embryonic stem cells containing a single human chromosome 21 (hChr21) to study neuron development and neuronal differentiation by microarray containing 15K developmentally expressed cDNAs. Defective neuronal differentiation in the presence of extra hChr21 manifested primarily the post-transcriptional and translational modification, such as Mrpl10, SNAPC3, Srprb, SF3a60 in the early neuronal stem cell stage, and Mrps18a, Eef1g, and Ubce8 in the late differentiated stage. Hierarchical clustering patterned specific expression of hChr21 gene dosage effects on neuron outgrowth, migration, and differentiation, such as Syngr2, Dncic2, Eif3sf, and Peg3.

Coordination of cellular differentiation, polarity, mitosis and meiosis - New findings from early vertebrate oogenesis.

PubMed

Elkouby, Yaniv M; Mullins, Mary C

2017-10-15

A mechanistic dissection of early oocyte differentiation in vertebrates is key to advancing our knowledge of germline development, reproductive biology, the regulation of meiosis, and all of their associated disorders. Recent advances in the field include breakthroughs in the identification of germline stem cells in Medaka, in the cellular architecture of the germline cyst in mice, in a mechanistic dissection of chromosomal pairing and bouquet formation in meiosis in mice, in tracing oocyte symmetry breaking to the chromosomal bouquet of meiosis in zebrafish, and in the biology of the Balbiani body, a universal oocyte granule. Many of the major events in early oogenesis are universally conserved, and some are co-opted for species-specific needs. The chromosomal events of meiosis are of tremendous consequence to gamete formation and have been extensively studied. New light is now being shed on other aspects of early oocyte differentiation, which were traditionally considered outside the scope of meiosis, and their coordination with meiotic events. The emerging theme is of meiosis as a common groundwork for coordinating multifaceted processes of oocyte differentiation. In an accompanying manuscript we describe methods that allowed for investigations in the zebrafish ovary to contribute to these breakthroughs. Here, we review these advances mostly from the zebrafish and mouse. We discuss oogenesis concepts across established model organisms, and construct an inclusive paradigm for early oocyte differentiation in vertebrates. Copyright © 2017 Elsevier Inc. All rights reserved.

Success of Maxillary Alveolar Defect Repair in Rats Using Osteoblast-Differentiated Human Deciduous Dental Pulp Stem Cells.

PubMed

Jahanbin, Arezoo; Rashed, Roozbeh; Alamdari, Daryoush Hamidi; Koohestanian, Niloufar; Ezzati, Atefeh; Kazemian, Mojgan; Saghafi, Shadi; Raisolsadat, Mohammad Ali

2016-04-01

The use of cell-based therapies represents one of the most advanced methods for enhancing the regenerative response in craniofacial abnormalities. The main aim of this study was to evaluate the regenerative potential of human dental pulp stem cells, isolated from deciduous teeth, for reconstructing maxillary alveolar defects in Wistar rats. Human deciduous dental pulp stem cells were isolated and stimulated to differentiate into osteoblasts in culture media. Maxillary alveolar defects were created in 60 Wistar rats by a surgical procedure. Then, on the basis of the type of graft used to repair the bone defect, the rats were divided into 6 equal groups: groups 1 and 2, transplantation of iliac bone graft; groups 3 and 4, transplantation of stem cells derived from deciduous dental pulp in addition to collagen matrix; groups 5 and 6, transplantation of just collagen matrix. Then, fetal bone formation, granulation tissue, fibrous tissue, and inflammatory tissue were evaluated by hematoxylin-eosin staining at 1 month (groups 1, 3, and 5) and 2 months (groups 2, 4, and 6) after surgery, and data were analyzed and compared using the Fisher exact test. Maximum fetal bone formation occurred in group 2, in which iliac bone graft was inserted into the defect area for 2 months; there also were significant differences among the groups for bone formation (P = .009). In the 1-month groups, there were no significant differences between the control and stem cell-plus-scaffold groups. There were significant differences between the 2-month groups for fetal bone formation only between the control and scaffold groups (P = .026). The study showed that human dental pulp stem cells are an additional cell resource for repairing maxillary alveolar defects in rats and constitute a promising model for reconstruction of human maxillary alveolar defects in patients with cleft lip and palate. Copyright © 2016 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc

periostin Null Mice Exhibit Dwarfism, Incisor Enamel Defects, and an Early-Onset Periodontal Disease-Like Phenotype

PubMed Central

Rios, Hector; Koushik, Shrinagesh V.; Wang, Haiyan; Wang, Jian; Zhou, Hong-Ming; Lindsley, Andrew; Rogers, Rhonda; Chen, Zhi; Maeda, Manabu; Kruzynska-Frejtag, Agnieszka; Feng, Jian Q.; Conway, Simon J.

2005-01-01

Periostin was originally identified as an osteoblast-specific factor and is highly expressed in the embryonic periosteum, cardiac valves, placenta, and periodontal ligament as well as in many adult cancerous tissues. To investigate its role during development, we generated mice that lack the periostin gene and replaced the translation start site and first exon with a lacZ reporter gene. Surprisingly, although periostin is widely expressed in many developing organs, periostin-deficient (perilacZ) embryos are grossly normal. Postnatally, however, ∼14% of the nulls die before weaning and all of the remaining perilacZ nulls are severely growth retarded. Skeletal analysis revealed that trabecular bone in adult homozygous skeletons was sparse, but overall bone growth was unaffected. Furthermore, by 3 months, the nulls develop an early-onset periodontal disease-like phenotype. Unexpectedly, these mice also show a severe incisor enamel defect, although there is no apparent change in ameloblast differentiation. Significantly, placing the perilacZ nulls on a soft diet that alleviated mechanical strain on the periodontal ligament resulted in a partial rescue of both the enamel and periodontal disease-like phenotypes. Combined, these data suggest that a healthy periodontal ligament is required for normal amelogenesis and that periostin is critically required for maintenance of the integrity of the periodontal ligament in response to mechanical stresses. PMID:16314533

Is MSAFP still a useful test for detecting open neural tube defects and ventral wall defects in the era of first-trimester and early second-trimester fetal anatomical ultrasounds?

PubMed

Roman, Ashley S; Gupta, Simi; Fox, Nathan S; Saltzman, Daniel; Klauser, Chad K; Rebarber, Andrei

2015-01-01

To evaluate whether maternal serum α-fetoprotein (MSAFP) improves the detection rate for open neural tube defects (ONTDs) and ventral wall defects (VWD) in patients undergoing first-trimester and early second-trimester fetal anatomical survey. A cohort of women undergoing screening between 2005 and 2012 was identified. All patients were offered an ultrasound at between 11 weeks and 13 weeks and 6 days of gestational age for nuchal translucency/fetal anatomy followed by an early second-trimester ultrasound at between 15 weeks and 17 weeks and 6 days of gestational age for fetal anatomy and MSAFP screening. All cases of ONTD and VWD were identified via query of billing and reporting software. Sensitivity and specificity for detection of ONTD/VWD were calculated, and groups were compared using the Fisher exact test, with p < 0.05 as significance. A total of 23,790 women met the criteria for inclusion. Overall, 15 cases of ONTD and 17 cases of VWD were identified; 100% of cases were diagnosed by ultrasound prior to 18 weeks' gestation; none were diagnosed via MSAFP screening (p < 0.001). First-trimester and early second-trimester ultrasound had 100% sensitivity and 100% specificity for diagnosing ONTD/VWD. Ultrasound for fetal anatomy during the first and early second trimester detected 100% of ONTD/VWD in our population. MSAFP is not useful as a screening tool for ONTD and VWD in the setting of this ultrasound screening protocol. © 2014 S. Karger AG, Basel.

Birth Defects Research and Tracking

MedlinePlus

... least one month before getting pregnant and during early pregnancy lowers the risk of having a baby with ... 2017) Key Findings: Use of Pain Medicine During Early Pregnancy May Be Related To Birth Defects A study ...

Newcomers in paediatric GI pathology: childhood enteropathies including very early onset monogenic IBD.

PubMed

Ensari, Arzu; Kelsen, Judith; Russo, Pierre

2018-01-01

Childhood enteropathies are a group of diseases causing severe chronic (>2-3 weeks) diarrhoea often starting in the first week of life with the potential for fatal complications for the affected infant. Early identification and accurate classification of childhood enteropathies are, therefore, crucial for making treatment decisions to prevent life-threatening complications. Childhood enteropathies are classified into four groups based on the underlying pathology: (i) conditions related to defective digestion, absorption and transport of nutrients and electrolytes; (ii) disorders related to enterocyte differentiation and polarization; (iii) defects of enteroendocrine cell differentiation; and (iv) disorders associated with defective modulation of intestinal immune response. While the intestinal mucosa is usually normal in enteropathies related to congenital transport or enzyme deficiencies, the intestinal biopsy in other disorders may reveal a wide range of abnormalities varying from normal villous architecture to villous atrophy and/or inflammation, or features specific to the underlying disorder including epithelial abnormalities, lipid vacuolization in the enterocytes, absence of plasma cells, lymphangiectasia, microorganisms, and mucosal eosinophilic or histiocytic infiltration. This review intends to provide an update on small intestinal biopsy findings in childhood enteropathies, the "newcomers", including very early onset monogenic inflammatory bowel disease (IBD), in particular, for the practicing pathologist.

Arid1a Inactivation in an Apc and Pten-defective Mouse Ovarian Cancer Model Enhances Epithelial Differentiation and Prolongs Survival

PubMed Central

Zhai, Yali; Kuick, Rork; Tipton, Courtney; Wu, Rong; Sessine, Michael; Wang, Zhong; Baker, Suzanne J.; Fearon, Eric R.; Cho, Kathleen R.

2015-01-01

Inactivation of the ARID1A tumor suppressor gene is frequent in ovarian endometrioid (OEC) and clear cell carcinomas (OCCC), often in conjunction with mutations activating the PI3K/AKT and/or canonical Wnt signaling pathways. Prior work has shown that conditional bi-allelic inactivation of the Apc and Pten tumor suppressor genes in the mouse ovarian surface epithelium (OSE) promotes outgrowth of tumors that reflect the biological behavior and gene expression profiles of human OECs harboring comparable Wnt and PI3K/AKT pathway defects, though the mouse tumors are more poorly differentiated than their human tumor counterparts. We found that conditional inactivation of one or both Arid1a alleles in OSE concurrently with Apc and Pten inactivation unexpectedly prolonged survival of tumor-bearing mice and promoted striking epithelial differentiation of the cancer cells, resulting in morphological features akin to those in human OECs. Enhanced epithelial differentiation was linked to reduced expression of mesenchymal markers N-cadherin and vimentin, and increased expression of epithelial markers Crb3 and E-cadherin. Global gene expression profiling showed enrichment for genes associated with mesenchymal-to-epithelial transition in the Arid1a-deficient tumors. We also found that an activating (E545K) Pik3ca mutation, unlike Pten inactivation or Pik3ca H1047R mutation, cannot cooperate with Arid1a loss to promote ovarian cancer development in the mouse. Our results indicate the Arid1a tumor suppressor gene has a key role in regulating OEC differentiation, and paradoxically the mouse cancers with more initiating tumor suppressor gene defects had a less aggressive phenotype than cancers arising from fewer gene alterations. PMID:26279473

SEMATECH produces defect-free EUV mask blanks: defect yield and immediate challenges

NASA Astrophysics Data System (ADS)

Antohe, Alin O.; Balachandran, Dave; He, Long; Kearney, Patrick; Karumuri, Anil; Goodwin, Frank; Cummings, Kevin

2015-03-01

Availability of defect-free reflective mask has been one of the most critical challenges to extreme ultraviolet lithography (EUVL). To mitigate the risk, significant progress has been made on defect detection, pattern shifting, and defect repair. Clearly such mitigation strategies are based on the assumption that defect counts and sizes from incoming mask blanks must be below practical levels depending on mask specifics. The leading industry consensus for early mask product development is that there should be no defects greater than 80 nm in the quality area, 132 mm x 132 mm. In addition less than 10 defects smaller than 80 nm may be mitigable. SEMATECH has been focused on EUV mask blank defect reduction using Veeco Nexus TM IBD platform, the industry standard for mask blank production, and assessing if IBD technology can be evolved to a manufacturing solution. SEMATECH has recently announced a breakthrough reduction of defects in the mask blank deposition process resulting in the production of two defect-free EUV mask blanks at 54 nm inspection sensitivity (SiO2 equivalent). This paper will discuss the dramatic reduction of baseline EUV mask blank defects, review the current deposition process run and compare results with previous process runs. Likely causes of remaining defects will be discussed based on analyses as characterized by their compositions and whether defects are embedded in the multilayer stack or non-embedded.

Zebrafish retinal defects induced by ethanol exposure are rescued by retinoic acid and folic acid supplement

PubMed Central

Muralidharan, Pooja; Sarmah, Swapnalee; Marrs, James A.

2014-01-01

Fetal Alcohol Spectrum Disorder (FASD) is caused by prenatal alcohol exposure, producing craniofacial, sensory, motor, and cognitive defects. FASD is highly prevalent in low socioeconomic populations, which are frequently accompanied by malnutrition. FASD-associated ocular pathologies include microphthalmia, optic nerve hypoplasia, and cataracts. The present study characterizes specific retinal tissue defects, identifies ethanol-sensitive stages during retinal development, and dissects the effect of nutrient supplements, such as retinoic acid (RA) and folic acid (FA) on ethanol-induced retinal defects. Exposure to pathophysiological concentrations of ethanol (during midblastula transition through somitogenesis; 2–24 hours post fertilization [hpf]) altered critical transcription factor expression involved in retinal cell differentiation, and produced severe retinal ganglion cell, photoreceptor, and Müller glial differentiation defects. Ethanol exposure did not alter retinal cell differentiation induction, but increased retinal cell death and proliferation. RA and FA nutrient co-supplementation rescued retinal photoreceptor and ganglion cell differentiation defects. Ethanol exposure during retinal morphogenesis stages (16–24 hpf) produced retinal defects like those seen with ethanol exposure between 2–24 hpf. Significantly, during an ethanol-sensitive time window (16–24 hpf), RA co-supplementation moderately rescued these defects, whereas FA co-supplementation showed significant rescue of optic nerve and photoreceptor differentiation defects. Interestingly, RA, but not FA, supplementation after ethanol exposure could reverse ethanol-induced optic nerve and photoreceptor differentiation defects. Our results indicate that various ethanol-sensitive events underlie FASD-associated retinal defects. Nutrient supplements like retinoids and folate were effective in alleviating ethanol-induced retinal defects. PMID:25541501

Zebrafish retinal defects induced by ethanol exposure are rescued by retinoic acid and folic acid supplement.

PubMed

Muralidharan, Pooja; Sarmah, Swapnalee; Marrs, James A

2015-03-01

Fetal Alcohol Spectrum Disorder (FASD) is caused by prenatal alcohol exposure, producing craniofacial, sensory, motor, and cognitive defects. FASD is highly prevalent in low socioeconomic populations, which are frequently accompanied by malnutrition. FASD-associated ocular pathologies include microphthalmia, optic nerve hypoplasia, and cataracts. The present study characterizes specific retinal tissue defects, identifies ethanol-sensitive stages during retinal development, and dissects the effect of nutrient supplements, such as retinoic acid (RA) and folic acid (FA) on ethanol-induced retinal defects. Exposure to pathophysiological concentrations of ethanol (during midblastula transition through somitogenesis; 2-24 h post fertilization [hpf]) altered critical transcription factor expression involved in retinal cell differentiation, and produced severe retinal ganglion cell, photoreceptor, and Müller glial differentiation defects. Ethanol exposure did not alter retinal cell differentiation induction, but increased retinal cell death and proliferation. RA and FA nutrient co-supplementation rescued retinal photoreceptor and ganglion cell differentiation defects. Ethanol exposure during retinal morphogenesis stages (16-24 hpf) produced retinal defects like those seen with ethanol exposure between 2 and 24 hpf. Significantly, during an ethanol-sensitive time window (16-24 hpf), RA co-supplementation moderately rescued these defects, whereas FA co-supplementation showed significant rescue of optic nerve and photoreceptor differentiation defects. Interestingly, RA, but not FA, supplementation after ethanol exposure could reverse ethanol-induced optic nerve and photoreceptor differentiation defects. Our results indicate that various ethanol-sensitive events underlie FASD-associated retinal defects. Nutrient supplements like retinoids and folate were effective in alleviating ethanol-induced retinal defects. Copyright © 2015 Elsevier Inc. All rights reserved.

Evaluation of hemifield sector analysis protocol in multifocal visual evoked potential objective perimetry for the diagnosis and early detection of glaucomatous field defects.

PubMed

Mousa, Mohammad F; Cubbidge, Robert P; Al-Mansouri, Fatima; Bener, Abdulbari

2014-02-01

Multifocal visual evoked potential (mfVEP) is a newly introduced method used for objective visual field assessment. Several analysis protocols have been tested to identify early visual field losses in glaucoma patients using the mfVEP technique, some were successful in detection of field defects, which were comparable to the standard automated perimetry (SAP) visual field assessment, and others were not very informative and needed more adjustment and research work. In this study we implemented a novel analysis approach and evaluated its validity and whether it could be used effectively for early detection of visual field defects in glaucoma. Three groups were tested in this study; normal controls (38 eyes), glaucoma patients (36 eyes) and glaucoma suspect patients (38 eyes). All subjects had a two standard Humphrey field analyzer (HFA) test 24-2 and a single mfVEP test undertaken in one session. Analysis of the mfVEP results was done using the new analysis protocol; the hemifield sector analysis (HSA) protocol. Analysis of the HFA was done using the standard grading system. Analysis of mfVEP results showed that there was a statistically significant difference between the three groups in the mean signal to noise ratio (ANOVA test, p < 0.001 with a 95% confidence interval). The difference between superior and inferior hemispheres in all subjects were statistically significant in the glaucoma patient group in all 11 sectors (t-test, p < 0.001), partially significant in 5 / 11 (t-test, p < 0.01), and no statistical difference in most sectors of the normal group (1 / 11 sectors was significant, t-test, p < 0.9). Sensitivity and specificity of the HSA protocol in detecting glaucoma was 97% and 86%, respectively, and for glaucoma suspect patients the values were 89% and 79%, respectively. The new HSA protocol used in the mfVEP testing can be applied to detect glaucomatous visual field defects in both glaucoma and glaucoma suspect patients. Using this protocol can provide

Evaluation of Hemifield Sector Analysis Protocol in Multifocal Visual Evoked Potential Objective Perimetry for the Diagnosis and Early Detection of Glaucomatous Field Defects

PubMed Central

Mousa, Mohammad F.; Cubbidge, Robert P.; Al-Mansouri, Fatima

2014-01-01

Purpose Multifocal visual evoked potential (mfVEP) is a newly introduced method used for objective visual field assessment. Several analysis protocols have been tested to identify early visual field losses in glaucoma patients using the mfVEP technique, some were successful in detection of field defects, which were comparable to the standard automated perimetry (SAP) visual field assessment, and others were not very informative and needed more adjustment and research work. In this study we implemented a novel analysis approach and evaluated its validity and whether it could be used effectively for early detection of visual field defects in glaucoma. Methods Three groups were tested in this study; normal controls (38 eyes), glaucoma patients (36 eyes) and glaucoma suspect patients (38 eyes). All subjects had a two standard Humphrey field analyzer (HFA) test 24-2 and a single mfVEP test undertaken in one session. Analysis of the mfVEP results was done using the new analysis protocol; the hemifield sector analysis (HSA) protocol. Analysis of the HFA was done using the standard grading system. Results Analysis of mfVEP results showed that there was a statistically significant difference between the three groups in the mean signal to noise ratio (ANOVA test, p < 0.001 with a 95% confidence interval). The difference between superior and inferior hemispheres in all subjects were statistically significant in the glaucoma patient group in all 11 sectors (t-test, p < 0.001), partially significant in 5 / 11 (t-test, p < 0.01), and no statistical difference in most sectors of the normal group (1 / 11 sectors was significant, t-test, p < 0.9). Sensitivity and specificity of the HSA protocol in detecting glaucoma was 97% and 86%, respectively, and for glaucoma suspect patients the values were 89% and 79%, respectively. Conclusions The new HSA protocol used in the mfVEP testing can be applied to detect glaucomatous visual field defects in both glaucoma and glaucoma suspect

Topological Defects and Structures in the Early Universe

NASA Astrophysics Data System (ADS)

Zhu, Yong

1997-08-01

This thesis discusses the topological defects generated in the early universe and their contributions to cosmic structure formation. First, we investigate non-Gaussian isocurvature perturbations generated by the evolution of Goldstone modes during inflation. If a global symmetry is broken before inflation, the resulting Goldstone modes are disordered during inflation in a precise and predictable way. After inflation these Goldstone modes order themselves in a self-similar way, much as Goldstone modes in field ordering scenarios based on the Kibble mechanism. For (Hi2/Mpl2)~10- 6, through their gravitational interaction these Goldstone modes generate density perturbations of approximately the right magnitude to explain the cosmic microwave background (CMB) anisotropy and seed the structure seen in the universe today. In such a model non-Gaussian perturbations result because to lowest order density perturbations are sourced by products of Gaussian fields. We explore the issue of phase dispersion and conclude that this non-Gaussian model predicts Doppler peaks in the CMB anisotropy. Topological defects generated from quantum fluctuations during inflation are studied in chapter four. We present a calculation of the power spectrum generated in a classically symmetry-breaking O(N) scalar field through inflationary quantum fluctuations, using the large-N limit. The effective potential of the theory in de Sitter space is obtained from a gap equation which is exact at large N. Quantum fluctuations restore the O(N) symmetry in de Sitter space, but for the finite values of N of interest, there is symmetry breaking and phase ordering after inflation, described by the classical nonlinear sigma model. The scalar field power spectrum is obtained as a function of the scalar field self-coupling. In the second part of the thesis, we investigate non-Abelian topological worm-holes, obtained when winding number one texture field is coupled to Einstein gravity with a conserved global

Induction of endoplasmic reticulum calcium pump expression during early leukemic B cell differentiation.

PubMed

Aït Ghezali, Lamia; Arbabian, Atousa; Roudot, Hervé; Brouland, Jean-Philippe; Baran-Marszak, Fanny; Salvaris, Evelyn; Boyd, Andrew; Drexler, Hans G; Enyedi, Agnes; Letestu, Remi; Varin-Blank, Nadine; Papp, Bela

2017-06-26

Endoplasmic reticulum (ER) calcium storage and release play important roles in B lymphocyte maturation, survival, antigen-dependent cell activation and immunoglobulin synthesis. Calcium is accumulated in the endoplasmic reticulum (ER) by Sarco/Endoplasmic Reticulum Calcium ATPases (SERCA enzymes). Because lymphocyte function is critically dependent on SERCA activity, it is important to understand qualitative and quantitative changes of SERCA protein expression that occur during B lymphoid differentiation and leukemogenesis. In this work we investigated the modulation of SERCA expression during the pharmacologically induced differentiation of leukemic precursor B lymphoblast cell lines that carry the E2A-PBX1 fusion oncoprotein. Changes of SERCA levels during differentiation were determined and compared to those of established early B lymphoid differentiation markers. SERCA expression of the cells was compared to that of mature B cell lines as well, and the effect of the direct inhibition of SERCA-dependent calcium transport on the differentiation process was investigated. We show that E2A-PBX1 + leukemia cells simultaneously express SERCA2 and SERCA3-type calcium pumps; however, their SERCA3 expression is markedly inferior to that of mature B cells. Activation of protein kinase C enzymes by phorbol ester leads to phenotypic differentiation of the cells, and this is accompanied by the induction of SERCA3 expression. Direct pharmacological inhibition of SERCA-dependent calcium transport during phorbol ester treatment interferes with the differentiation process. These data show that the calcium pump composition of the ER is concurrent with increased SERCA3 expression during the differentiation of precursor B acute lymphoblastic leukemia cells, that a cross-talk exists between SERCA function and the control of differentiation, and that SERCA3 may constitute an interesting new marker for the study of early B cell phenotype.

Differential Activation of Cellular DNA Damage Responses by Replication-Defective and Replication-Competent Adenovirus Mutants

PubMed Central

Prakash, Anand; Jayaram, Sumithra

2012-01-01

Adenovirus (Ad) mutants that lack early region 4 (E4) activate the phosphorylation of cellular DNA damage response proteins. In wild-type Ad type 5 (Ad5) infections, E1b and E4 proteins target the cellular DNA repair protein Mre11 for redistribution and degradation, thereby interfering with its ability to activate phosphorylation cascades important during DNA repair. The characteristics of Ad infection that activate cellular DNA repair processes are not yet well understood. We investigated the activation of DNA damage responses by a replication-defective Ad vector (AdRSVβgal) that lacks E1 and fails to produce the immediate-early E1a protein. E1a is important for activating early gene expression from the other viral early transcription units, including E4. AdRSVβgal can deliver its genome to the cell, but it is subsequently deficient for viral early gene expression and DNA replication. We studied the ability of AdRSVβgal-infected cells to induce cellular DNA damage responses. AdRSVβgal infection does activate formation of foci containing the Mdc1 protein. However, AdRSVβgal fails to activate phosphorylation of the damage response proteins Nbs1 and Chk1. We found that viral DNA replication is important for Nbs1 phosphorylation, suggesting that this step in the viral life cycle may provide an important trigger for activating at least some DNA repair proteins. PMID:23015708

Phenotypic Spectrum in Osteogenesis Imperfecta Due to Mutations in TMEM38B: Unraveling a Complex Cellular Defect.

PubMed

Webb, Emma A; Balasubramanian, Meena; Fratzl-Zelman, Nadja; Cabral, Wayne A; Titheradge, Hannah; Alsaedi, Atif; Saraff, Vrinda; Vogt, Julie; Cole, Trevor; Stewart, Susan; Crabtree, Nicola J; Sargent, Brandi M; Gamsjaeger, Sonja; Paschalis, Eleftherios P; Roschger, Paul; Klaushofer, Klaus; Shaw, Nick J; Marini, Joan C; Högler, Wolfgang

2017-06-01

Recessive mutations in TMEM38B cause type XIV osteogenesis imperfecta (OI) by dysregulating intracellular calcium flux. Clinical and bone material phenotype description and osteoblast differentiation studies. Natural history study in pediatric research centers. Eight patients with type XIV OI. Clinical examinations included bone mineral density, radiographs, echocardiography, and muscle biopsy. Bone biopsy samples (n = 3) were analyzed using histomorphometry, quantitative backscattered electron microscopy, and Raman microspectroscopy. Cellular differentiation studies were performed on proband and control osteoblasts and normal murine osteoclasts. Type XIV OI clinical phenotype ranges from asymptomatic to severe. Previously unreported features include vertebral fractures, periosteal cloaking, coxa vara, and extraskeletal features (muscular hypotonia, cardiac abnormalities). Proband lumbar spine bone density z score was reduced [median -3.3 (range -4.77 to +0.1; n = 7)] and increased by +1.7 (1.17 to 3.0; n = 3) following bisphosphonate therapy. TMEM38B mutant bone has reduced trabecular bone volume, osteoblast, and particularly osteoclast numbers, with >80% reduction in bone resorption. Bone matrix mineralization is normal and nanoporosity low. We demonstrate a complex osteoblast differentiation defect with decreased expression of early markers and increased expression of late and mineralization-related markers. Predominance of trimeric intracellular cation channel type B over type A expression in murine osteoclasts supports an intrinsic osteoclast defect underlying low bone turnover. OI type XIV has a bone histology, matrix mineralization, and osteoblast differentiation pattern that is distinct from OI with collagen defects. Probands are responsive to bisphosphonates and some show muscular and cardiovascular features possibly related to intracellular calcium flux abnormalities. Copyright © 2017 Endocrine Society

Birth defects related to bendectin use in pregnancy. I. Oral clefts and cardiac defects.

PubMed

Mitchell, A A; Rosenberg, L; Shapiro, S; Slone, D

1981-06-12

The risk of birth defects previously associated with Bendectin use in early pregnancy were evaluated in a case-control study of malformed infants whose mothers were interviewed in three regional centers; 98 infants with isolated cleft palate (CP), 221 with cleft lip with or without cleft palate (CL +/- CP), and 122 with selected heart defects (HD) were compared with 970 other malformed infants who served as controls. Relative risk estimates (with their 95% confidence limits) for first-trimester exposure to Bendectin were as follows: CP, 0.9 (0.5 to 1.5); CL +/- CP, 0.6 (0.4 to 0.8); and HD, 1.0 (0.6 to 1.6). Allowance for a large number of potentially confounding factors did not materially influence the risk estimates. These findings suggest that early in utero exposure to Bendectin does not appreciably increase the risk of oral clefts or selected cardiac defects.

Catheter closure of secundum atrial septal defects.

PubMed

O'Laughlin, M P

1997-01-01

Catheter occlusion of atrial septal defects has its roots in the 1950s, with early devices being implanted during closed-heart surgery without cardiopulmonary bypass. For the past 20 years, various catheter-delivered devices have undergone testing and refinement. Designs have included single- and double-disk prostheses, with a variety of materials, delivery systems, and techniques. In this monograph, the history of atrial septal defect occluders and their evaluation, results, and prognoses will be outlined. The early work of King and Mills has been advanced in the forms of the Rashkind and Lock-USCI Clamshell occluders (USCI; Billerica, Mass), the "buttoned" device (custom made by E.B. Sideris), the Babic atrial septal defect occlusion system (Osypka, GmbH; Grenzach-Wyhlen, Germany), the Das-Angel Wings atrial septal defect occlusion device (Microvena Corporation; White Bear Lake, Minn), and others. The future holds promise for approved devices in the treatment of selected secundum atrial septal defects.

Differentiating early-onset persistent versus childhood-limited conduct problem youth.

PubMed

Barker, Edward D; Maughan, Barbara

2009-08-01

Among young children who demonstrate high levels of conduct problems, less than 50% will continue to exhibit these problems into adolescence. Such developmental heterogeneity presents a serious challenge for intervention and diagnostic screening in early childhood. The purpose of the present study was to inform diagnostic screening and preventive intervention efforts by identifying youths whose conduct problems persist. The authors examined 1) the extent to which early-onset persistent versus childhood-limited trajectories can be identified from repeated assessments of childhood and early-adolescent conduct problems and 2) how prenatal and early postnatal risks differentiate these two groups. To identify heterogeneity in early-onset conduct problems, the authors used data from a large longitudinal population-based cohort of children followed from the prenatal period to age 13. Predictive risk factors examined were prenatal and postnatal measures of maternal distress (anxiety, depression), emotional and practical support, and family and child characteristics (from birth to 4 years of age). Findings revealed a distinction between early-onset persistent versus childhood-limited conduct problems in youths. Robust predictors of the early-onset persistent trajectory were maternal anxiety during pregnancy (32 weeks gestation), partner cruelty to the mother (from age 0 to 4 years), harsh parenting, and higher levels of child undercontrolled temperament. Sex differences in these risks were not identified. Interventions aiming to reduce childhood conduct problems should address prenatal risks in mothers and early postnatal risks in both mothers and their young children.

The Potential of Gait Analysis to Contribute to Differential Diagnosis of Early Stage Dementia: Current Research and Future Directions

ERIC Educational Resources Information Center

Morgan, Debra; Funk, Melanie; Crossley, Margaret; Basran, Jenny; Kirk, Andrew; Bello-Haas, Vanina Dal

2007-01-01

Early differential diagnosis of dementia is becoming increasingly important as new pharmacologic therapies are developed, as these treatments are not equally effective for all types of dementia. Early detection and differential diagnosis also facilitates informed family decision making and timely access to appropriate services. Information about…

Automatic classification of blank substrate defects

NASA Astrophysics Data System (ADS)

Boettiger, Tom; Buck, Peter; Paninjath, Sankaranarayanan; Pereira, Mark; Ronald, Rob; Rost, Dan; Samir, Bhamidipati

2014-10-01

Mask preparation stages are crucial in mask manufacturing, since this mask is to later act as a template for considerable number of dies on wafer. Defects on the initial blank substrate, and subsequent cleaned and coated substrates, can have a profound impact on the usability of the finished mask. This emphasizes the need for early and accurate identification of blank substrate defects and the risk they pose to the patterned reticle. While Automatic Defect Classification (ADC) is a well-developed technology for inspection and analysis of defects on patterned wafers and masks in the semiconductors industry, ADC for mask blanks is still in the early stages of adoption and development. Calibre ADC is a powerful analysis tool for fast, accurate, consistent and automatic classification of defects on mask blanks. Accurate, automated classification of mask blanks leads to better usability of blanks by enabling defect avoidance technologies during mask writing. Detailed information on blank defects can help to select appropriate job-decks to be written on the mask by defect avoidance tools [1][4][5]. Smart algorithms separate critical defects from the potentially large number of non-critical defects or false defects detected at various stages during mask blank preparation. Mechanisms used by Calibre ADC to identify and characterize defects include defect location and size, signal polarity (dark, bright) in both transmitted and reflected review images, distinguishing defect signals from background noise in defect images. The Calibre ADC engine then uses a decision tree to translate this information into a defect classification code. Using this automated process improves classification accuracy, repeatability and speed, while avoiding the subjectivity of human judgment compared to the alternative of manual defect classification by trained personnel [2]. This paper focuses on the results from the evaluation of Automatic Defect Classification (ADC) product at MP Mask

Early prenatal exposure to air pollution and its associations with birth defects in a state-wide birth cohort from North Carolina.

PubMed

Vinikoor-Imler, Lisa C; Davis, J Allen; Meyer, Robert E; Luben, Thomas J

2013-10-01

Few studies have examined the potential relationship between air pollution and birth defects. The objective of this study was to investigate whether maternal exposure to particulate matter (PM2.5 ) and ozone (O3 ) during pregnancy is associated with birth defects among women living throughout North Carolina. Information on maternal and infant characteristics was obtained from North Carolina birth certificates and health service data (2003-2005) and linked with information on birth defects from the North Carolina Birth Defects Monitoring Program. The 24-hr PM2.5 and O3 concentrations were estimated using a hierarchical Bayesian model of air pollution generated by combining modeled air pollution predictions from the U.S. Environmental Protection Agency's Community Multi-Scale Air Quality model with air monitor data from the Environmental Protection Agency's Air Quality System. Maternal residence was geocoded and assigned pollutant concentrations averaged over weeks 3 to 8 of gestation. Binomial regression was performed and adjusted for potential confounders. No association was observed between either PM2.5 or O3 concentrations and most birth defects. Positive effect estimates were observed between air pollution and microtia/anotia and lower limb deficiency defects, but the 95% confidence intervals were wide and included the null. Overall, this study suggested a possible relationship between air pollution concentration during early pregnancy and certain birth defects (e.g., microtia/anotia, lower limb deficiency defects), although this study did not have the power to detect such an association. The risk for most birth defects does not appear to be affected by ambient air pollution. Copyright © 2013 Wiley Periodicals, Inc.

Right ventricular pressure response to exercise in adults with isolated ventricular septal defect closed in early childhood.

PubMed

Moller, Thomas; Lindberg, Harald; Lund, May Brit; Holmstrom, Henrik; Dohlen, Gaute; Thaulow, Erik

2018-06-01

We previously demonstrated an abnormally high right ventricular systolic pressure response to exercise in 50% of adolescents operated on for isolated ventricular septal defect. The present study investigated the prevalence of abnormal right ventricular systolic pressure response in 20 adult (age 30-45 years) patients who underwent surgery for early ventricular septal defect closure and its association with impaired ventricular function, pulmonary function, or exercise capacity. The patients underwent cardiopulmonary tests, including exercise stress echocardiography. Five of 19 patients (26%) presented an abnormal right ventricular systolic pressure response to exercise ⩾ 52 mmHg. Right ventricular systolic function was mixed, with normal tricuspid annular plane systolic excursion and fractional area change, but abnormal tricuspid annular systolic motion velocity (median 6.7 cm/second) and isovolumetric acceleration (median 0.8 m/second2). Left ventricular systolic and diastolic function was normal at rest as measured by the peak systolic velocity of the lateral wall and isovolumic acceleration, early diastolic velocity, and ratio of early diastolic flow to tissue velocity, except for ejection fraction (median 53%). The myocardial performance index was abnormal for both the left and right ventricle. Peak oxygen uptake was normal (mean z score -0.4, 95% CI -2.8-0.3). There was no association between an abnormal right ventricular systolic pressure response during exercise and right or left ventricular function, pulmonary function, or exercise capacity. Abnormal right ventricular pressure response is not more frequent in adult patients compared with adolescents. This does not support the theory of progressive pulmonary vascular disease following closure of left-to-right shunts.

Mass Defect from Nuclear Physics to Mass Spectral Analysis.

PubMed

Pourshahian, Soheil

2017-09-01

Mass defect is associated with the binding energy of the nucleus. It is a fundamental property of the nucleus and the principle behind nuclear energy. Mass defect has also entered into the mass spectrometry terminology with the availability of high resolution mass spectrometry and has found application in mass spectral analysis. In this application, isobaric masses are differentiated and identified by their mass defect. What is the relationship between nuclear mass defect and mass defect used in mass spectral analysis, and are they the same? Graphical Abstract ᅟ.

Clinicopathological features of alpha-fetoprotein producing early gastric cancer with enteroblastic differentiation.

PubMed

Matsumoto, Kohei; Ueyama, Hiroya; Matsumoto, Kenshi; Akazawa, Yoichi; Komori, Hiroyuki; Takeda, Tsutomu; Murakami, Takashi; Asaoka, Daisuke; Hojo, Mariko; Tomita, Natsumi; Nagahara, Akihito; Kajiyama, Yoshiaki; Yao, Takashi; Watanabe, Sumio

2016-09-28

To investigate clinicopathological features of early stage gastric cancer with enteroblastic differentiation (GCED). We retrospectively investigated data on 6 cases of early stage GCED and 186 cases of early stage conventional gastric cancer (CGC: well or moderately differentiated adenocarcinoma) who underwent endoscopic submucosal dissection or endoscopic mucosal resection from September 2011 to February 2015 in our hospital. GCED was defined as a tumor having a primitive intestine-like structure composed of cuboidal or columnar cells with clear cytoplasm and immunohistochemical positivity for either alpha-fetoprotein, Glypican 3 or SALL4. The following were compared between GCED and CGC: age, gender, location and size of tumor, macroscopic type, ulceration, depth of invasion, lymphatic and venous invasion, positive horizontal and vertical margin, curative resection rate. Six cases (5 males, 1 female; mean age 75.7 years; 6 lesions) of early gastric cancer with a GCED component and 186 cases (139 males, 47 females; mean age 72.7 years; 209 lesions) of early stage CGC were investigated. Mean tumor diameters were similar but rates of submucosal invasion, lymphatic invasion, venous invasion, and non-curative resection were higher in GCED than CGC (66.6% vs 11.4%, 33.3% vs 2.3%, 66.6% vs 0.4%, 83.3% vs 11% respectively, P < 0.01). Deep submucosal invasion was not revealed endoscopically or by preoperative biopsy. Histologically, in GCED the superficial mucosal layer was covered with a CGC component. The GCED component tended to exist in the deeper part of the mucosa to the submucosa by lymphatic and/or venous invasion, without severe stromal reaction. In addition, Glypican 3 was the most sensitive marker for GCED (positivity, 83.3%), immunohistochemically. Even in the early stage GCED has high malignant potential, and preoperative diagnosis is considered difficult. Endoscopists and pathologists should know the clinicopathological features of this highly malignant type

Recurrent neural tube defects, risk factors and vitamins.

PubMed Central

Wild, J; Read, A P; Sheppard, S; Seller, M J; Smithells, R W; Nevin, N C; Schorah, C J; Fielding, D W; Walker, S; Harris, R

1986-01-01

Data from our trial of periconceptional vitamin supplementation for the prevention of neural tube defects have been analysed to assess the influence of various factors on recurrence rates of neural tube defect. Our data suggest that the risk of recurrence of neural tube defect is influenced by the number of previous neural tube defects, area of residence, immediately prior miscarriage, and interpregnancy interval. None of these factors, however, contributed any significant differential risk between supplemented and unsupplemented mothers. Hence we conclude that the highly significant difference in recurrence rates of neural tube defect between supplemented and unsupplemented mothers was due to vitamin supplementation. PMID:3521496

Using birth defects registry data to evaluate infant and childhood mortality associated with birth defects: an alternative to traditional mortality assessment using underlying cause of death statistics.

PubMed

Copeland, Glenn E; Kirby, Russell S

2007-11-01

Although birth defects are a leading cause of death in infancy and early childhood, the proportion of all deaths to children with clinically diagnosed birth defects is not well documented. The study is intended to measure the proportion of all deaths to infants and children under age 10 occurring to children with birth defects and how and why this proportion differs from the proportion of deaths due to an underlying cause of congenital anomalies using standard mortality statistics. A linked file of Michigan livebirths and deaths was combined with data from a comprehensive multisource birth defects registry of Michigan livebirths born during the years 1992 through 2000. The data were analyzed to determine the mortality rate for infants and children with birth defects and for children with no reported birth defect. Mortality risk ratios were calculated. The underlying causes of death for children with birth defects were also categorized and compared to cause- specific mortality rates for the general population. Congenital anomalies were the underlying cause of death for 17.8% of all infant deaths while infants with birth defects were 33.7% of all infant deaths in the study. Almost half of all Michigan deaths to children aged 1 to 2 were within the birth defects registry, though only 15.0% had an underlying cause of death of a congenital anomaly based upon standard mortality statistics. The mortality experience among children with birth defects was significantly higher than other children throughout the first 9 years of life, ranging from 4.6 for 5 year olds to 12.8 for children 1 to 2. Mortality risk ratios examined by cause of death for infants with birth defects were highest for other endocrine (28.1), other CNS (28.1), and heart (21.9) conditions. For children 1 through 9, the highest differential risk was seen for other perinatal conditions (39.0), other endocrine (29.7), other CNS (24.5), and heart (21.4). Childhood mortality analyses that incorporate birth

Calvarial cleidocraniodysplasia-like defects with ENU-induced Nell-1 deficiency.

PubMed

Zhang, Xinli; Ting, Kang; Pathmanathan, Dharmini; Ko, Theodore; Chen, Weiwei; Chen, Feng; Lee, Haofu; James, Aaron W; Siu, Ronald K; Shen, Jia; Culiat, Cymbeline T; Soo, Chia

2012-01-01

Nell-1, first identified by its overexpression in synostotic cranial sutures, is a novel osteoinductive growth and differentiation factor. To further define Nell-1's role in craniofacial patterning, we characterized defects of the ENU-induced Nell-1-deficient (END) mice, focusing on both intramembranous and endochondral cranial bones. Results showed that calvarial bones of neonatal END mice were reduced in thickness and density, with a phenotype resembling calvarial cleidocraniodysplasia. In addition, a global reduction in osteoblast markers was observed, including reductions in Runx2, alkaline phosphatase, and osteocalcin. Remarkably, detailed analysis of endochondral bones showed dysplasia as well. The chondrocranium in the END mouse showed enrichment for early, proliferating Sox9⁺ chondrocytes, whereas in contrast markers of chondrocytes maturation were reduced. These data suggest that Nell-1 is an important growth factor for regulation of osteochondral differentiation, by regulating both Runx2 and Sox9 expression within the calvarium. In summary, Nell-1 is required for normal craniofacial membranous and endochondral skeletal development.

Diverse roles of actin in C. elegans early embryogenesis

PubMed Central

Velarde, Nathalie; Gunsalus, Kristin C; Piano, Fabio

2007-01-01

Background The actin cytoskeleton plays critical roles in early development in Caenorhabditis elegans. To further understand the complex roles of actin in early embryogenesis we use RNAi and in vivo imaging of filamentous actin (F-actin) dynamics. Results Using RNAi, we found processes that are differentially sensitive to levels of actin during early embryogenesis. Mild actin depletion shows defects in cortical ruffling, pseudocleavage, and establishment of polarity, while more severe depletion shows defects in polar body extrusion, cytokinesis, chromosome segregation, and eventually, egg production. These defects indicate that actin is required for proper oocyte development, fertilization, and a wide range of important events during early embryogenesis, including proper chromosome segregation. In vivo visualization of the cortical actin cytoskeleton shows dynamics that parallel but are distinct from the previously described myosin dynamics. Two distinct types of actin organization are observed at the cortex. During asymmetric polarization to the anterior, or the establishment phase (Phase I), actin forms a meshwork of microfilaments and focal accumulations throughout the cortex, while during the anterior maintenance phase (Phase II) it undergoes a morphological transition to asymmetrically localized puncta. The proper asymmetric redistribution is dependent on the PAR proteins, while both asymmetric redistribution and morphological transitions are dependent upon PFN-1 and NMY-2. Just before cytokinesis, actin disappears from most of the cortex and is only found around the presumptive cytokinetic furrow. Finally, we describe dynamic actin-enriched comets in the early embryo. Conclusion During early C. elegans embryogenesis actin plays more roles and its organization is more dynamic than previously described. Morphological transitions of F-actin, from meshwork to puncta, as well as asymmetric redistribution, are regulated by the PAR proteins. Results from this study

Evaluation of right ventricular function in early period following transcatheter closure of atrial septal defect.

PubMed

Ağaç, Mustafa Tarık; Akyüz, Ali Rıza; Acar, Zeydin; Akdemir, Ramazan; Korkmaz, Levent; Kırış, Abdülkadir; Erkuş, Emre; Erkan, Hakan; Celik, Sükrü

2012-03-01

There is limited data on alterations in novel right ventricular (RV) function indices like tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular systolic velocity (TASV) after transcatheter atrial septal defect (ASD) closure. We aimed to evaluate RV function by echocardiography (ECG) with these novel indices in early period in patients with secundum-type ASD that was closed percutaneously. Patients were enrolled to study if they had secundum-type ASD that was suitable for percutaneous closure. Patient population consisted of 4 men and 16 women. Echocardiography was performed before and 1 month after closure. Mean age was 37 ± 16. Mean diameter of ASD and total atrial septum length measured by ECG were 19 ± 6 mm and 49 ± 7 mm, respectively. Mean diameter of defect in transesophageal echocardiography was 20 ± 6 mm. Stretched mean diameter in catheterization was 23 ± 6 mm. One month after closure, there were statistically significant decreases in RV end-diastolic diameters (43.3 ± 10.7 mm vs. 34.9 ± 5.5 mm; P < 0.001), RV/left ventricular (LV) end-diastolic diameter ratio (1.1 ± 0.3 vs. 0.87 ± 0.1; P < 0.001), TASV (16.9 ± 3.2 cm/sec vs. 14.3 ± 3.3 cm/sec; P < 0.05), early diastolic tricuspid annular velocity (15.3 ± 3.1 cm/sec vs. 13.4 ± 2.4 cm/sec P <0.05), late diastolic tricuspid annular velocity (16.2 ± 5.4 cm/sec vs. 14.3 ± 6.3 cm/sec; P < 0.05), and TAPSE (29.9 ± 6.2 mm vs. 22.4 ± 7.4 mm; P < 0.001). LV end-diastolic diameter (38.0 ± 6.9 mm and 40.0 ± 4.5 P < 0.05) was increased, whereas there was no change in LV ejection fraction. Closure of ASD by using Amplatzer devices led to decrease in right heart chamber size, tissue Doppler-derived tricuspid annular velocities and TAPSE in early period. © 2011, Wiley Periodicals, Inc.

Early results of immediate repair of obstetric third-degree tears: 65% are completely asymptomatic despite persistent sphincter defects in 61%.

PubMed

Hayes, J; Shatari, T; Toozs-Hobson, P; Busby, K; Pretlove, S; Radley, S; Keighley, M

2007-05-01

The outcome of immediate repair of obstetric third-degree tears is poorly documented. Immediate repair may give better functional results than delayed repair because scarring is reduced. This aim of this prospective study was to examine the early outcome of immediate repair of third-degree tears. A total of 121 women who had immediate repair of obstetric third-degree tears underwent interview, anal ultrasonography and anorectal physiology. At review, 79 (65%) were completely asymptomatic (score = 0), 23 (19%), had minor flatus incontinence or mild urgency causing no compromise to their quality of life (score 1-4), and 19 (16%) had clinically embarrassing faecal incontinence (score 5-24). Thirty-nine (32%) had an intact internal anal sphincter (IAS) and external anal sphincter (EAS) (i.e. a successful repair), eight (7%) had a defect in the IAS alone but the EAS was intact (i.e. a successful repair but a residual IAS defect), 43 (35%) had a residual defect in the EAS alone (IAS intact) and 31 (26%) had a persistent defect in the IAS and EAS. Residual defects in either or both of the sphincters were associated with a significantly higher incidence of abnormal resting and squeeze anal pressures. Anal manometry had no correlation with symptoms. The highest proportion of severe incontinence was in those with an IAS defect alone (37%) and when there was a residual IAS and EAS defect (24%). Only 2 of 39 (5%) with an intact IAS and EAS had severe incontinence and only 8 of 43 (18%) with a residual EAS defect alone had severe faecal incontinence. These results indicate a good outcome following immediate repair of third-degree obstetric tears and emphasize the role of the IAS in providing continence.

Carbon nanotubes as VEGF carriers to improve the early vascularization of porcine small intestinal submucosa in abdominal wall defect repair

PubMed Central

Liu, Zhengni; Feng, Xueyi; Wang, Huichun; Ma, Jun; Liu, Wei; Cui, Daxiang; Gu, Yan; Tang, Rui

2014-01-01

Insufficient early vascularization in biological meshes, resulting in limited host tissue incorporation, is thought to be the primary cause for the failure of abdominal wall defect repair after implantation. The sustained release of exogenous angiogenic factors from a biocompatible nanomaterial might be a way to overcome this limitation. In the study reported here, multiwalled carbon nanotubes (MWNT) were functionalized by plasma polymerization to deliver vascular endothelial growth factor165 (VEGF165). The novel VEGF165-controlled released system was incorporated into porcine small intestinal submucosa (PSIS) to construct a composite scaffold. Scaffolds incorporating varying amounts of VEGF165-loaded functionalized MWNT were characterized in vitro. At 5 weight percent MWNT, the scaffolds exhibited optimal properties and were implanted in rats to repair abdominal wall defects. PSIS scaffolds incorporating VEGF165-loaded MWNT (VEGF–MWNT–PSIS) contributed to early vascularization from 2–12 weeks postimplantation and obtained more effective collagen deposition and exhibited improved tensile strength at 24 weeks postimplantation compared to PSIS or PSIS scaffolds, incorporating MWNT without VEGF165 loading (MWNT–PSIS). PMID:24648727

Loss of Sip1 leads to migration defects and retention of ectodermal markers during lens development.

PubMed

Manthey, Abby L; Lachke, Salil A; FitzGerald, Paul G; Mason, Robert W; Scheiblin, David A; McDonald, John H; Duncan, Melinda K

2014-02-01

SIP1 encodes a DNA-binding transcription factor that regulates multiple developmental processes, as highlighted by the pleiotropic defects observed in Mowat-Wilson syndrome, which results from mutations in this gene. Further, in adults, dysregulated SIP1 expression has been implicated in both cancer and fibrotic diseases, where it functionally links TGFβ signaling to the loss of epithelial cell characteristics and gene expression. In the ocular lens, an epithelial tissue important for vision, Sip1 is co-expressed with epithelial markers, such as E-cadherin, and is required for the complete separation of the lens vesicle from the head ectoderm during early ocular morphogenesis. However, the function of Sip1 after early lens morphogenesis is still unknown. Here, we conditionally deleted Sip1 from the developing mouse lens shortly after lens vesicle closure, leading to defects in coordinated fiber cell tip migration, defective suture formation, and cataract. Interestingly, RNA-Sequencing analysis on Sip1 knockout lenses identified 190 differentially expressed genes, all of which are distinct from previously described Sip1 target genes. Furthermore, 34% of the genes with increased expression in the Sip1 knockout lenses are normally downregulated as the lens transitions from the lens vesicle to early lens, while 49% of the genes with decreased expression in the Sip1 knockout lenses are normally upregulated during early lens development. Overall, these data imply that Sip1 plays a major role in reprogramming the lens vesicle away from a surface ectoderm cell fate towards that necessary for the development of a transparent lens and demonstrate that Sip1 regulates distinctly different sets of genes in different cellular contexts. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Loss of Sip1 leads to migration defects and retention of ectodermal markers during lens development

PubMed Central

Manthey, Abby L.; Lachke, Salil A.; FitzGerald, Paul G.; Mason, Robert W.; Scheiblin, David A.; McDonald, John H.; Duncan, Melinda K.

2014-01-01

SIP1 encodes a DNA-binding transcription factor that regulates multiple developmental processes, as highlighted by the pleiotropic defects observed in Mowat-Wilson Syndrome, which results from mutations in this gene. Further, in adults, dysregulated SIP1 expression has been implicated in both cancer and fibrotic diseases, where it functionally links TGFβ signaling to the loss of epithelial cell characteristics and gene expression. In the ocular lens, an epithelial tissue important for vision, Sip1 is co-expressed with epithelial markers, such as E-cadherin, and is required for the complete separation of the lens vesicle from the head ectoderm during early ocular morphogenesis. However, the function of Sip1 after early lens morphogenesis is still unknown. Here, we conditionally deleted Sip1 from the developing mouse lens shortly after lens vesicle closure, leading to defects in coordinated fiber cell tip migration, defective suture formation, and cataract. Interestingly, RNA-Sequencing analysis on Sip1 knockout lenses identified 190 differentially expressed genes, all of which are distinct from previously described Sip1 target genes. Furthermore, 34% of the genes with increased expression in the Sip1 knockout lenses are normally downregulated as the lens transitions from the lens vesicle to early lens, while 49% of the genes with decreased expression in the Sip1 knockout lenses are normally upregulated during early lens development. Overall, these data imply that Sip1 plays a major role in reprogramming the lens vesicle away from a surface ectoderm cell fate towards that necessary for the development of a transparent lens and demonstrate that Sip1 regulates distinctly different sets of genes in different cellular contexts. PMID:24161570

Heparan sulfates and the decrease of N-glycans promote early adipogenic differentiation rather than myogenesis of murine myogenic progenitor cells.

PubMed

Grassot, Vincent; Bouchatal, Amel; Da Silva, Anne; Chantepie, Sandrine; Papy-Garcia, Dulce; Maftah, Abderrahman; Gallet, Paul-François; Petit, Jean-Michel

In vitro, extracted muscle satellite cells, called myogenic progenitor cells, can differentiate either in myotubes or preadipocytes, depending on environmental factors and the medium. Transcriptomic analyses on glycosylation genes during satellite cells differentiation into myotubes showed that 31 genes present a significant variation of expression at the early stages of murine myogenic progenitor cells (MPC) differentiation. In the present study, we analyzed the expression of 383 glycosylation related genes during murine MPC differentiation into preadipocytes and compared the data to those previously obtained during their differentiation into myotubes. Fifty-six glycosylation related genes are specifically modified in their expression during early adipogenesis. The variations correspond mainly to: a decrease of N-glycans, and of alpha (2,3) and (2,6) linked sialic acids, and to a high level of heparan sulfates. A high amount of TGF-β1 in extracellular media during early adipogenesis was also observed. It seems that the increases of heparan sulfates and TGF-β1 favor pre-adipogenic differentition of MPC and possibly prevent their myogenic differentiation. Copyright © 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

Usherin defects lead to early-onset retinal dysfunction in zebrafish.

PubMed

Dona, Margo; Slijkerman, Ralph; Lerner, Kimberly; Broekman, Sanne; Wegner, Jeremy; Howat, Taylor; Peters, Theo; Hetterschijt, Lisette; Boon, Nanda; de Vrieze, Erik; Sorusch, Nasrin; Wolfrum, Uwe; Kremer, Hannie; Neuhauss, Stephan; Zang, Jingjing; Kamermans, Maarten; Westerfield, Monte; Phillips, Jennifer; van Wijk, Erwin

2018-05-16

Mutations in USH2A are the most frequent cause of Usher syndrome and autosomal recessive nonsyndromic retinitis pigmentosa. To unravel the pathogenic mechanisms underlying USH2A-associated retinal degeneration and to evaluate future therapeutic strategies that could potentially halt the progression of this devastating disorder, an animal model is needed. The available Ush2a knock-out mouse model does not mimic the human phenotype, because it presents with only a mild and late-onset retinal degeneration. Using CRISPR/Cas9-technology, we introduced protein-truncating germline lesions into the zebrafish ush2a gene (ush2a rmc1 : c.2337_2342delinsAC; p.Cys780GlnfsTer32 and ush2a b1245 : c.15520_15523delinsTG; p.Ala5174fsTer). Homozygous mutants were viable and displayed no obvious morphological or developmental defects. Immunohistochemical analyses with antibodies recognizing the N- or C-terminal region of the ush2a-encoded protein, usherin, demonstrated complete absence of usherin in photoreceptors of ush2a rmc1 , but presence of the ectodomain of usherin at the periciliary membrane of ush2a b1245 -derived photoreceptors. Furthermore, defects of usherin led to a reduction in localization of USH2 complex members, whirlin and Adgrv1, at the photoreceptor periciliary membrane of both mutants. Significantly elevated levels of apoptotic photoreceptors could be observed in both mutants when kept under constant bright illumination for three days. Electroretinogram (ERG) recordings revealed a significant and similar decrease in both a- and b-wave amplitudes in ush2a rmc1 as well as ush2a b1245 larvae as compared to strain- and age-matched wild-type larvae. In conclusion, this study shows that mutant ush2a zebrafish models present with early-onset retinal dysfunction that is exacerbated by light exposure. These models provide a better understanding of the pathophysiology underlying USH2A-associated RP and a unique opportunity to evaluate future therapeutic strategies. Copyright

IL-6-mediated environmental conditioning of defective Th1 differentiation dampens antitumour immune responses in old age.

PubMed

Tsukamoto, Hirotake; Senju, Satoru; Matsumura, Keiko; Swain, Susan L; Nishimura, Yasuharu

2015-04-07

Decline in immune function and inflammation concomitantly develop with ageing. Here we focus on the impact of this inflammatory environment on T cells, and demonstrate that in contrast to successful tumour elimination in young mice, replenishment of tumour-specific CD4(+) T cells fails to induce tumour regression in aged hosts. The impaired antitumour effect of CD4(+) T cells with their defective Th1 differentiation in an aged environment is restored by interleukin (IL)-6 blockade or IL-6 deficiency. IL-6 blockade also restores the impaired ability of CD4(+) T cells to promote CD8(+) T-cell-dependent tumour elimination in aged mice, which requires IFN-γ. Furthermore, IL-6-stimulated production of IL-4/IL-21 through c-Maf induction is responsible for impaired Th1 differentiation. IL-6 also contributes to IL-10 production from CD4(+) T cells in aged mice, causing attenuated responses of CD8(+) T cells. These findings suggest that IL-6 serves as an extrinsic factor counteracting CD4(+) T-cell-mediated immunity against tumour in old age.

An exploratory analysis of the relationship between ambient ozone and particulate matter concentrations during early pregnancy and selected birth defects in Texas

EPA Science Inventory

Background: Associations between ozone (O3) and fine particulate matter (PM2.5) concentrations and birth outcomes have been previously demonstrated. We perform an exploratory analysis of O3 and PM2.5 concentrations during early pregnancy and multiple types of birth defects. Met...

Overlapping DNA Methylation Dynamics in Mouse Intestinal Cell Differentiation and Early Stages of Malignant Progression

PubMed Central

Forn, Marta; Díez-Villanueva, Anna; Merlos-Suárez, Anna; Muñoz, Mar; Lois, Sergi; Carriò, Elvira; Jordà, Mireia; Bigas, Anna; Batlle, Eduard; Peinado, Miguel A.

2015-01-01

Mouse models of intestinal crypt cell differentiation and tumorigenesis have been used to characterize the molecular mechanisms underlying both processes. DNA methylation is a key epigenetic mark and plays an important role in cell identity and differentiation programs and cancer. To get insights into the dynamics of cell differentiation and malignant transformation we have compared the DNA methylation profiles along the mouse small intestine crypt and early stages of tumorigenesis. Genome-scale analysis of DNA methylation together with microarray gene expression have been applied to compare intestinal crypt stem cells (EphB2high), differentiated cells (EphB2negative), ApcMin/+ adenomas and the corresponding non-tumor adjacent tissue, together with small and large intestine samples and the colon cancer cell line CT26. Compared with late stages, small intestine crypt differentiation and early stages of tumorigenesis display few and relatively small changes in DNA methylation. Hypermethylated loci are largely shared by the two processes and affect the proximities of promoter and enhancer regions, with enrichment in genes associated with the intestinal stem cell signature and the PRC2 complex. The hypermethylation is progressive, with minute levels in differentiated cells, as compared with intestinal stem cells, and reaching full methylation in advanced stages. Hypomethylation shows different signatures in differentiation and cancer and is already present in the non-tumor tissue adjacent to the adenomas in ApcMin/+ mice, but at lower levels than advanced cancers. This study provides a reference framework to decipher the mechanisms driving mouse intestinal tumorigenesis and also the human counterpart. PMID:25933092

Early transcriptional responses of internalization defective Brucella abortus mutants in professional phagocytes, RAW 264.7.

PubMed

Cha, Seung Bin; Lee, Won Jung; Shin, Min Kyoung; Jung, Myung Hwan; Shin, Seung Won; Yoo, An Na; Kim, Jong Wan; Yoo, Han Sang

2013-06-27

Brucella abortus is an intracellular zoonotic pathogen which causes undulant fever, endocarditis, arthritis and osteomyelitis in human and abortion and infertility in cattle. This bacterium is able to invade and replicate in host macrophage instead of getting removed by this defense mechanism. Therefore, understanding the interaction between virulence of the bacteria and the host cell is important to control brucellosis. Previously, we generated internalization defective mutants and analyzed the envelope proteins. The present study was undertaken to evaluate the changes in early transcriptional responses between wild type and internalization defective mutants infected mouse macrophage, RAW 264.7. Both of the wild type and mutant infected macrophages showed increased expression levels in proinflammatory cytokines, chemokines, apoptosis and G-protein coupled receptors (Gpr84, Gpr109a and Adora2b) while the genes related with small GTPase which mediate intracellular trafficking was decreased. Moreover, cytohesin 1 interacting protein (Cytip) and genes related to ubiquitination (Arrdc3 and Fbxo21) were down-regulated, suggesting the survival strategy of this bacterium. However, we could not detect any significant changes in the mutant infected groups compared to the wild type infected group. In summary, it was very difficult to clarify the alterations in host cellular transcription in response to infection with internalization defective mutants. However, we found several novel gene changes related to the GPCR system, ubiquitin-proteosome system, and growth arrest and DNA damages in response to B. abortus infection. These findings may contribute to a better understanding of the molecular mechanisms underlying host-pathogen interactions and need to be studied further.

A novel inspection system for cosmetic defects

NASA Astrophysics Data System (ADS)

Hazra, S.; Roy, R.; Williams, D.; Aylmore, R.; Hollingdale, D.

2013-12-01

The appearance of automotive skin panels creates desirability for a product and differentiates it from the competition. Because of the importance of skin panels, considerable care is taken in minimizing defects such as the 'hollow' defect that occur around door-handle depressions. However, the inspection process is manual, subjective and time-consuming. This paper describes the development of an objective and inspection scheme for the 'hollow' defect. In this inspection process, the geometry of a panel is captured using a structured lighting system. The geometry data is subsequently analyzed by a purpose-built wavelet-based algorithm to identify the location of any defects that may be present and to estimate the perceived severity of the defects without user intervention. This paper describes and critically evaluates the behavior of this physically-based algorithm on an ideal and real geometry and compares its result to an actual audit. The results show that the algorithm is capable of objectively locating and classifying 'hollow' defects in actual panels.

Clinical differentiation of patent foramen ovale and secundum atrial septal defect: a survey of pediatric cardiologists in Dallas, Texas, USA.

PubMed

Scheuerle, Angela

2011-01-01

Public health birth defect surveillance registries rely on health care provider diagnosis and definition of congenital anomalies. Major anomalies are likely to have consistent diagnoses across providers; however, definition of some more common, often minor, defects can be problematic. Of particular frustration are the transient neonatal heart findings: patent ductus arteriosus, patent foramen ovale, and pulmonary artery branch stenosis. Under certain circumstances these findings may be considered true anomalies-patent foramen ovale (PFO) as a clinical finding overlaps significantly with atrial septal defect (ASD) of secundum type, the latter being considered a true congenital malformation. Some criteria must be established to separate these conditions in case ascertainment. It is therefore helpful to understand the clinical definitions of patent foramen ovale and secundum atrial septal defect. Pediatric cardiologists in the greater Dallas, Texas metropolitan area were surveyed by telephone, fax, and/or email and asked what criteria they use to distinguish a PFO from a secundum ASD. This was an open-ended question. No baseline parameters were suggested or introduced by the interviewer. Pediatric cardiology fellowship training was identified for each physician to examine the hypothesis that graduates of a given program would use the same diagnostic criteria. Responses were obtained from 22 of 23 pediatric cardiologists. Four measurement criteria were identified: size of the opening, presence or absence of a flap of septal tissue, appearance of the defect on echocardiogram and presence/absence/amount of blood shunting across through the opening. Though there was overlap, diagnostic criteria differentiating PFO and secundum ASD varied among pediatric cardiologists. Two fellowship programs were well represented by the respondent population. Eight respondents were trained at Fellowship 1 and 5 at Fellowship 2. Place of fellowship training was not a strong indicator of

Fluconazole use and birth defects in the National Birth Defects Prevention Study.

PubMed

Howley, Meredith M; Carter, Tonia C; Browne, Marilyn L; Romitti, Paul A; Cunniff, Christopher M; Druschel, Charlotte M

2016-05-01

Low-dose fluconazole is used commonly to treat vulvovaginal candidiasis, a condition occurring frequently during pregnancy. Conflicting information exists on the association between low-dose fluconazole use among pregnant women and the risk of major birth defects. We used data from the National Birth Defects Prevention Study to examine this association. The National Birth Defects Prevention Study is a multisite, population-based, case-control study that includes pregnancies with estimated delivery dates from 1997 to 2011. Information on fluconazole use in early pregnancy was collected by self-report from 31,645 mothers of birth defect cases and 11,612 mothers of unaffected controls. Adjusted odds ratios and 95% confidence intervals were estimated for birth defects with 5 or more exposed cases; crude odds ratios and exact 95% confidence intervals were estimated for birth defects with 3-4 exposed cases. Of the 43,257 mothers analyzed, 44 case mothers and 6 control mothers reported using fluconazole. Six exposed infants had cleft lip with cleft palate, 4 had an atrial septal defect, and each of the following defects had 3 exposed cases: hypospadias, tetralogy of Fallot, d-transposition of the great arteries, and pulmonary valve stenosis. Fluconazole use was associated with cleft lip with cleft palate (odds ratio = 5.53; confidence interval = 1.68-18.24) and d-transposition of the great arteries (odds ratio = 7.56; confidence interval = 1.22-35.45). The associations between fluconazole and both cleft lip with cleft palate and d-transposition of the great arteries are consistent with earlier published case reports but not recent epidemiologic studies. Despite the larger sample size of the National Birth Defects Prevention Study, fluconazole use was rare. Further investigation is needed in large studies, with particular emphasis on oral clefts and conotruncal heart defects. Copyright © 2016 Elsevier Inc. All rights reserved.

Methylation Markers for Early Detection and Differentiation of Follicular Thyroid Cancer Subtypes

PubMed Central

Stephen, Josena K.; Chen, Kang Mei; Merritt, Jason; Chitale, Dhananjay; Divine, George; Worsham, Maria J.

2016-01-01

Thyroid cancer has the fastest rising incidence rates and is the fifth most common cancer in women. There are four main types of which the papillary and follicular types together account for >90%, followed by medullary cancers (3%−5%) and anaplastic carcinomas (<3%). For individuals who present with early stage disease of papillary and follicular cancers, there are no accurate markers to predict whether they will develop metastatic or recurrent disease. Our immediate goal is to molecularly differentiate follicular cancer subtypes for enhanced classification. Promoter methylation status of genes with reported associations in thyroid cancer (CASP8, CDKN2A, DAPK1, ESR1, NIS, RASSF1 and TIMP3) were examined in a cohort of follicular thyroid cancers comprising of 26 Hurthle and 27 Classic subtypes utilizing quantitative methylation-specific PCR. RASSF1 was differentially methylated in Classic tumor tissue compared to Hurthle (p<0.001). Methylation of RASSF1 pointed to racial group differences between African Americans and Caucasian Americans (p=0.05). Extra thyroidal extension was found to be associated with DAPK1 (p=0.014) and ESR1 (p=0.036) methylation. Late stage disease was associated with older age (p<0.001) and methylation of DAPK1 (p=0.034) and ESR1 (p=0.035). The methylation status of RASSF1, DAPK1 and ESR1 suggests the utility of methylation markers to molecularly differentiate thyroid cancer subtypes for enhanced classification and early detection of thyroid cancer. PMID:27158284

Inferior sinus venosus defects: anatomic features and echocardiographic correlates.

PubMed

Plymale, Jennifer; Kolinski, Kellen; Frommelt, Peter; Bartz, Peter; Tweddell, James; Earing, Michael G

2013-02-01

Inferior sinus venosus defects (SVDs) are rare imperfections located in the inferior portion of the atrial septum, leading to an overriding inferior vena cava (IVC) and an interatrial connection. These defects have increased risk of anomalous pulmonary venous return (PAPVR) and often are confused with secundum atrial septal defects (ASDs) with inferior extension. The authors sought to review their experience with inferior SVDs and to establish at their institution an echocardiographic definition that differentiates inferior SVDs from secundum ASDs with inferior extension. The study identified 161 patients 1.5 to 32 years of age who had undergone repair of a secundum ASD with inferior extension or inferior SVD over the preceding 10 years. All surgical notes, preoperative transthoracic echocardiograms (TTEs), and preoperative transesophageal echocardiograms (TEEs) were reviewed. Based on the surgical notes, 147 patients were classified as having a secundum ASD (147/161, 91 %) and 14 patients (9 %) as having an inferior SVD. The study identified PAPVR in 7 % (1/14) of the patients with inferior SVDs and 3.5 % (5/14) of the patients with secundum ASDs. Surgical diagnosis and preoperative TTE correlated for 143 (89 %) of the 161 patients. Using a strict anatomic and echocardiographic definition with a blinded observer, the majority of the defects (14/18, 78 %) were reclassified correctly after review of their TTE images, and 100 % of the defects were correctly reclassified after TEE image review. Accurate diagnosis of inferior SVDs remains challenging. The data from this study demonstrate that use of a strict anatomic and echocardiographic definition (a defect that originates in the mouth of the IVC and continues into the inferoposterior border of the left atrium, leaving no residual atrial septal tissue at the inferior margin) allows for accurate differentiation between secundum ASDs with inferior extension and inferior SVDs. This differentiation is extremely important

Early transcriptional responses of internalization defective Brucella abortus mutants in professional phagocytes, RAW 264.7

PubMed Central

2013-01-01

Background Brucella abortus is an intracellular zoonotic pathogen which causes undulant fever, endocarditis, arthritis and osteomyelitis in human and abortion and infertility in cattle. This bacterium is able to invade and replicate in host macrophage instead of getting removed by this defense mechanism. Therefore, understanding the interaction between virulence of the bacteria and the host cell is important to control brucellosis. Previously, we generated internalization defective mutants and analyzed the envelope proteins. The present study was undertaken to evaluate the changes in early transcriptional responses between wild type and internalization defective mutants infected mouse macrophage, RAW 264.7. Results Both of the wild type and mutant infected macrophages showed increased expression levels in proinflammatory cytokines, chemokines, apoptosis and G-protein coupled receptors (Gpr84, Gpr109a and Adora2b) while the genes related with small GTPase which mediate intracellular trafficking was decreased. Moreover, cytohesin 1 interacting protein (Cytip) and genes related to ubiquitination (Arrdc3 and Fbxo21) were down-regulated, suggesting the survival strategy of this bacterium. However, we could not detect any significant changes in the mutant infected groups compared to the wild type infected group. Conclusions In summary, it was very difficult to clarify the alterations in host cellular transcription in response to infection with internalization defective mutants. However, we found several novel gene changes related to the GPCR system, ubiquitin-proteosome system, and growth arrest and DNA damages in response to B. abortus infection. These findings may contribute to a better understanding of the molecular mechanisms underlying host-pathogen interactions and need to be studied further. PMID:23802650

[Early complications following transcatheter occlusion of perimembranous ventricular septal defects in children].

PubMed

Li, Jun-jie; Zhang, Zhi-wei; Qian, Ming-yang; Wang, Hui-shen; Li, Yu-fen

2006-11-01

To evaluate the early complications during and after transcatheter closure of perimembranous ventricular septal defects (PMVSDs) in children. A total of 223 patients received transcatheter closure of PMVSDs from March 2002 to December 2005 in our hospital were included in this retrospective study. The overall complications rate was 26.9% (60/223). Major complications occurred in 9 patients (4.0%) including III degrees atrioventricular block (AVB) in 2 (0.9%), hemolysis in 3 (1.3%) and surgical interventions in 4 patients (1.8%) because of device malposition (1), mild aortic regurgitation (2) and device embolization (1) and all 4 patients recovered without further complications. The 2 patients with III degrees AVB were completely recovered to normal sinus rhythm after 7 days treatment with temporary pacemaker and corticosteroid. Hemolysis in 3 patients disappeared after corticosteroid treatment. Minor complications occurred in 51 patients (22.8%) including bundle branch block (BBB) in 37 (16.6%), first-degree AVB in 2 (0.9%), second-degree AVB in 1 (0.4%), new-onset mild aortic regurgitation in 5 (2.2%) and new-onset mild to moderate tricuspid regurgitation in 6 patients (2.6%). Except for right bundle branch blocks, other BBBs were treated with albumin and corticosteroid and completely recovered. No treatment was applied for new-onset valve regurgitations. There was no death in all 223 patients. Early complications post PMVSDs in children are mostly minor with good prognosis and the prognosis for major complications post PMVSDs is good after proper treatment.

The gga-let-7 family post-transcriptionally regulates TGFBR1 and LIN28B during the differentiation process in early chick development.

PubMed

Lee, Sang In; Jeon, Mi-Hyang; Kim, Jeom Sun; Jeon, Ik-Soo; Byun, Sung June

2015-12-01

Early chick embryogenesis is governed by a complex mechanism involving transcriptional and post-transcriptional regulation, although how post-transcriptional processes influence the balance between pluripotency and differentiation during early chick development have not been previously investigated. Here, we characterized the microRNA (miRNA) signature associated with differentiation in the chick embryo, and found that as expression of the gga-let-7 family increases through early development, expression of their direct targets, TGFBR1 and LIN28B, decreases; indeed, gga-let-7a-5p and gga-let-7b miRNAs directly bind to TGFBR1 and LIN28B transcripts. Our data further indicate that TGFBR1 and LIN28B maintain pluripotency by regulating POUV, NANOG, and CRIPTO. Therefore, gga-let-7 miRNAs act as post-transcriptional regulators of differentiation in blastodermal cells by repressing the expression of the TGFBR1 and LIN28B, which intrinsically controls blastodermal cell differentiation in early chick development. © 2015 Wiley Periodicals, Inc.

Differential associations of early callous-unemotional, oppositional, and ADHD behaviors: multiple domains within early-starting conduct problems?

PubMed

Waller, Rebecca; Hyde, Luke W; Grabell, Adam S; Alves, Martha L; Olson, Sheryl L

2015-06-01

Early-starting child conduct problems (CP) are linked to the development of persistent antisocial behavior. Researchers have theorized multiple pathways to CP and that CP comprise separable domains, marked by callous-unemotional (CU) behavior, oppositional behavior, or ADHD symptoms. However, a lack of empirical evidence exists from studies that have examined whether there are unique correlates of these domains. We examined differential correlates of CU, oppositional, and ADHD behaviors during the preschool years to test their potentially distinct nomological networks. Multimethod data, including parent and teacher reports and observations of child behavior, were drawn from a prospective, longitudinal study of children assessed at age 3 and age 6 (N = 240; 48% female). Dimensions of CU, oppositional, and ADHD behaviors were separable within Confirmatory Factor Analyses across mother and father reports. There were differential associations between CU, oppositional, and ADHD behaviors and socioemotional, cognitive, and behavioral outcomes: CU behavior was uniquely related to lower moral regulation, guilt, and empathy. ADHD was uniquely related to lower attentional focusing and observed effortful control. Finally, CU behavior uniquely predicted increases in teacher-reported externalizing from ages 3-6 over and above covariates, and ADHD and oppositional behavior. Consistent with theory, dimensions of CU, ADHD, and oppositional behavior demonstrated separable nomological networks representing separable facets within early-starting CP. © 2014 Association for Child and Adolescent Mental Health.

Arrhythmias after transcatheter closure of perimembranous ventricular septal defects with a modified double-disk occluder: early and long-term results.

PubMed

Li, Pan; Zhao, Xian-xian; Zheng, Xing; Qin, Yong-wen

2012-07-01

With the development of interventional techniques and devices, transcatheter closure of perimembranous ventricular septal defect has been widely performed. However, there has been a lack of long-term follow-up results about postoperative ECG changes of PmVSD patients. We report our experience of early and late arrhythmias after transcatheter closure of PmVSD with a modified double-disk occluder (MDVO). We performed a retrospective review of 79 patients (47 males, 32 females) between September 2002 and May 2007 who underwent transcatheter closure of perimembranous ventricular septal defect. Symmetric and asymmetric PmVSD occluders were used. The diameter of the evaluated defects ranged from 3 to 12 mm, as measured by TTE and 3 to 15 mm by left ventriculography. Most cases of PmVSD were treated successfully with a single procedure, resulting in a successful closure rate of 97% (77/79 patients). There was no death in any of the patients. After the operation, 79 patients were followed-up for a range of 10-76 months (35.3 ± 17.4 months). In this series, 11 cases of incomplete right bundle branch block and five cases of complete right bundle branch block occurred during the early period after operation. During long-term follow-up, these issues declined in prevalence to five and four cases, respectively. Moreover, reversible third-degree AVB occurred during closure or after the procedure, and two of the three patients with reversible AVB received a temporary heart pacemaker implantation. These patients recovered 1 h, 6 days, and 9 days later, respectively. During 10-76 months of follow-up, no complications occurred in any of the patients, including residual shunt, severe aortic valve, or tricuspid valve regurgitation. Device closure of perimembranous ventricular septal defects with a modified double-disk occluder (MDVO) resulted in excellent closure rates and acceptably low arrhythmia rates.

Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1.

PubMed

Kim, Edward; Wang, Yuan; Kim, Sun-Jung; Bornhorst, Miriam; Jecrois, Emmanuelle S; Anthony, Todd E; Wang, Chenran; Li, Yi E; Guan, Jun-Lin; Murphy, Geoffrey G; Zhu, Yuan

2014-12-23

Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodevelopmental disorders. Here we show that Nf1 inactivation during early, but not late stages of cerebellar development, disrupts neuronal lamination, which is partially caused by overproduction of glia and subsequent disruption of the Bergmann glia (BG) scaffold. Specific Nf1 inactivation in glutamatergic neuronal precursors causes premature differentiation of granule cell (GC) precursors and ectopic production of unipolar brush cells (UBCs), indirectly disrupting neuronal migration. Transient MEK inhibition during a neonatal window prevents cerebellar developmental defects and improves long-term motor performance of Nf1-deficient mice. This study reveals essential roles of Nf1 in GC/UBC migration by generating correct numbers of glia and controlling GC/UBC fate-specification/differentiation, identifying a therapeutic prevention strategy for multiple NF1-associcated developmental abnormalities.

Topological defects from the multiverse

NASA Astrophysics Data System (ADS)

Zhang, Jun; Blanco-Pillado, Jose J.; Garriga, Jaume; Vilenkin, Alexander

2015-05-01

Many theories of the early universe predict the existence of a multiverse where bubbles continuously nucleate giving rise to observers in their interior. In this paper, we point out that topological defects of several dimensionalities will also be produced in de Sitter like regions of the multiverse. In particular, defects could be spontaneously nucleated in our parent vacuum. We study the evolution of these defects as they collide with and propagate inside of our bubble. We estimate the present distribution of defects in the observable part of the universe. The expected number of such nearby defects turns out to be quite small, even for the highest nucleation rate. We also study collisions of strings and domain walls with our bubble in our past light cone. We obtain simulated full-sky maps of the loci of such collisions, and find their angular size distribution. Similarly to what happens in the case of bubble collisions, the prospect of detecting any collisions of our bubble with ambient defects is greatly enhanced in the case where the cosmological constant of our parent vacuum is much higher than the vacuum energy density during inflation in our bubble.

Topological defects from the multiverse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Jun; Vilenkin, Alexander; Blanco-Pillado, Jose J.

2015-05-01

Many theories of the early universe predict the existence of a multiverse where bubbles continuously nucleate giving rise to observers in their interior. In this paper, we point out that topological defects of several dimensionalities will also be produced in de Sitter like regions of the multiverse. In particular, defects could be spontaneously nucleated in our parent vacuum. We study the evolution of these defects as they collide with and propagate inside of our bubble. We estimate the present distribution of defects in the observable part of the universe. The expected number of such nearby defects turns out to bemore » quite small, even for the highest nucleation rate. We also study collisions of strings and domain walls with our bubble in our past light cone. We obtain simulated full-sky maps of the loci of such collisions, and find their angular size distribution. Similarly to what happens in the case of bubble collisions, the prospect of detecting any collisions of our bubble with ambient defects is greatly enhanced in the case where the cosmological constant of our parent vacuum is much higher than the vacuum energy density during inflation in our bubble.« less

Topological defects from the multiverse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Jun; Blanco-Pillado, Jose J.; IKERBASQUE, Basque Foundation for Science, 48013, Bilbao

2015-05-28

Many theories of the early universe predict the existence of a multiverse where bubbles continuously nucleate giving rise to observers in their interior. In this paper, we point out that topological defects of several dimensionalities will also be produced in de Sitter like regions of the multiverse. In particular, defects could be spontaneously nucleated in our parent vacuum. We study the evolution of these defects as they collide with and propagate inside of our bubble. We estimate the present distribution of defects in the observable part of the universe. The expected number of such nearby defects turns out to bemore » quite small, even for the highest nucleation rate. We also study collisions of strings and domain walls with our bubble in our past light cone. We obtain simulated full-sky maps of the loci of such collisions, and find their angular size distribution. Similarly to what happens in the case of bubble collisions, the prospect of detecting any collisions of our bubble with ambient defects is greatly enhanced in the case where the cosmological constant of our parent vacuum is much higher than the vacuum energy density during inflation in our bubble.« less

Dexamethasone induces dysferlin in myoblasts and enhances their myogenic differentiation

PubMed Central

Belanto, Joseph J.; Diaz-Perez, Silvia V.; Magyar, Clara E.; Maxwell, Michele M.; Yilmaz, Yasemin; Topp, Kasey; Boso, Guney; Jamieson, Catriona H.; Cacalano, Nicholas A.; Jamieson, Christina A.M.

2010-01-01

Glucocorticoids are beneficial in many muscular dystrophies but they are ineffective in treating dysferlinopathy, a rare muscular dystrophy caused by loss of dysferlin. We sought to understand the molecular basis for this disparity by studying the effects of a glucocorticoid on differentiation of the myoblast cell line, C2C12, and dysferlin-deficient C2C12s. We found that pharmacologic doses of dexamethasone enhanced the myogenic fusion efficiency of C2C12s and increased the induction of dysferlin, along with specific myogenic transcription factors, sarcolemmal and structural proteins. In contrast, the dysferlin-deficient C2C12 cell line demonstrated a reduction in long myotubes and early induction of particular muscle differentiation proteins, most notably, myosin heavy chain. Dexamethasone partially reversed the defect in myogenic fusion in the dysferlin-deficient C2C12 cells. We hypothesize that a key therapeutic benefit of glucocorticoids may be the up-regulation of dysferlin as an important component of glucocorticoid-enhanced myogenic differentiation. PMID:20080405

Early Terrestrial Mantle Differentiation Recorded in Paleoarchean Komatiites

NASA Astrophysics Data System (ADS)

Puchtel, I. S.; Blichert-Toft, J.; Touboul, M.; Horan, M. F.; Walker, R. J.

2016-12-01

Geochmical signatures generated in the manle as a result of radioactive decay of short- and long-lived nuclides can be used to constrain the timing of formation and the nature of now mostly vanished early terrestrial reservoirs. The 3.55 Ga komatiites from the Schapenburg Greenstone Remnant (SGR) located in the Barberton Greenstone Belt in South Africa have a unique combination of trace element abundances and isotopic compositions that place strong constraints on the origin of these reservoirs. The SGR komatiites define a Re-Os isochron with an age of 3550±87 Ma and an initial γ187Os = +3.7±0.2 (2SD). The absolute HSE abundances in the mantle source of the SGR komatiite system are estimated to be only 29±5% of those in the present-day bulk silicate Earth (BSE) estimates. The SGR komatiites show coupled depletion, relative to the modern mantle, in 142Nd and 182W (μ142Nd = -5.0±2.8, μ182W = -8.4±4.5), the decay products of the short-lived 146Sm and 182Hf nuclides, respectively, indicating derivation from a mantle domain that was enriched in incompatible elements 30 Ma after Solar System formation. Early Hadean contributors to this mantle domain could include high-pressure fractionates from a primordial magma ocean. By contrast, the long-lived Sm-Nd and Lu-Hf isotope systems (ɛ143Nd = +2.4±0.1, ɛ176Hf = +5.7±0.3) indicate that the mantle domain that the SGR komatiites were ultimately derived from underwent additional processing after the early Hadean, including melt depletion at lower pressures. The preservation of early-formed 182W and 142Nd anomalies in the mantle until at least 3.55 Ga indicates that the products of early planetary differentiation survived both later planetary accretion and convective mantle mixing during the Hadean. This study lends further support to the notion that variable late accretion, by itself, cannot account for all of the observed W isotope and absolute and relative HSE abundance variations in the Archean mantle recorded by

[SOX2 defect and anophthalmia and microphthalmia].

PubMed

Ye, Fu-xiang; Fan, Xian-qun

2012-11-01

As a severe congenital developmental disorder, anophthalmia and microphthalmia are usually accompanied with vision impairment and hypoevolutism of the orbit in the affected side. Many genes are involved in anophthalmia and microphthalmia, in which, SOX2 is an important one. The defect of SOX2 causes multiple system disorders, including anophthalmia and microphthalmia. We describe the relationship between the SOX2 defect and anophthalmia/microphthalmia, in order to offer some proposals for the differential diagnosis, treatment and research of anophthalmia and microphthalmia.

Embryonic Ethanol Exposure Dysregulates BMP and Notch Signaling, Leading to Persistent Atrio-Ventricular Valve Defects in Zebrafish

PubMed Central

Sarmah, Swapnalee; Muralidharan, Pooja

2016-01-01

Fetal alcohol spectrum disorder (FASD), birth defects associated with ethanol exposure in utero, includes a wide spectrum of congenital heart defects (CHDs), the most prevalent of which are septal and conotruncal defects. Zebrafish FASD model was used to dissect the mechanisms underlying FASD-associated CHDs. Embryonic ethanol exposure (3–24 hours post fertilization) led to defects in atrio-ventricular (AV) valvulogenesis beginning around 37 hpf, a morphogenetic event that arises long after ethanol withdrawal. Valve leaflets of the control embryos comprised two layers of cells confined at the compact atrio-ventricular canal (AVC). Ethanol treated embryos had extended AVC and valve forming cells were found either as rows of cells spanning the AVC or as unorganized clusters near the AV boundary. Ethanol exposure reduced valve precursors at the AVC, but some ventricular cells in ethanol treated embryos exhibited few characteristics of valve precursors. Late staged larvae and juvenile fish exposed to ethanol during embryonic development had faulty AV valves. Examination of AVC morphogenesis regulatory networks revealed that early ethanol exposure disrupted the Bmp signaling gradient in the heart during valve formation. Bmp signaling was prominent at the AVC in controls, but ethanol-exposed embryos displayed active Bmp signaling throughout the ventricle. Ethanol exposure also led to mislocalization of Notch signaling cells in endocardium during AV valve formation. Normally, highly active Notch signaling cells were organized at the AVC. In ethanol-exposed embryos, highly active Notch signaling cells were dispersed throughout the ventricle. At later stages, ethanol-exposed embryos exhibited reduced Wnt/β-catenin activity at the AVC. We conclude that early embryonic ethanol exposure alters Bmp, Notch and other signaling activities during AVC differentiation leading to faulty valve morphogenesis and valve defects persist in juvenile fish. PMID:27556898

Embryonic Ethanol Exposure Dysregulates BMP and Notch Signaling, Leading to Persistent Atrio-Ventricular Valve Defects in Zebrafish.

PubMed

Sarmah, Swapnalee; Muralidharan, Pooja; Marrs, James A

2016-01-01

Fetal alcohol spectrum disorder (FASD), birth defects associated with ethanol exposure in utero, includes a wide spectrum of congenital heart defects (CHDs), the most prevalent of which are septal and conotruncal defects. Zebrafish FASD model was used to dissect the mechanisms underlying FASD-associated CHDs. Embryonic ethanol exposure (3-24 hours post fertilization) led to defects in atrio-ventricular (AV) valvulogenesis beginning around 37 hpf, a morphogenetic event that arises long after ethanol withdrawal. Valve leaflets of the control embryos comprised two layers of cells confined at the compact atrio-ventricular canal (AVC). Ethanol treated embryos had extended AVC and valve forming cells were found either as rows of cells spanning the AVC or as unorganized clusters near the AV boundary. Ethanol exposure reduced valve precursors at the AVC, but some ventricular cells in ethanol treated embryos exhibited few characteristics of valve precursors. Late staged larvae and juvenile fish exposed to ethanol during embryonic development had faulty AV valves. Examination of AVC morphogenesis regulatory networks revealed that early ethanol exposure disrupted the Bmp signaling gradient in the heart during valve formation. Bmp signaling was prominent at the AVC in controls, but ethanol-exposed embryos displayed active Bmp signaling throughout the ventricle. Ethanol exposure also led to mislocalization of Notch signaling cells in endocardium during AV valve formation. Normally, highly active Notch signaling cells were organized at the AVC. In ethanol-exposed embryos, highly active Notch signaling cells were dispersed throughout the ventricle. At later stages, ethanol-exposed embryos exhibited reduced Wnt/β-catenin activity at the AVC. We conclude that early embryonic ethanol exposure alters Bmp, Notch and other signaling activities during AVC differentiation leading to faulty valve morphogenesis and valve defects persist in juvenile fish.

Metabolic Differentiation of Early Lyme Disease from Southern Tick-Associated Rash Illness (STARI)

PubMed Central

Molins, C. R.; Ashton, L. V.; Wormser, G. P.; Andre, B. G.; Hess, A. M.; Delorey, M. J.; Pilgard, M. A.; Johnson, B. J.; Webb, K.; Islam, M. N.; Pegalajar-Jurado, A; Molla, I.; Jewett, M. W.; Belisle, J. T.

2017-01-01

Lyme disease, the most commonly reported vector-borne disease in the United States, results from infection with Borrelia burgdorferi. Early clinical diagnosis of this disease is largely based on the presence of an erythematous skin lesion for individuals in high-risk regions. This, however, can be confused with other illnesses including southern tick-associated rash illness (STARI), an illness that lacks a defined etiological agent or laboratory diagnostic test, and is co-prevalent with Lyme disease in portions of the Eastern United States. By applying an unbiased metabolomics approach with sera retrospectively obtained from well-characterized patients we defined biochemical and diagnostic differences between early Lyme disease and STARI. Specifically, a metabolic biosignature consisting of 261 molecular features (MFs) revealed that altered N-acyl ethanolamine and primary fatty acid amide metabolism discriminated early Lyme disease from STARI. More importantly, development of classification models with the 261 MF biosignature and testing against validation samples differentiated early Lyme disease from STARI with an accuracy of 85 to 98%. These findings revealed metabolic dissimilarity between early Lyme disease and STARI, and provide a powerful and new approach to objectively distinguish early Lyme disease from an illness with nearly identical symptoms. PMID:28814545

A new color vision test to differentiate congenital and acquired color vision defects.

PubMed

Shin, Young Joo; Park, Kyu Hyung; Hwang, Jeong-Min; Wee, Won Ryang; Lee, Jin Hak

2007-07-01

To investigate the efficacy of a novel computer-controlled color test for the differentiation of congenital and acquired color vision deficiency. Observational cross-sectional study. Thirty-one patients with congenital color vision deficiency and 134 patients with acquired color vision deficiency with a Snellen visual acuity better than 20/30 underwent an ophthalmologic examination including the Ishihara color test, Hardy-Rand-Rittler test, Nagel anomaloscopy, and the Seohan computerized hue test between June, 2003, and January, 2004. To investigate the type of color vision defect, a graph of the Seohan computerized hue test was divided into 4 quadrants and error scores in each quadrant were summated. The ratio between the sums of error scores of quadrants I and III (Q1+Q3) and those of quadrants II and IV (Q2+Q4) was calculated. Error scores and ratio in quadrant analysis of the Seohan computerized hue test. The Seohan computerized hue test showed that the sum of Q2+Q4 was significantly higher than the sum of Q1+Q3 in congenital color vision deficiency (P<0.01, paired t test) and that the sum of Q2+Q4 was significantly lower than the sum of Q1+Q3 in acquired color vision deficiency (P<0.01, paired t test). In terms of discriminating congenital and acquired color vision deficiency, the ratio in quadrant analysis had 93.3% sensitivity and 98.5% specificity with a reference value of 1.5 by the Seohan computerized hue test (95% confidence interval). The quadrant analysis and ratio of (Q2+Q4)/(Q1+Q3) using the Seohan computerized hue test effectively differentiated congenital and acquired color vision deficiency.

Sex Differential Item Functioning in the Inventory of Early Development III Social-Emotional Skills

ERIC Educational Resources Information Center

Beaver, Jessica L.; French, Brian F.; Finch, W. Holmes; Ullrich-French, Sarah C.

2014-01-01

Social-emotional (SE) skills in the early developmental years of children influence outcomes in psychological, behavioral, and learning domains. The adult ratings of a child's SE skills can be influenced by sex stereotypes. These rating differences could lead to differential conclusions about developmental progress or risk. To ensure that…

Proteomic approach to characterize biochemistry of meat quality defects.

PubMed

Schilling, M W; Suman, S P; Zhang, X; Nair, M N; Desai, M A; Cai, K; Ciaramella, M A; Allen, P J

2017-10-01

Proteomics can be used to characterize quality defects including pale, soft, and exudative (PSE) meat (pork and poultry), woody broiler breast meat, reddish catfish fillets, meat toughness, and beef myoglobin oxidation. PSE broiler meat was characterized by 15 proteins that differed in abundance in comparison to normal broiler breast meat, and eight proteins were differentially expressed in woody breast meat in comparison to normal breast meat. Hemoglobin was the only protein that was differentially expressed between red and normal catfish fillets. However, inducing low oxygen and/or heat stress conditions to catfish fillets did not lead to the production of red fillets. Proteomic data provided information pertaining to the protein differences that exist in meat quality defects. However, these data need to be evaluated in conjunction with information pertaining to genetics, nutrition, environment of the live animal, muscle to meat conversion, meat quality analyses and sensory attributes to understand causality, protein biomarkers, and ultimately how to prevent quality defects. Copyright © 2017 Elsevier Ltd. All rights reserved.

Early-life sexual segregation: ontogeny of isotopic niche differentiation in the Antarctic fur seal

NASA Astrophysics Data System (ADS)

Kernaléguen, L.; Arnould, J. P. Y.; Guinet, C.; Cazelles, B.; Richard, P.; Cherel, Y.

2016-09-01

Investigating the ontogeny of niche differentiation enables to determine at which life-stages sexual segregation arises, providing insights into the main factors driving resource partitioning. We investigated the ontogeny of foraging ecology in Antarctic fur seals (Arctocephalus gazella), a highly dimorphic species with contrasting breeding strategies between sexes. Sequential δ13C and δ15N values of whiskers provided a longitudinal proxy of the foraging niche throughout the whole life of seals, from weaning, when size dimorphism is minimal to the age of 5. Females exhibited an early-life ontogenetic shift, from a total segregation during their first year at-sea, to a similar isotopic niche as breeding females as early as age 2. In contrast, males showed a progressive change in isotopic niche throughout their development such that 5-year-old males did not share the same niche as territorial bulls. Interestingly, males and females segregated straight after weaning with males appearing to feed in more southerly habitats than females. This spatial segregation was of similar amplitude as observed in breeding adults and was maintained throughout development. Such early-life niche differentiation is an unusual pattern and indicates size dimorphism and breeding constraints do not directly drive sexual segregation contrary to what has been assumed in otariid seals.

Near-infrared imaging of developmental defects in dental enamel.

PubMed

Hirasuna, Krista; Fried, Daniel; Darling, Cynthia L

2008-01-01

Polarization-sensitive optical coherence tomography (PS-OCT) and near-infrared (NIR) imaging are promising new technologies under development for monitoring early carious lesions. Fluorosis is a growing problem in the United States, and the more prevalent mild fluorosis can be visually mistaken for early enamel demineralization. Unfortunately, there is little quantitative information available regarding the differences in optical properties of sound enamel, enamel developmental defects, and caries. Thirty extracted human teeth with various degrees of suspected fluorosis were imaged using PS-OCT and NIR. An InGaAs camera and a NIR diode laser were used to measure the optical attenuation through transverse tooth sections (approximately 200 microm). A digital microradiography system was used to quantify the enamel defect severity by measurement of the relative mineral loss for comparison with optical scattering measurements. Developmental defects were clearly visible in the polarization-resolved OCT images, demonstrating that PS-OCT can be used to nondestructively measure the depth and possible severity of the defects. Enamel defects on whole teeth that could be imaged with high contrast with visible light were transparent in the NIR. This study suggests that PS-OCT and NIR methods may potentially be used as tools to assess the severity and extent of enamel defects.

A preliminary study comparing the use of allogenic chondrogenic pre-differentiated and undifferentiated mesenchymal stem cells for the repair of full thickness articular cartilage defects in rabbits.

PubMed

Dashtdar, Havva; Rothan, Hussin A; Tay, Terence; Ahmad, Raja Elina; Ali, Razif; Tay, Liang Xin; Chong, Pan Pan; Kamarul, Tunku

2011-09-01

Chondrogenic differentiated mesenchymal stem cells (CMSCs) have been shown to produce superior chondrogenic expression markers in vitro. However, the use of these cells in vivo has not been fully explored. In this study, in vivo assessment of cartilage repair potential between allogenic-derived chondrogenic pre-differentiated mesenchymal stem cells and undifferentiated MSCs (MSCs) were compared. Bilateral full thickness cartilage defects were created on the medial femoral condyles of 12 rabbits (n = 12). Rabbits were divided into two groups. In one group, the defects in the right knees were repaired using alginate encapsulated MSCs while in the second group, CMSCs were used. The animals were sacrificed and the repaired and control knees were assessed at 3 and 6 months after implantation. Quantitative analysis was performed by measuring the Glycosaminoglycans (GAGs)/total protein content. The mean Brittberg score was higher in the transplanted knees as compared to the untreated knee at 6 months (p < 0.05). Quantitative analysis of GAGs was consistent with these results. Histological and immunohistochemical analysis demonstrated hyaline-like cartilage regeneration in the transplanted sites. Significant differences between the histological scores based on O'Driscoll histological grading were observed between contralateral knees at both 3 and 6 months (p < 0.05). No significant differences were observed between the Britberg, O'Driscoll scores, and GAGs/total protein content when comparing defect sites treated with MSC and CMSC (p > 0.05). This study demonstrates that the use of either MSC or CMSC produced superior healing when compared to cartilage defects that were untreated. However, both cells produced comparable treatment outcomes. Copyright © 2011 Orthopaedic Research Society.

21 CFR 101.79 - Health claims: Folate and neural tube defects.

Code of Federal Regulations, 2013 CFR

2013-04-01

... result in infant mortality or serious disability. The birth defects anencephaly and spina bifida are the... development. Because the neural tube forms and closes during early pregnancy, the defect may occur before a... pregnancy had a reduced risk of having a child with a neural tube defect. (Products containing this level of...

21 CFR 101.79 - Health claims: Folate and neural tube defects.

Code of Federal Regulations, 2014 CFR

2014-04-01

... result in infant mortality or serious disability. The birth defects anencephaly and spina bifida are the... development. Because the neural tube forms and closes during early pregnancy, the defect may occur before a... pregnancy had a reduced risk of having a child with a neural tube defect. (Products containing this level of...

21 CFR 101.79 - Health claims: Folate and neural tube defects.

Code of Federal Regulations, 2012 CFR

2012-04-01

... result in infant mortality or serious disability. The birth defects anencephaly and spina bifida are the... development. Because the neural tube forms and closes during early pregnancy, the defect may occur before a... pregnancy had a reduced risk of having a child with a neural tube defect. (Products containing this level of...

The underlying process of early ecological and genetic differentiation in a facultative mutualistic Sinorhizobium meliloti population.

PubMed

Toro, Nicolás; Villadas, Pablo J; Molina-Sánchez, María Dolores; Navarro-Gómez, Pilar; Vinardell, José M; Cuesta-Berrio, Lidia; Rodríguez-Carvajal, Miguel A

2017-04-06

The question of how genotypic and ecological units arise and spread in natural microbial populations remains controversial in the field of evolutionary biology. Here, we investigated the early stages of ecological and genetic differentiation in a highly clonal sympatric Sinorhizobium meliloti population. Whole-genome sequencing revealed that a large DNA region of the symbiotic plasmid pSymB was replaced in some isolates with a similar synteny block carrying densely clustered SNPs and displaying gene acquisition and loss. Two different versions of this genomic island of differentiation (GID) generated by multiple genetic exchanges over time appear to have arisen recently, through recombination in a particular clade within this population. In addition, these isolates display resistance to phages from the same geographic region, probably due to the modification of surface components by the acquired genes. Our results suggest that an underlying process of early ecological and genetic differentiation in S. meliloti is primarily triggered by acquisition of genes that confer resistance to soil phages within particular large genomic DNA regions prone to recombination.

The value of cyclooxygenase-2 expression in differentiating between early melanomas and histopathologically difficult types of benign human skin lesions.

PubMed

Kuźbicki, Łukasz; Lange, Dariusz; Strączyńska-Niemiec, Anita; Chwirot, Barbara W

2012-02-01

Early cutaneous melanomas may present a substantial diagnostic challenge. We have already reported that expression of cyclooxygenase-2 (COX-2) may be useful for differentiating between cutaneous melanomas and naevi. The purpose of this study was to examine the value of COX-2 in a challenging task of differential diagnosis of early melanomas and melanocytic naevi considered by histopathologists as morphologically difficult to unequivocally diagnose as benign lesions. The material for the study comprised formalin-fixed paraffin-embedded samples of 46 naevi (including 27 cases of dysplastic, Spitz and Reed naevi) and 30 early human cutaneous melanomas. The expression of COX-2 was detected immunohistochemically. Melanomas expressed COX-2 significantly more strongly compared with naevi. The test, on the basis of determination of the percentage fractions of COX-2-positive cells, allows for differentiation of early skin melanomas and naevi with high sensitivity and specificity. Receiver operating characteristic analysis of the test results yielded areas under receiver operating characteristics curves (AUC)=0.946±0.030 for central regions and AUC=0.941±0.031 for the peripheries of the lesions. The performance of the test in differentiating between melanomas and the naevi group comprising dysplastic, Spitz and Reed naevi was also good, with AUC=0.933±0.034 and 0.923±0.037 for the central and the border regions of the lesions, respectively. Using a more complex diagnostic algorithm also accounting for the staining intensity did not result in an improvement in the resolving power of the assay. A diagnostic algorithm using differences in the percentage fractions of cells expressing COX-2 may serve as a useful tool in aiding the differential diagnosis of 'histopathologically difficult' benign melanocytic skin lesions and early melanomas.

In vitro expansion impaired the stemness of early passage mesenchymal stem cells for treatment of cartilage defects

PubMed Central

Jiang, Tongmeng; Xu, Guojie; Wang, Qiuyan; Yang, Lihui; Zheng, Li; Zhao, Jinmin; Zhang, Xingdong

2017-01-01

In vitro cultured autologous mesenchymal stem cells (MSCs) within passage 5 have been approved for clinical application in stem cell-based treatment of cartilage defects. However, their chondrogenic potential has not yet been questioned or verified. In this study, the chondrogenic potential of bone marrow MSCs at passage 3 (P3 BMSCs) was investigated both in cartilage repair and in vitro, with freshly isolated bone marrow mononuclear cells (BMMNCs) as controls. The results showed that P3 BMSCs were inferior to BMMNCs not only in their chondrogenic differentiation ability but also as candidates for long-term repair of cartilage defects. Compared with BMMNCs, P3 BMSCs presented a decay in telomerase activity and a change in chromosomal morphology with potential anomalous karyotypes, indicating senescence. In addition, interindividual variability in P3 BMSCs is much higher than in BMMNCs, demonstrating genomic instability. Interestingly, remarkable downregulation in cell cycle, DNA replication and mismatch repair (MMR) pathways as well as in multiple genes associated with telomerase activity and chromosomal stability were found in P3 BMSCs. This result indicates that telomerase and chromosome anomalies might originate from expansion, leading to impaired stemness and pluripotency of stem cells. In vitro culture and expansion are not recommended for cell-based therapy, and fresh BMMNCs are the first choice. PMID:28569773

Interleukin-6 inhibits early differentiation of ATDC5 chondrogenic progenitor cells.

PubMed

Nakajima, Shoko; Naruto, Takuya; Miyamae, Takako; Imagawa, Tomoyuki; Mori, Masaaki; Nishimaki, Shigeru; Yokota, Shumpei

2009-08-01

Interleukin (IL)-6 is a causative agent of systemic juvenile idiopathic arthritis (sJIA), a chronic inflammatory disease complicated with severe growth impairment. Recent trials of anti-IL-6 receptor monoclonal antibody, tocilizumab, indicated that tocilizumab blocks IL-6/IL-6 receptor-mediated inflammation, and induces catch-up growth in children with sJIA. This study evaluates the effects of IL-6 on chondrogenesis by ATDC5 cells, a clonal murine chondrogenic cell line that provides an excellent model for studying endochondral ossification at growth plate. ATDC5 cells were examined for the expression of IL-6 receptor and gp130 by fluorescence-activated cell sorting analysis. Recombinant murine IL-6 was added to ATDC5 cultures to observe cell differentiation, using a quantitative RT-PCR for the chondrogenic differentiation markers type II collagen, aggrecan, and type X collagen. To block IL-6, the anti-mouse IL-6 receptor monoclonal antibody MR16-1 was added. As a result, the cells expressed IL-6 receptor and gp130. The expression of chondrogenic differentiation marker gene was reduced by IL-6, but this was abrogated by MR16-1. We conclude that IL-6 inhibits early chondrogenesis of ATDC5 cells suggesting that IL-6 may affect committed stem cells at a cellular level during chondrogenic differentiation of growth plate chondrocytes, and that IL-6 may be a cellular-level factor in growth impairment in sJIA.

Tuberin and PRAS40 are anti-apoptotic gatekeepers during early human amniotic fluid stem-cell differentiation.

PubMed

Fuchs, Christiane; Rosner, Margit; Dolznig, Helmut; Mikula, Mario; Kramer, Nina; Hengstschläger, Markus

2012-03-01

Embryoid bodies (EBs) are three-dimensional multicellular aggregates allowing the in vitro investigation of stem-cell differentiation processes mimicking early embryogenesis. Human amniotic fluid stem (AFS) cells harbor high proliferation potential, do not raise the ethical issues of embryonic stem cells, have a lower risk for tumor development, do not need exogenic induction of pluripotency and are chromosomal stable. Starting from a single human AFS cell, EBs can be formed accompanied by the differentiation into cells of all three embryonic germ layers. Here, we report that siRNA-mediated knockdown of the endogenous tuberous sclerosis complex-2 (TSC2) gene product tuberin or of proline-rich Akt substrate of 40 kDa (PRAS40), the two major negative regulators of mammalian target of rapamycin (mTOR), leads to massive apoptotic cell death during EB development of human AFS cells without affecting the endodermal, mesodermal and ectodermal cell differentiation spectrum. Co-knockdown of endogenous mTOR demonstrated these effects to be mTOR-dependent. Our findings prove this enzyme cascade to be an essential anti-apoptotic gatekeeper of stem-cell differentiation during EB formation. These data allow new insights into the regulation of early stem-cell maintenance and differentiation and identify a new role of the tumor suppressor tuberin and the oncogenic protein PRAS40 with the relevance for a more detailed understanding of the pathogenesis of diseases associated with altered activities of these gene products.

Nell-1-Induced Bone Regeneration in Calvarial Defects

PubMed Central

Aghaloo, Tara; Cowan, Catherine M.; Chou, Yu-Fen; Zhang, Xinli; Lee, Haofu; Miao, Steve; Hong, Nichole; Kuroda, Shun’ichi; Wu, Benjamin; Ting, Kang; Soo, Chia

2006-01-01

Many craniofacial birth defects contain skeletal components requiring bone grafting. We previously identified the novel secreted osteogenic molecule NELL-1, first noted to be overexpressed during premature bone formation in calvarial sutures of craniosynostosis patients. Nell-1 overexpression significantly increases differentiation and mineralization selectively in osteoblasts, while newborn Nell-1 transgenic mice significantly increase premature bone formation in calvarial sutures. In the current study, cultured calvarial explants isolated from Nell-1 transgenic newborn mice (with mild sagittal synostosis) demonstrated continuous bone growth and overlapping sagittal sutures. Further investigation into gene expression cascades revealed that fibroblast growth factor-2 and transforming growth factor-β1 stimulated Nell-1 expression, whereas bone morphogenetic protein (BMP)-2 had no direct effect. Additionally, Nell-1-induced osteogenesis in MC3T3-E1 osteoblasts through reduction in the expression of early up-regulated osteogenic regulators (OSX and ALP) but induction of later markers (OPN and OCN). Grafting Nell-1 protein-coated PLGA scaffolds into rat calvarial defects revealed the osteogenic potential of Nell-1 to induce bone regeneration equivalent to BMP-2, whereas immunohistochemistry indicated that Nell-1 reduced osterix-producing cells and increased bone sialoprotein, osteocalcin, and BMP-7 expression. Insights into Nell-1-regulated osteogenesis coupled with its ability to stimulate bone regeneration revealed a potential therapeutic role and an alternative to the currently accepted techniques for bone regeneration. PMID:16936265

Usefulness of Demarcation of Differentiated-Type Early Gastric Cancers after Helicobacter pylori Eradication by Magnifying Endoscopy with Narrow-Band Imaging.

PubMed

Akazawa, Yoichi; Ueyama, Hiroya; Yao, Takashi; Komori, Hiroyuki; Takeda, Tsutomu; Matsumoto, Kohei; Matsumoto, Kenshi; Asaoka, Daisuke; Hojo, Mariko; Watanabe, Sumio; Nagahara, Akihito

2018-06-05

Early gastric cancer after Helicobacter pylori (Hp) eradication is difficult to demarcate. We used the vessel plus surface classification system (VSCS) to determine whether magnifying endoscopy with narrow-band imaging (ME-NBI) could demarcate differentiated-type early gastric cancers after Hp eradication, and to identify causes of an unclear demarcation line (DL). Among 100 lesions of differentiated-type early gastric cancer resected endoscopically, 34 lesions in the Hp-eradicated group and 66 in the Hp-infected group were retrospectively compared. Clinicopathological factors and ME-NBI findings, including the presence or absence of the DL, were examined. Histopathologically, histological gastritis, the surface structure at the tumor border, well-differentiated adenocarcinoma with low-grade atypia (tub1-low), and non-neoplastic epithelium (NE) coverage rate on the tumor surface and at the tumor border were evaluated. DL (-) cases were more frequent in the Hp-eradicated group (11.8%, 4/34) than in the Hp-infected group (1.5%, 1/66; p < 0.05). The Hp-eradicated group had a higher NE coverage rate than the Hp-infected group (p < 0.05). All DL (-) cases had tub1-low or NE at the tumor border. ME-NBI with VSCS can identify the DL in most patients (88.2%) with differentiated-type early gastric cancer after Hp eradication. © 2018 S. Karger AG, Basel.

Negative differential resistance and effect of defects and deformations in MoS{sub 2} armchair nanoribbon metal-oxide-semiconductor field effect transistor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sengupta, Amretashis, E-mail: amretashis@dese.iisc.ernet.in; Mahapatra, Santanu

In this work, we present a study on the negative differential resistance (NDR) behavior and the impact of various deformations (like ripple, twist, wrap) and defects like vacancies and edge roughness on the electronic properties of short-channel MoS{sub 2} armchair nanoribbon MOSFETs. The effect of deformation (3°–7° twist or wrap and 0.3–0.7 Å ripple amplitude) and defects on a 10 nm MoS2 ANR FET is evaluated by the density functional tight binding theory and the non-equilibrium Green's function approach. We study the channel density of states, transmission spectra, and the I{sub D}–V{sub D} characteristics of such devices under the varying conditions, withmore » focus on the NDR behavior. Our results show significant change in the NDR peak to valley ratio and the NDR window with such minor intrinsic deformations, especially with the ripple.« less

Chronology of Planetesimal Differentiation Based on the Timing of Achondrite Formation in the Early Solar System

NASA Astrophysics Data System (ADS)

Dunlap, D. R.; Wadhwa, M.

2018-05-01

Chronology of achondrites provide critical insights into accretion and differentiation timescales in the early solar system. A diverse suite of achondrites are presented here to constrain the thermal histories of a number of distinct planetesimals.

Early endocrine disruptors exposure acts on 3T3-L1 differentiation and endocrine activity

PubMed Central

Boudalia, Sofiane; Belloir, Christine; Miller, Marie-Louise; Canivenc-Lavier, Marie-Chantal

2017-01-01

Introduction: Data from last years suggested that early exposure to endocrine disruptors (EDs) can predispose newborns to endocrine dysfunction of adipocytes, obesity, and associated disorders. The implication of EDs at low doses on adipocyte development has been poorly investigated. For instance, vinclozolin (V) is a dicarboximide fungicide widely used in agriculture since the 90's, alone or in mixture with genistein (G), an isoflavonoid from Leguminosae. This study aims to identify the effect of vinclozolin alone or with genistein, on adipose tissue properties using cell culture. Methods: In steroid-free conditions, 3T3-L1 pre-adipocytes were induced to differentiate in the presence of EDs, singularly or in mixtures, for 2 days. DNA and triglyceride (TG) levels were measured on days 0, 2 and 8 of differentiation. Leptin secretion was measured only on the eighth day. Results: We show that low doses of G (25 µM) and V (0.1 µM) inhibit pre-adipocytes differentiation. This inhibition has been represented by a decreasing in DNA content (µg/well) and decreasing in TG accumulation (mg/mL) in 3T3-L1 cells. Nevertheless, V increased the anti-adipogenic properties of G. Conclusion: This study confirms that EDs singularly or in mixtures, introduced during early stages of life, could affect the differentiation and the endocrine activity of adipocytes, and can act as potential factors for obesity. PMID:28752072

ILT based defect simulation of inspection images accurately predicts mask defect printability on wafer

NASA Astrophysics Data System (ADS)

Deep, Prakash; Paninjath, Sankaranarayanan; Pereira, Mark; Buck, Peter

2016-05-01

At advanced technology nodes mask complexity has been increased because of large-scale use of resolution enhancement technologies (RET) which includes Optical Proximity Correction (OPC), Inverse Lithography Technology (ILT) and Source Mask Optimization (SMO). The number of defects detected during inspection of such mask increased drastically and differentiation of critical and non-critical defects are more challenging, complex and time consuming. Because of significant defectivity of EUVL masks and non-availability of actinic inspection, it is important and also challenging to predict the criticality of defects for printability on wafer. This is one of the significant barriers for the adoption of EUVL for semiconductor manufacturing. Techniques to decide criticality of defects from images captured using non actinic inspection images is desired till actinic inspection is not available. High resolution inspection of photomask images detects many defects which are used for process and mask qualification. Repairing all defects is not practical and probably not required, however it's imperative to know which defects are severe enough to impact wafer before repair. Additionally, wafer printability check is always desired after repairing a defect. AIMSTM review is the industry standard for this, however doing AIMSTM review for all defects is expensive and very time consuming. Fast, accurate and an economical mechanism is desired which can predict defect printability on wafer accurately and quickly from images captured using high resolution inspection machine. Predicting defect printability from such images is challenging due to the fact that the high resolution images do not correlate with actual mask contours. The challenge is increased due to use of different optical condition during inspection other than actual scanner condition, and defects found in such images do not have correlation with actual impact on wafer. Our automated defect simulation tool predicts

Identification of MS4A3 as a reliable marker for early myeloid differentiation in human hematopoiesis.

PubMed

Ishibashi, Tomohiko; Yokota, Takafumi; Satoh, Yusuke; Ichii, Michiko; Sudo, Takao; Doi, Yukiko; Ueda, Tomoaki; Nagate, Yasuhiro; Hamanaka, Yuri; Tanimura, Akira; Ezoe, Sachiko; Shibayama, Hirohiko; Oritani, Kenji; Kanakura, Yuzuru

2018-01-15

Information of myeloid lineage-related antigen on hematopoietic stem/progenitor cells (HSPCs) is important to clarify the mechanisms regulating hematopoiesis, as well as for the diagnosis and treatment of myeloid malignancies. We previously reported that special AT-rich sequence binding protein 1 (SATB1), a global chromatin organizer, promotes lymphoid differentiation from HSPCs. To search a novel cell surface molecule discriminating early myeloid and lymphoid differentiation, we performed microarray analyses comparing SATB1-overexpressed HSPCs with mock-transduced HSPCs. The results drew our attention to membrane-spanning 4-domains, subfamily A, member 3 (Ms4a3) as the most downregulated molecule in HSPCs with forced overexpression of SATB1. Ms4a3 expression was undetectable in hematopoietic stem cells, but showed a concomitant increase with progressive myeloid differentiation, whereas not only lymphoid but also megakaryocytic-erythrocytic progenitors were entirely devoid of Ms4a3 expression. Further analysis revealed that a subset of CD34 + CD38 + CD33 + progenitor population in human adult bone marrow expressed MS4A3, and those MS4A3 + progenitors only produced granulocyte/macrophage colonies, losing erythroid colony- and mixed colony-forming capacity. These results suggest that cell surface expression of MS4A3 is useful to distinguish granulocyte/macrophage lineage-committed progenitors from other lineage-related ones in early human hematopoiesis. In conclusion, MS4A3 is useful to monitor early stage of myeloid differentiation in human hematopoiesis. Copyright © 2017 Elsevier Inc. All rights reserved.

Proteomic Analysis Profile of Engineered Articular Cartilage with Chondrogenic Differentiated Adipose Tissue-Derived Stem Cells Loaded Polyglycolic Acid Mesh for Weight-Bearing Area Defect Repair

PubMed Central

Gong, Lunli; Zhou, Xiao; Wu, Yaohao; Zhang, Yun; Wang, Chen; Zhou, Heng; Guo, Fangfang

2014-01-01

The present study was designed to investigate the possibility of full-thickness defects repair in porcine articular cartilage (AC) weight-bearing area using chondrogenic differentiated autologous adipose-derived stem cells (ASCs) with a follow-up of 3 and 6 months, which is successive to our previous study on nonweight-bearing area. The isolated ASCs were seeded onto the phosphoglycerate/polylactic acid (PGA/PLA) with chondrogenic induction in vitro for 2 weeks as the experimental group prior to implantation in porcine AC defects (8 mm in diameter, deep to subchondral bone), with PGA/PLA only as control. With follow-up time being 3 and 6 months, both neo-cartilages of postimplantation integrated well with the neighboring normal cartilage and subchondral bone histologically in experimental group, whereas only fibrous tissue in control group. Immunohistochemical and toluidine blue staining confirmed similar distribution of COL II and glycosaminoglycan in the regenerated cartilage to the native one. A vivid remolding process with repair time was also witnessed in the neo-cartilage as the compressive modulus significantly increased from 70% of the normal cartilage at 3 months to nearly 90% at 6 months, which is similar to our former research. Nevertheless, differences of the regenerated cartilages still could be detected from the native one. Meanwhile, the exact mechanism involved in chondrogenic differentiation from ASCs seeded on PGA/PLA is still unknown. Therefore, proteome is resorted leading to 43 proteins differentially identified from 20 chosen two-dimensional spots, which do help us further our research on some committed factors. In conclusion, the comparison via proteome provided a thorough understanding of mechanisms implicating ASC differentiation toward chondrocytes, which is further substantiated by the present study as a perfect supplement to the former one in nonweight-bearing area. PMID:24044689

Spin-on bottom antireflective coating defect reduction by proper filter selection and process optimization

NASA Astrophysics Data System (ADS)

Brakensiek, Nickolas L.; Kidd, Brian; Mesawich, Michael; Stevens, Don, Jr.; Gotlinsky, Barry

2003-06-01

A design of experiment (DOE) was implemented to show the effects of various point of use filters on the coat process. The DOE takes into account the filter media, pore size, and pumping means, such as dispense pressure, time, and spin speed. The coating was executed on a TEL Mark 8 coat track, with an IDI M450 pump, and PALL 16 stack Falcon filters. A KLA 2112 set at 0.69 μm pixel size was used to scan the wafers to detect and identify the defects. The process found for DUV42P to maintain a low defect coating irrespective of the filter or pore size is a high start pressure, low end pressure, low dispense time, and high dispense speed. The IDI M450 pump has the capability to compensate for bubble type defects by venting the defects out of the filter before the defects are in the dispense line and the variable dispense rate allows the material in the dispense line to slow down at the end of dispense and not create microbubbles in the dispense line or tip. Also the differential pressure sensor will alarm if the pressure differential across the filter increases over a user-determined setpoint. The pleat design allows more surface area in the same footprint to reduce the differential pressure across the filter and transport defects to the vent tube. The correct low defect coating process will maximize the advantage of reducing filter pore size or changing the filter media.

UTX regulates mesoderm differentiation of embryonic stem cells independent of H3K27 demethylase activity.

PubMed

Wang, Chaochen; Lee, Ji-Eun; Cho, Young-Wook; Xiao, Ying; Jin, Qihuang; Liu, Chengyu; Ge, Kai

2012-09-18

To investigate the role of histone H3K27 demethylase UTX in embryonic stem (ES) cell differentiation, we have generated UTX knockout (KO) and enzyme-dead knock-in male ES cells. Deletion of the X-chromosome-encoded UTX gene in male ES cells markedly decreases expression of the paralogous UTY gene encoded by Y chromosome, but has no effect on global H3K27me3 level, Hox gene expression, or ES cell self-renewal. However, UTX KO cells show severe defects in mesoderm differentiation and induction of Brachyury, a transcription factor essential for mesoderm development. Surprisingly, UTX regulates mesoderm differentiation and Brachyury expression independent of its enzymatic activity. UTY, which lacks detectable demethylase activity, compensates for the loss of UTX in regulating Brachyury expression. UTX and UTY bind directly to Brachyury promoter and are required for Wnt/β-catenin signaling-induced Brachyury expression in ES cells. Interestingly, male UTX KO embryos express normal levels of UTY and survive until birth. In contrast, female UTX KO mice, which lack the UTY gene, show embryonic lethality before embryonic day 11.5. Female UTX KO embryos show severe defects in both Brachyury expression and embryonic development of mesoderm-derived posterior notochord, cardiac, and hematopoietic tissues. These results indicate that UTX controls mesoderm differentiation and Brachyury expression independent of H3K27 demethylase activity, and suggest that UTX and UTY are functionally redundant in ES cell differentiation and early embryonic development.

Lanthony 15-Hue Desaturated Test for screening of early color vision defects in uncomplicated juvenile diabetes.

PubMed

Giusti, C

2001-01-01

To identify the most appropriate test for screening of early color vision abnormalities in uncomplicated juvenile diabetes. Enrolled in this study were 39 diabetic adolescents, characterized by optimal Early Treatment Diabetic Retinopathy Study criteria for visual acuity, transparent dioptric means and angiographically normal retinas. Color vision was examined with Standard Pseudoisochromatic Plates (Part 2, SPP2), Roth 28-Hue Test (R28), Farnsworth-Munsell 100-Hue Tests (FM100), and Lanthony 15-Hue Desaturated Test (L15). Color confusion score (CCS) and desaturation angle (DSAT) were measured on L15 only. Thirty-nine normal subjects served as a control group. Poor metabolic control was an exclusion criteria. CCS was significantly higher in the patients than in the controls (37.8 +/- 11.1 vs 0 +/- P < .001) and normal scores were found in only 4 diabetic patients. DSAT values were spread, not showing a well-defined axis of the defect. The results of FM100 were clinically reliable but affected by a longer execution time. R28 and SPP2 demonstrated a low sensitivity, as all patients scored normally with both tests. Impaired color vision is a common observation even in patients with uncomplicated juvenile diabetes. Our results indicate that L15 is the most suitable test for screening of early color vision abnormalities in these subjects.

Prolyl Isomerase Pin1 Regulates Neuronal Differentiation via β-Catenin

PubMed Central

Nakamura, Kazuhiro; Kosugi, Isao; Lee, Daniel Y.; Hafner, Angela; Sinclair, David A.

2012-01-01

The Wnt/β-catenin pathway promotes proliferation of neural progenitor cells (NPCs) at early stages and induces neuronal differentiation from NPCs at late stages, but the molecular mechanisms that control this stage-specific response are unclear. Pin1 is a prolyl isomerase that regulates cell signaling uniquely by controlling protein conformation after phosphorylation, but its role in neuronal differentiation is not known. Here we found that whereas Pin1 depletion suppresses neuronal differentiation, Pin1 overexpression enhances it, without any effects on gliogenesis from NPCs in vitro. Consequently, Pin1-null mice have significantly fewer upper layer neurons in the motor cortex and severely impaired motor activity during the neonatal stage. A proteomic approach identified β-catenin as a major substrate for Pin1 in NPCs, in which Pin1 stabilizes β-catenin. As a result, Pin1 knockout leads to reduced β-catenin during differentiation but not proliferation of NPCs in developing brains. Importantly, defective neuronal differentiation in Pin1 knockout NPCs is fully rescued in vitro by overexpression of β-catenin but not a β-catenin mutant that fails to act as a Pin1 substrate. These results show that Pin1 is a novel regulator of NPC differentiation by acting on β-catenin and provides a new postphosphorylation signaling mechanism to regulate developmental stage-specific functioning of β-catenin signaling in neuronal differentiation. PMID:22645310

Long-term Associations of an Early Corrected Ventricular Septal Defect and Stress Systems of Child and Mother at Primary School Age.

PubMed

Stonawski, Valeska; Vollmer, Laura; Köhler-Jonas, Nicola; Rohleder, Nicolas; Golub, Yulia; Purbojo, Ariawan; Moll, Gunther H; Heinrich, Hartmut; Cesnjevar, Robert A; Kratz, Oliver; Eichler, Anna

2017-01-01

Ventricular septal defect (VSD) is the most common congenital heart defect, with larger VSDs typically being corrected with an open-heart surgery during infancy. Long-term consequences of a VSD-corrective surgery on stress systems of child and mother are still unknown. The aim of the present study is to investigate the associations of an early corrected VSD and diurnal cortisol release of child and mother. 26 children (12 boys) between 6 and 9 years old, who underwent surgery for an isolated VSD within the first 3 years of life, and their mothers participated in the study. Their diurnal cortisol profiles were compared to a sex-, age-, and socioeconomic status-matched healthy control group. Within the VSD group, associations between cortisol and characteristics of surgery and hospitalization were investigated. Child and mother psychopathological symptoms were considered as a possible interfering mechanism of altered cortisol profiles. Diurnal cortisol profiles of children with an early corrected VSD did not differ from those of controls. However, mothers of affected children exhibited higher cortisol levels in the morning ( p  < 0.001, [Formula: see text]) and a steeper diurnal cortisol slope ( p  = 0.016, [Formula: see text]) than mothers of healthy children. Results indicate a favorable development of children with an early corrected VSD, in terms of comparable diurnal cortisol profiles with healthy controls, according to a comparable mother-rated psychopathology. Mothers of affected children reveal altered diurnal cortisol levels, without differences in self-rated psychopathology. This divergence should be clarified in future research.

Six1 overexpression at early stages of HPV16-mediated transformation of human keratinocytes promotes differentiation resistance and EMT

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Hanwen; Pirisi, Lucia; Creek, Kim E., E-mail: creekk@sccp.sc.edu

Previous studies in our laboratory discovered that SIX1 mRNA expression increased during in vitro progression of HPV16-immortalized human keratinocytes (HKc/HPV16) toward a differentiation-resistant (HKc/DR) phenotype. In this study, we explored the role of Six1 at early stages of HPV16-mediated transformation by overexpressing Six1 in HKc/HPV16. We found that Six1 overexpression in HKc/HPV16 increased cell proliferation and promoted cell migration and invasion by inducing epithelial–mesenchymal transition (EMT). Moreover, the overexpression of Six1 in HKc/HPV16 resulted in resistance to serum and calcium-induced differentiation, which is the hallmark of the HKc/DR phenotype. Activation of MAPK in HKc/HPV16 overexpressing Six1 is linked to resistancemore » to calcium-induced differentiation. In conclusion, this study determined that Six1 overexpression resulted in differentiation resistance and promoted EMT at early stages of HPV16-mediated transformation of human keratinocytes. - Highlights: • Six1 expression increases during HPV16-mediated transformation. • Six1 overexpression causes differentiation resistance in HPV16-immortalized cells. • Six1 overexpression in HPV16-immortalized keratinocytes activates MAPK. • Activation of MAPK promotes EMT and differentiation resistance. • Six1 overexpression reduces Smad-dependent TGF-β signaling.« less

Early differentiation of the Earth and the Moon.

PubMed

Bourdon, Bernard; Touboul, Mathieu; Caro, Guillaume; Kleine, Thorsten

2008-11-28

We examine the implications of new 182W and 142Nd data for Mars and the Moon for the early evolution of the Earth. The similarity of 182W in the terrestrial and lunar mantles and their apparently differing Hf/W ratios indicate that the Moon-forming giant impact most probably took place more than 60Ma after the formation of calcium-aluminium-rich inclusions (4.568Gyr). This is not inconsistent with the apparent U-Pb age of the Earth. The new 142Nd data for Martian meteorites show that Mars probably has a super-chondritic Sm/Nd that could coincide with that of the Earth and the Moon. If this is interpreted by an early mantle differentiation event, this requires a buried enriched reservoir for the three objects. This is highly unlikely. For the Earth, we show, based on new mass-balance calculations for Nd isotopes, that the presence of a hidden reservoir is difficult to reconcile with the combined 142Nd-143Nd systematics of the Earth's mantle. We argue that a likely possibility is that the missing component was lost during or prior to accretion. Furthermore, the 142Nd data for the Moon that were used to argue for the solidification of the magma ocean at ca 200Myr are reinterpreted. Cumulate overturn, magma mixing and melting following lunar magma ocean crystallization at 50-100Myr could have yielded the 200Myr model age.

Proteomic-based detection of a protein cluster dysregulated during cardiovascular development identifies biomarkers of congenital heart defects.

PubMed

Nath, Anjali K; Krauthammer, Michael; Li, Puyao; Davidov, Eugene; Butler, Lucas C; Copel, Joshua; Katajamaa, Mikko; Oresic, Matej; Buhimschi, Irina; Buhimschi, Catalin; Snyder, Michael; Madri, Joseph A

2009-01-01

Cardiovascular development is vital for embryonic survival and growth. Early gestation embryo loss or malformation has been linked to yolk sac vasculopathy and congenital heart defects (CHDs). However, the molecular pathways that underlie these structural defects in humans remain largely unknown hindering the development of molecular-based diagnostic tools and novel therapies. Murine embryos were exposed to high glucose, a condition known to induce cardiovascular defects in both animal models and humans. We further employed a mass spectrometry-based proteomics approach to identify proteins differentially expressed in embryos with defects from those with normal cardiovascular development. The proteins detected by mass spectrometry (WNT16, ST14, Pcsk1, Jumonji, Morca2a, TRPC5, and others) were validated by Western blotting and immunoflorescent staining of the yolk sac and heart. The proteins within the proteomic dataset clustered to adhesion/migration, differentiation, transport, and insulin signaling pathways. A functional role for several proteins (WNT16, ADAM15 and NOGO-A/B) was demonstrated in an ex vivo model of heart development. Additionally, a successful application of a cluster of protein biomarkers (WNT16, ST14 and Pcsk1) as a prenatal screen for CHDs was confirmed in a study of human amniotic fluid (AF) samples from women carrying normal fetuses and those with CHDs. The novel finding that WNT16, ST14 and Pcsk1 protein levels increase in fetuses with CHDs suggests that these proteins may play a role in the etiology of human CHDs. The information gained through this bed-side to bench translational approach contributes to a more complete understanding of the protein pathways dysregulated during cardiovascular development and provides novel avenues for diagnostic and therapeutic interventions, beneficial to fetuses at risk for CHDs.

Proteomic-Based Detection of a Protein Cluster Dysregulated during Cardiovascular Development Identifies Biomarkers of Congenital Heart Defects

PubMed Central

Nath, Anjali K.; Krauthammer, Michael; Li, Puyao; Davidov, Eugene; Butler, Lucas C.; Copel, Joshua; Katajamaa, Mikko; Oresic, Matej; Buhimschi, Irina; Buhimschi, Catalin; Snyder, Michael; Madri, Joseph A.

2009-01-01

Background Cardiovascular development is vital for embryonic survival and growth. Early gestation embryo loss or malformation has been linked to yolk sac vasculopathy and congenital heart defects (CHDs). However, the molecular pathways that underlie these structural defects in humans remain largely unknown hindering the development of molecular-based diagnostic tools and novel therapies. Methodology/Principal Findings Murine embryos were exposed to high glucose, a condition known to induce cardiovascular defects in both animal models and humans. We further employed a mass spectrometry-based proteomics approach to identify proteins differentially expressed in embryos with defects from those with normal cardiovascular development. The proteins detected by mass spectrometry (WNT16, ST14, Pcsk1, Jumonji, Morca2a, TRPC5, and others) were validated by Western blotting and immunoflorescent staining of the yolk sac and heart. The proteins within the proteomic dataset clustered to adhesion/migration, differentiation, transport, and insulin signaling pathways. A functional role for several proteins (WNT16, ADAM15 and NOGO-A/B) was demonstrated in an ex vivo model of heart development. Additionally, a successful application of a cluster of protein biomarkers (WNT16, ST14 and Pcsk1) as a prenatal screen for CHDs was confirmed in a study of human amniotic fluid (AF) samples from women carrying normal fetuses and those with CHDs. Conclusions/Significance The novel finding that WNT16, ST14 and Pcsk1 protein levels increase in fetuses with CHDs suggests that these proteins may play a role in the etiology of human CHDs. The information gained through this bed-side to bench translational approach contributes to a more complete understanding of the protein pathways dysregulated during cardiovascular development and provides novel avenues for diagnostic and therapeutic interventions, beneficial to fetuses at risk for CHDs. PMID:19156209

Transient inhibition of the ERK pathway prevents cerebellar developmental defects and improves long-term motor functions in murine models of neurofibromatosis type 1

PubMed Central

Kim, Edward; Wang, Yuan; Kim, Sun-Jung; Bornhorst, Miriam; Jecrois, Emmanuelle S; Anthony, Todd E; Wang, Chenran; Li, Yi E; Guan, Jun-Lin; Murphy, Geoffrey G; Zhu, Yuan

2014-01-01

Individuals with neurofibromatosis type 1 (NF1) frequently exhibit cognitive and motor impairments and characteristics of autism. The cerebellum plays a critical role in motor control, cognition, and social interaction, suggesting that cerebellar defects likely contribute to NF1-associated neurodevelopmental disorders. Here we show that Nf1 inactivation during early, but not late stages of cerebellar development, disrupts neuronal lamination, which is partially caused by overproduction of glia and subsequent disruption of the Bergmann glia (BG) scaffold. Specific Nf1 inactivation in glutamatergic neuronal precursors causes premature differentiation of granule cell (GC) precursors and ectopic production of unipolar brush cells (UBCs), indirectly disrupting neuronal migration. Transient MEK inhibition during a neonatal window prevents cerebellar developmental defects and improves long-term motor performance of Nf1-deficient mice. This study reveals essential roles of Nf1 in GC/UBC migration by generating correct numbers of glia and controlling GC/UBC fate-specification/differentiation, identifying a therapeutic prevention strategy for multiple NF1-associcated developmental abnormalities. DOI: http://dx.doi.org/10.7554/eLife.05151.001 PMID:25535838

Do Guilt- and Shame-Proneness Differentially Predict Prosocial, Aggressive, and Withdrawn Behaviors during Early Adolescence?

ERIC Educational Resources Information Center

Roos, Sanna; Hodges, Ernest V. E.; Salmivalli, Christina

2014-01-01

In this short-term longitudinal study, we systematically examined the distinctiveness of guilt- and shame-proneness in early adolescents (N = 395, mean age = 11.8 years) in terms of differential relations with peer reported prosocial behavior, withdrawal, and aggression. Results from structural equation modeling indicated that guilt-proneness…

Isotopic constraints on the age and early differentiation of the Earth.

PubMed

McCulloch, M T

1996-03-01

The Earth's age and early differentiation history are re-evaluated using updated isotopic constraints. From the most primitive terrestrial Pb isotopic compositions found at Isua Greenland, and the Pilbara of Western Australia, combined with precise geochronology of these localities, an age 4.49 +/- 0.02 Ga is obtained. This is interpreted as the mean age of core formation as U/Pb is fractionated due to sequestering of Pb into the Earth's core. The long-lived Rb-Sr isotopic system provides constraints on the time interval for the accretion of the Earth as Rb underwent significant depletion by volatile loss during accretion of the Earth or its precursor planetesimals. A primitive measured 87Sr/86Sr initial ratio of 0.700502 +/- 10 has been obtained for an early Archean (3.46 Ga) barite from the Pilbara Block of Western Australia. Using conservative models for the evolution of Rb/Sr in the early Archean mantle allows an estimate to be placed on the Earth's initial Sr ratio at approximately 4.50 Ga, of 0.69940 +/- 10. This is significantly higher than that measured for the Moon (0.69900 +/- 2) or in the achondrite, Angra dos Reis (0.69894 +/- 2) and for a Rb/Sr ratio of approximately 1/2 of chondrites corresponds to a mean age for accretion of the Earth of 4.48 + /- 0.04 Ga. The now extinct 146Sm-142Nd (T1/2(146)=103 l0(6)yrs) combined with the long-lived 147Sm-143Nd isotopic systematics can also be used to provide limits on the time of early differentiation of the Earth. High precision analyses of the oldest (3.8-3.9 Ga) Archean gneisses from Greenland (Amitsoq and Akilia gneisses), and Canada (Acasta gneiss) do not show measurable (> +/- l0ppm) variations of 142Nd, in contrast to the 33 ppm 142Nd excess reported for an Archean sample. The general lack of 142Nd variations, combined with the presence of highly positive epsilon 143 values (+4.0) at 3.9 Ga, indicates that the record of large-scale Sm/Nd fractionation events was not preserved in the early-Earth from 4

Morphological and proteomic analysis of early stage of osteoblast differentiation in osteoblastic progenitor cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Dun; Orthopedic Department, Taizhou Hospital, Wenzhou Medical College, Linhai, Zhejiang 317000; Chen, Hai-Xiao, E-mail: Hxchen-1@163.net

Bone remodeling relies on a dynamic balance between bone formation and resorption, mediated by osteoblasts and osteoclasts, respectively. Under certain stimuli, osteoprogenitor cells may differentiate into premature osteoblasts and further into mature osteoblasts. This process is marked by increased alkaline phosphatase (ALP) activity and mineralized nodule formation. In this study, we induced osteoblast differentiation in mouse osteoprogenitor MC3T3-E1 cells and divided the process into three stages. In the first stage (day 3), the MC3T3-E1 cell under osteoblast differentiation did not express ALP or deposit a mineralized nodule. In the second stage, the MC3T3-E1 cell expressed ALP but did not formmore » a mineralized nodule. In the third stage, the MC3T3-E1 cell had ALP activity and formed mineralized nodules. In the present study, we focused on morphological and proteomic changes of MC3T3-E1 cells in the early stage of osteoblast differentiation - a period when premature osteoblasts transform into mature osteoblasts. We found that mean cell area and mean stress fiber density were increased in this stage due to enhanced cell spreading and decreased cell proliferation. We further analyzed the proteins in the signaling pathway of regulation of the cytoskeleton using a proteomic approach and found upregulation of IQGAP1, gelsolin, moesin, radixin, and Cfl1. After analyzing the focal adhesion signaling pathway, we found the upregulation of FLNA, LAMA1, LAMA5, COL1A1, COL3A1, COL4A6, and COL5A2 as well as the downregulation of COL4A1, COL4A2, and COL4A4. In conclusion, the signaling pathway of regulation of the cytoskeleton and focal adhesion play critical roles in regulating cell spreading and actin skeleton formation in the early stage of osteoblast differentiation.« less

[Early application of the antibiotic-laden bone cement (ALBC) combined with the external fixation support in treating the open fractures of lower limbs complicated with bone defect].

PubMed

Xiao, Jian; Mao, Zhao-Guang; Zhu, Hui-Hua; Guo, Liang

2017-03-25

To discuss the curative effect of the early application of the antibiotic-laden bone cement (ALBC) combined with the external fixation support in treating the open fractures of lower limbs complicated with bone defect. From December 2013 to January 2015, 36 cases of lower limb open comminuted fractures complicated with bone defects were treated by the vancomycin ALBC combined with the external fixation support, including 26 males and 10 females with an average age of 38.0 years old ranging from 19 to 65 years old. The included cases were all open fractures of lower limbs complicated with bone defects with different degree of soft tissue injuries. Among them, 25 cases were tibial fractures, 11 cases were femoral fractures. The radiographs indicated a presence of bone defects, which ranged from 3.0 to 6.1 cm with an average of 4.0 cm. The Gustilo classification of open fractures:24 cases were type IIIA, 12 cases were typr IIIB. The percentage of wound infection, bone grafting time, fracture healing time and postoperative joint function of lower limb were observed. The function of injured limbs was evaluated at 1 month after the clinical healing of fracture based on Paley evaluation criterion. All cases were followed up for 3 to 24 months with an average of (6.0±3.0) months. The wound surface was healed well, neither bone infections nor unhealed bone defects were presented. The reoperation of bone grafting was done at 6 weeks after the patients received an early treatment with ALBC, some of them were postponed to 8 weeks till the approximate healing of fractures, the treatment course lasted for 4 to 8 months with an average of(5.5±1.5) months. According to Paley and other grading evaluations of bone and function, there were 27 cases as excellent, 5 cases as good, 3 cases as ordinary. The ALBC combined with external fixation support was an effective method for early treatment to treat the traumatic lower limb open fractures complicated with bone defects. This method

Analysis of the Material Properties of Early Chondrogenic Differentiated Adipose-Derived Stromal Cells (ASC) Using an in vitro Three-dimensional Micromass Culture System

PubMed Central

Xu, Yue; Balooch, Guive; Chiou, Michael; Bekerman, Elena; Ritchie, Robert O.; Longaker, Michael T.

2009-01-01

Cartilage is an avascular tissue with only a limited potential to heal and chondrocytes in vitro have poor proliferative capacity. Recently, adipose-derived stromal cells (ASC) have demonstrated a great potential for application to tissue engineering due to their ability to differentiate into cartilage, bone, and fat. In this study, we have utilized a high density three-dimensional (3D) micromass model system of early chondrogenesis with ASC. The material properties of these micromasses showed a significant increase in dynamic and static elastic modulus during the early chondrogenic differentiation process. These data suggest that the 3D micromass culture system represents an in vitro model of early chondrogenesis with dynamic cell signaling interactions associated with the mechanical properties of chondrocyte differentiation. PMID:17543281

Analysis of the material properties of early chondrogenic differentiated adipose-derived stromal cells (ASC) using an in vitro three-dimensional micromass culture system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Yue; Balooch, Guive; Chiou, Michael

2007-07-27

Cartilage is an avascular tissue with only a limited potential to heal and chondrocytes in vitro have poor proliferative capacity. Recently, adipose-derived stromal cells (ASC) have demonstrated a great potential for application to tissue engineering due to their ability to differentiate into cartilage, bone, and fat. In this study, we have utilized a high density three-dimensional (3D) micromass model system of early chondrogenesis with ASC. The material properties of these micromasses showed a significant increase in dynamic and static elastic modulus during the early chondrogenic differentiation process. These data suggest that the 3D micromass culture system represents an in vitromore » model of early chondrogenesis with dynamic cell signaling interactions associated with the mechanical properties of chondrocyte differentiation.« less

Metabolic differentiation of early Lyme disease from southern tick-associated rash illness (STARI).

PubMed

Molins, Claudia R; Ashton, Laura V; Wormser, Gary P; Andre, Barbara G; Hess, Ann M; Delorey, Mark J; Pilgard, Mark A; Johnson, Barbara J; Webb, Kristofor; Islam, M Nurul; Pegalajar-Jurado, Adoracion; Molla, Irida; Jewett, Mollie W; Belisle, John T

2017-08-16

Lyme disease, the most commonly reported vector-borne disease in the United States, results from infection with Borrelia burgdorferi. Early clinical diagnosis of this disease is largely based on the presence of an erythematous skin lesion for individuals in high-risk regions. This, however, can be confused with other illnesses including southern tick-associated rash illness (STARI), an illness that lacks a defined etiological agent or laboratory diagnostic test, and is coprevalent with Lyme disease in portions of the eastern United States. By applying an unbiased metabolomics approach with sera retrospectively obtained from well-characterized patients, we defined biochemical and diagnostic differences between early Lyme disease and STARI. Specifically, a metabolic biosignature consisting of 261 molecular features (MFs) revealed that altered N -acyl ethanolamine and primary fatty acid amide metabolism discriminated early Lyme disease from STARI. Development of classification models with the 261-MF biosignature and testing against validation samples differentiated early Lyme disease from STARI with an accuracy of 85 to 98%. These findings revealed metabolic dissimilarity between early Lyme disease and STARI, and provide a powerful and new approach to inform patient management by objectively distinguishing early Lyme disease from an illness with nearly identical symptoms. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Reconstitution of wild type viral DNA in simian cells transfected with early and late SV40 defective genomes.

PubMed

O'Neill, F J; Gao, Y; Xu, X

1993-11-01

The DNAs of polyomaviruses ordinarily exist as a single circular molecule of approximately 5000 base pairs. Variants of SV40, BKV and JCV have been described which contain two complementing defective DNA molecules. These defectives, which form a bipartite genome structure, contain either the viral early region or the late region. The defectives have the unique property of being able to tolerate variable sized reiterations of regulatory and terminus region sequences, and portions of the coding region. They can also exchange coding region sequences with other polyomaviruses. It has been suggested that the bipartite genome structure might be a stage in the evolution of polyomaviruses which can uniquely sustain genome and sequence diversity. However, it is not known if the regulatory and terminus region sequences are highly mutable. Also, it is not known if the bipartite genome structure is reversible and what the conditions might be which would favor restoration of the monomolecular genome structure. We addressed the first question by sequencing the reiterated regulatory and terminus regions of E- and L-SV40 DNAs. This revealed a large number of mutations in the regulatory regions of the defective genomes, including deletions, insertions, rearrangements and base substitutions. We also detected insertions and base substitutions in the T-antigen gene. We addressed the second question by introducing into permissive simian cells, E- and L-SV40 genomes which had been engineered to contain only a single regulatory region. Analysis of viral DNA from transfected cells demonstrated recombined genomes containing a wild type monomolecular DNA structure. However, the complete defectives, containing reiterated regulatory regions, could often compete away the wild type genomes. The recombinant monomolecular genomes were isolated, cloned and found to be infectious. All of the DNA alterations identified in one of the regulatory regions of E-SV40 DNA were present in the recombinant

Efficacy of a sheet combined with fibrin glue in repair of pleural defect at the early phase after lung surgery in a canine model.

PubMed

Sakai, Takashi; Matsutani, Noriyuki; Kanai, Eiichi; Yamauchi, Yoshikane; Uehara, Hirofumi; Iinuma, Hisae; Kawamura, Masafumi

2018-02-01

Polyglycolic acid and oxidized regenerated cellulose have been widely used as a sealant for repairing pulmonary air leakage during respiratory surgery. However, fundamental research of these materials has not been sufficiently conducted. Therefore, we conducted studies to assess the pressure resistance ability of these materials using a canine visceral pleural defect model at the early phase. The 6-mm circular defect and the 12-mm square defect were created on the visceral pleura of anesthetized beagles. These defects were then repaired using one of four methods: method A using polyglycolic acid and fibrin glue; method B using oxidized regenerated cellulose and fibrin glue; method C using oxidized regenerated cellulose; method D using fibrin glue. Airway pressure was measured as bursting pressure when air leakage from the repaired areas occurred at 5 min, 3 h, and 24 h after repair. For the 6-mm circle defect, method A showed higher bursting pressures than the other methods at 5 min and 3 h (p < 0.05); method B showed higher than methods C and D at 5 min and 3 h (p < 0.05). For the 12-mm square defect, method A showed higher bursting pressures than the other methods at all time points (p < 0.05). Moreover, method B showed higher than method C at 24 h (p < 0.05). Visceral pleural repairs using polyglycolic acid combined with fibrin glue showed the highest bursting pressure. Oxidized regenerated cellulose combined with fibrin glue showed sufficiently high bursting pressure in repair of small 6-mm circular defects.

Enteric neural crest cells regulate vertebrate stomach patterning and differentiation.

PubMed

Faure, Sandrine; McKey, Jennifer; Sagnol, Sébastien; de Santa Barbara, Pascal

2015-01-15

In vertebrates, the digestive tract develops from a uniform structure where reciprocal epithelial-mesenchymal interactions pattern this complex organ into regions with specific morphologies and functions. Concomitant with these early patterning events, the primitive GI tract is colonized by the vagal enteric neural crest cells (vENCCs), a population of cells that will give rise to the enteric nervous system (ENS), the intrinsic innervation of the GI tract. The influence of vENCCs on early patterning and differentiation of the GI tract has never been evaluated. In this study, we report that a crucial number of vENCCs is required for proper chick stomach development, patterning and differentiation. We show that reducing the number of vENCCs by performing vENCC ablations induces sustained activation of the BMP and Notch pathways in the stomach mesenchyme and impairs smooth muscle development. A reduction in vENCCs also leads to the transdifferentiation of the stomach into a stomach-intestinal mixed phenotype. In addition, sustained Notch signaling activity in the stomach mesenchyme phenocopies the defects observed in vENCC-ablated stomachs, indicating that inhibition of the Notch signaling pathway is essential for stomach patterning and differentiation. Finally, we report that a crucial number of vENCCs is also required for maintenance of stomach identity and differentiation through inhibition of the Notch signaling pathway. Altogether, our data reveal that, through the regulation of mesenchyme identity, vENCCs act as a new mediator in the mesenchymal-epithelial interactions that control stomach development. © 2015. Published by The Company of Biologists Ltd.

Pristine Igneous Rocks and the Early Differentiation of Planetary Materials

NASA Technical Reports Server (NTRS)

Warren, Paul H.

2005-01-01

Our studies are highly interdisciplinary, but are focused on the processes and products of early planetary and asteroidal differentiation, especially the genesis of the ancient lunar crust. The compositional diversity that we explore is the residue of process diversity, which has strong relevance for comparative planetology. Most of the accessible lunar crust consists of materials hybridized by impact-mixing. Our lunar research concentrates on the rare pristine (unmixed) samples that reflect the original genetic diversity of the early crust. Among HED basalts (eucrites and clasts in howardites), we distinguish as pristine the small minority that escaped the pervasive thermal metamorphism of the parent asteroid's crust. We have found a correlation between metamorphically pristine HED basalts and the similarly small minority of compositionally evolved "Stannern trend" samples, which are enriched in incompatible elements and titanium compared to main group eucrites, and yet have relatively high mg ratios. Other topics under investigation included: lunar and SNC (martian?) meteorites; igneous meteorites in general; impact breccias, especially metal-rich Apollo samples and polymict eucrites; siderophile compositions of the lunar and martian mantles; and planetary bulk compositions and origins.

Improving bone repair of femoral and radial defects in rabbit by incorporating PRP into PLGA/CPC composite scaffold with unidirectional pore structure.

PubMed

He, Fupo; Chen, Yan; Li, Jiyan; Lin, Bomiao; Ouyang, Yi; Yu, Bo; Xia, Yuanyou; Yu, Bo; Ye, Jiandong

2015-04-01

In this study, a platelet-rich plasma poly(lactic-co-glycolic acid) (PRP-PLGA)/calcium phosphate cement (CPC) composite scaffold was prepared by incorporating PRP into PLGA/CPC scaffold with unidirectional pore structure, which was fabricated by the unidirectional freeze casting of CPC slurry and the following infiltration of PLGA. The results from in vitro cell experiments and in vivo implantation in femoral defects manifested that incorporation of PRP into PLGA/CPC scaffold improved in vitro cell response (cell attachment, proliferation, and differentiation), and markedly boosted bone formation, angiogenesis and material degradation. The incorporation of PRP into scaffold showed more outstanding improvement in osteogenesis as the scaffolds were used to repair the segmental radial defects, especially at the early stage. The new bone tissues grew along the unidirectional lamellar pores of scaffold. At 12 weeks postimplantation, the segmental radial defects treated with PRP-PLGA/CPC scaffold had almost recuperated, whereas treated with the scaffold without PRP was far from healed. Taken together, the PRP-PLGA/CPC scaffold with unidirectional pore structure is a promising candidate to repair bone defects at various sites. © 2014 Wiley Periodicals, Inc.

Increased body mass in infancy and early toddlerhood in Angelman syndrome patients with uniparental disomy and imprinting center defects.

PubMed

Brennan, Marie-Luise; Adam, Margaret P; Seaver, Laurie H; Myers, Angela; Schelley, Susan; Zadeh, Neda; Hudgins, Louanne; Bernstein, Jonathan A

2015-01-01

The diagnosis of Angelman syndrome (AS) is based on clinical features and genetic testing. Developmental delay, severe speech impairment, ataxia, atypical behavior and microcephaly by two years of age are typical. Feeding difficulties in young infants and obesity in late childhood can also be seen. The NIH Angelman-Rett-Prader-Willi Consortium and others have documented genotype-phenotype associations including an increased body mass index in children with uniparental disomy (UPD) or imprinting center (IC) defects. We recently encountered four cases of infantile obesity in non-deletion AS cases, and therefore examined body mass measures in a cohort of non-deletion AS cases. We report on 16 infants and toddlers (ages 6 to 44 months; 6 female, and 10 male) with severe developmental delay. Birth weights were appropriate for gestational age in most cases, >97th% in one case and not available in four cases. The molecular subclass case distribution consisted of: UPD (n = 2), IC defect (n = 3), UPD or IC defect (n = 3), and UBE3A mutation (n = 8). Almost all (7 out of 8) UPD, IC and UPD/IC cases went on to exhibit >90th% age- and gender-appropriate weight for height or BMI within the first 44 months. In contrast, no UBE3A mutation cases exhibited obesity or pre-obesity measures (percentiles ranged from <3% to 55%). These findings demonstrate that increased body mass may be evident as early as the first year of life and highlight the utility of considering the diagnosis of AS in the obese infant or toddler with developmental delay, especially when severe. Although a mechanism explaining the association of UPD, and IC defects with obesity has not been identified, recognition of this correlation may inform investigation of imprinting at the PWS/AS locus and obesity. © 2014 Wiley Periodicals, Inc.

Early-onset sleep defects in Drosophila models of Huntington's disease reflect alterations of PKA/CREB signaling

PubMed Central

Gonzales, Erin D.; Tanenhaus, Anne K.; Zhang, Jiabin; Chaffee, Ryan P.; Yin, Jerry C.P.

2016-01-01

Huntington's disease (HD) is a progressive neurological disorder whose non-motor symptoms include sleep disturbances. Whether sleep and activity abnormalities are primary molecular disruptions of mutant Huntingtin (mutHtt) expression or result from neurodegeneration is unclear. Here, we report Drosophila models of HD exhibit sleep and activity disruptions very early in adulthood, as soon as sleep patterns have developed. Pan-neuronal expression of full-length or N-terminally truncated mutHtt recapitulates sleep phenotypes of HD patients: impaired sleep initiation, fragmented and diminished sleep, and nighttime hyperactivity. Sleep deprivation of HD model flies results in exacerbated sleep deficits, indicating that homeostatic regulation of sleep is impaired. Elevated PKA/CREB activity in healthy flies produces patterns of sleep and activity similar to those in our HD models. We were curious whether aberrations in PKA/CREB signaling were responsible for our early-onset sleep/activity phenotypes. Decreasing signaling through the cAMP/PKA pathway suppresses mutHtt-induced developmental lethality. Genetically reducing PKA abolishes sleep/activity deficits in HD model flies, restores the homeostatic response and extends median lifespan. In vivo reporters, however, show dCREB2 activity is unchanged, or decreased when sleep/activity patterns are abnormal, suggesting dissociation of PKA and dCREB2 occurs early in pathogenesis. Collectively, our data suggest that sleep defects may reflect a primary pathological process in HD, and that measurements of sleep and cAMP/PKA could be prodromal indicators of disease, and serve as therapeutic targets for intervention. PMID:26604145

Transient Early Embryonic Expression of Nkx2-5 Mutations Linked to Congenital Heart Defects in Human Causes Heart Defects in Xenopus laevis

PubMed Central

Bartlett, Heather L.; Sutherland, Lillian; Kolker, Sandra J.; Welp, Chelsea; Tajchman, Urszula; Desmarais, Vera; Weeks, Daniel L.

2007-01-01

Nkx2-5 is a homeobox containing transcription factor that is conserved and expressed in organisms that form hearts. Fruit flies lacking the gene (tinman) fail to form a dorsal vessel, mice that are homozygous null for Nkx2-5 form small, deformed hearts, and several human cardiac defects have been linked to dominant mutations in the Nkx2-5 gene. The Xenopus homologs (XNkx2-5) of two truncated forms of Nkx2-5 that have been identified in humans with congenital heart defects were used in the studies reported here. mRNAs encoding these mutations were injected into single cell Xenopus embryos, and heart development was monitored. Our results indicate that the introduction of truncated XNkx2-5 variants leads to three principle developmental defects. The atrial septum and the valve of the atrioventricular canal were both abnormal. In addition, video microscopic timing of heart contraction indicated that embryos injected with either mutant form of XNkx2-5 have conduction defects. PMID:17685485

Pair-wise comparison analysis of differential expression of mRNAs in early and advanced stage primary colorectal adenocarcinomas

PubMed Central

Lau, Tze Pheng; Roslani, April Camilla; Lian, Lay Hoong; Chai, Hwa Chia; Lee, Ping Chin; Hilmi, Ida; Goh, Khean Lee; Chua, Kek Heng

2014-01-01

Objectives To characterise the mRNA expression patterns of early and advanced stage colorectal adenocarcinomas of Malaysian patients. Design Comparative expression analysis. Setting and participants We performed a combination of annealing control primer (ACP)-based PCR and reverse transcription-quantitative real-time PCR for the identification of differentially expressed genes (DEGs) associated with early and advanced stage primary colorectal tumours. We recruited four paired samples from patients with colorectal cancer (CRC) of Dukes’ A and B for the preliminary differential expression study, and a total of 27 paired samples, ranging from CRC stages I to IV, for subsequent confirmatory test. The tumouric samples were obtained from the patients with CRC undergoing curative surgical resection without preoperative chemoradiotherapy. The recruited patients with CRC were newly diagnosed with CRC, and were not associated with any hereditary syndromes, previously diagnosed cancer or positive family history of CRC. The paired non-cancerous tissue specimens were excised from macroscopically normal colonic mucosa distally located from the colorectal tumours. Primary and secondary outcome measures The differential mRNA expression patterns of early and advanced stage colorectal adenocarcinomas compared with macroscopically normal colonic mucosa were characterised by ACP-based PCR and reverse transcription-quantitative real-time PCR. Results The RPL35, RPS23 and TIMP1 genes were found to be overexpressed in both early and advanced stage colorectal adenocarcinomas (p<0.05). However, the ARPC2 gene was significantly underexpressed in early colorectal adenocarcinomas, while the advanced stage primary colorectal tumours exhibited an additional overexpression of the C6orf173 gene (p<0.05). Conclusions We characterised two distinctive gene expression patterns to aid in the stratification of primary colorectal neoplasms among Malaysian patients with CRC. Further work can be done to

MicroRNA changes through Müller glia dedifferentiation and early/late rod photoreceptor differentiation.

PubMed

Quintero, H; Gómez-Montalvo, A I; Lamas, M

2016-03-01

Cell-type determination is a complex process driven by the combinatorial effect of extrinsic signals and the expression of transcription factors and regulatory genes. MicroRNAs (miRNAs) are non-coding RNAs that, generally, inhibit the expression of target genes and have been involved, among other processes, in cell identity acquisition. To search for candidate miRNAs putatively involved in mice rod photoreceptor and Müller glia (MG) identity, we compared miRNA expression profiles between late-stage retinal progenitor cells (RPCs), CD73-immunopositive (CD73+) rods and postnatal MG. We found a close similarity between RPCs and CD73+ miRNA expression profiles but a divergence between CD73+ and MG miRNA signatures. We validated preferentially expressed miRNAs in the CD73+ subpopulation (miR-182, 183, 124a, 9(∗), 181c and 301b(∗)) or MG (miR-143, 145, 214, 199a-5p, 199b(∗), and 29a). Taking advantage of the unique capacity of MG to dedifferentiate into progenitor-like cells that can be differentiated to a rod phenotype in response to external cues, we evaluated changes of selected miRNAs in MG-derived progenitors (MGDP) during neuronal differentiation. We found decreased levels of miR-143 and 145, but increased levels of miR-29a in MGDP. In MGDPs committed to early neuronal lineages we found increased levels of miR-124a and upregulation of miR-124a, 9(∗) and 181c during MGDP acquisition of rod phenotypes. Furthermore, we demonstrated that ectopic miR-124 expression is sufficient to enhance early neuronal commitment of MGDP. Our data reveal a dynamic regulation of miRNAs in MGDP through early and late neuronal commitment and miRNAs that could be potential targets to exploit the silent neuronal differentiation capacity of MG in mammals. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Effects of administration of a proton pump inhibitor before endoscopic submucosal dissection for differentiated early gastric cancer with ulcer.

PubMed

Myung, Yu Sik; Hong, Su Jin; Han, Jae Pil; Park, Kyung Woo; Ko, Bong Min; Lee, Moon Sung

2017-01-01

In ulcerative early gastric cancer, improvement and exacerbation of ulceration repeat as a malignant cycle. Moreover, early gastric cancer combined with ulcer is associated with a low curative resection rate and high risk of adverse events. The aim of this study was to investigate the ulcer healing rate and clinical outcomes with the administration of a proton pump inhibitor before endoscopic submucosal dissection for differentiated early gastric cancer with ulcer. A total of 136 patients with differentiated early gastric cancer with ulcer who met the expanded indications for endoscopic submucosal dissection were reviewed between June 2005 and June 2014. Eighty-one patients were given PPI before endoscopic submucosal dissection and 55 patients were not given PPI. The complete ulcer healing rate was significantly different between the two groups (59.3 % vs. 23.6 %, P < 0.001). The procedure time was 38.1 ± 35.7 and 50.8 ± 50.2 min (P = 0.047). However, no significant differences were detected in the en bloc resection rate, complete resection rate, and adverse events including bleeding and perforation. Multivariate analysis showed that administration of PPI (OR = 10.83, P < 0.001) and mucosal invasion (OR = 24.43, P < 0.001) were independent factors that predicted complete healing of ulceration. The calculated accuracy for whether complete healing of the ulcer after PPI administration can differentiate mucosal from submucosal invasion was 75.3 %. Administration of PPI before ESD in differentiated EGC meeting the expanded criteria is effective to heal the ulcer lesion and reduce the mean procedure time. Complete healing of the ulcer after PPI administration suggests mucosal cancer.

Defects and Disorder in the Drosophila Eye

NASA Astrophysics Data System (ADS)

Kim, Sangwoo; Carthew, Richard; Hilgenfeldt, Sascha

Cell division and differentiation tightly control the regular pattern in the normal eye of the Drosophila fruit fly while certain genetic mutations introduce disorder in the form of topological defects. Analyzing data from pupal retinas, we develop a model based on Voronoi construction that explains the defect statistics as a consequence of area variation of individual facets (ommatidia). The analysis reveals a previously unknown systematic long-range area variation that spans the entire eye, with distinct effects on topological disorder compared to local fluctuations. The internal structure of the ommatidia and the stiffness of their interior cells also plays a crucial role in the defect generation. Accurate predictions of the correlation between the area variation and the defect density in both normal and mutant animals are obtained without free parameters. This approach can potentially be applied to cellular systems in many other contexts to identify size-topology correlations near the onset of symmetry breaking. This work has been supported by the NIH (GM098077) and the NSF (Grant No. 1504301).

Effects of Earth's rotation on the early differentiation of a terrestrial magma ocean

NASA Astrophysics Data System (ADS)

Maas, Christian; Hansen, Ulrich

2015-11-01

Similar to other terrestrial planets like Moon and Mars, Earth experienced a magma ocean period about 4.5 billion years ago. On Earth differentiation processes in the magma ocean set the initial conditions for core formation and mantle evolution. During the magma ocean period Earth was rotating significantly faster than today. Further, the viscosity of the magma was low, thus that planetary rotation potentially played an important role for differentiation. However, nearly all previous studies neglect rotational effects. All in all, our results suggest that planetary rotation plays an important role for magma ocean crystallization. We employ a 3-D numerical model to study crystal settling in a rotating and vigorously convecting early magma ocean. We show that crystal settling in a terrestrial magma ocean is crucially affected by latitude as well as by rotational strength and crystal density. Due to rotation an inhomogeneous accumulation of crystals during magma ocean solidification with a distinct crystal settling between pole and equator could occur. One could speculate that this may have potentially strong effects on the magma ocean solidification time and the early mantle composition. It could support the development of a basal magma ocean and the formation of anomalies at the core-mantle boundary in the equatorial region, reaching back to the time of magma ocean solidification.

Dynamic Organization of lncRNA and Circular RNA Regulators Collectively Controlled Cardiac Differentiation in Humans.

PubMed

Li, Yongsheng; Zhang, Jinwen; Huo, Caiqin; Ding, Na; Li, Junyi; Xiao, Jun; Lin, Xiaoyu; Cai, Benzhi; Zhang, Yunpeng; Xu, Juan

2017-10-01

Advances in developmental cardiology have increased our understanding of the early aspects of heart differentiation. However, understanding noncoding RNA (ncRNA) transcription and regulation during this process remains elusive. Here, we constructed transcriptomes for both long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in four important developmental stages ranging from early embryonic to cardiomyocyte based on high-throughput sequencing datasets, which indicate the high stage-specific expression patterns of two ncRNA types. Additionally, higher similarities of samples within each stage were found, highlighting the divergence of samples collected from distinct cardiac developmental stages. Next, we developed a method to identify numerous lncRNA and circRNA regulators whose expression was significantly stage-specific and shifted gradually and continuously during heart differentiation. We inferred that these ncRNAs are important for the stages of cardiac differentiation. Moreover, transcriptional regulation analysis revealed that the expression of stage-specific lncRNAs is controlled by known key stage-specific transcription factors (TFs). In addition, circRNAs exhibited dynamic expression patterns independent from their host genes. Functional enrichment analysis revealed that lncRNAs and circRNAs play critical roles in pathways that are activated specifically during heart differentiation. We further identified candidate TF-ncRNA-gene network modules for each differentiation stage, suggesting the dynamic organization of lncRNAs and circRNAs collectively controlled cardiac differentiation, which may cause heart-related diseases when defective. Our study provides a foundation for understanding the dynamic regulation of ncRNA transcriptomes during heart differentiation and identifies the dynamic organization of novel key lncRNAs and circRNAs to collectively control cardiac differentiation. Copyright © 2017. Published by Elsevier B.V.

Decursin inhibits vasculogenesis in early tumor progression by suppression of endothelial progenitor cell differentiation and function.

PubMed

Jung, Seok Yun; Choi, Jin Hwa; Kwon, Sang-Mo; Masuda, Haruchika; Asahara, Takayuki; Lee, You-Mie

2012-05-01

Endothelial progenitor cells (EPCs) contribute to the tumor vasculature during tumor progression. Decursin isolated from the herb Angelica gigas is known to possess potent anti-inflammatory activities. Recently, we reported that decursin is a novel candidate for an angiogenesis inhibitor [Jung et al., 2009]. In this study, we investigated whether decursin regulates EPC differentiation and function to inhibit tumor vasculogenesis. We isolated AC133+ cells from human cord blood and decursin significantly decreased the number of EPC colony forming units of human cord blood-derived AC133+ cells that produce functional EPC progenies. Decursin dose-dependently decreased the cell number of EPC committing cells as demonstrated by EPC expansion studies. Decursin inhibited EPC differentiation from progenitor cells into spindle-shaped EPC colonies. Additionally, decursin inhibited proliferation and migration of early EPCs isolated from mouse bone marrow. Furthermore, decursin suppressed expression of angiopoietin-2, angiopoietin receptor Tie-2, Flk-1 (vascular endothelial growth factor receptor-2), and endothelial nitric oxide synthase in mouse BM derived EPCs in a dose-dependent manner. Decursin suppressed tube formation ability of EPCs in collaboration with HUVEC. Decursin (4 mg/kg) inhibited tumor-induced mobilization of circulating EPCs (CD34 + /VEGFR-2+ cells) from bone marrow and early incorporation of Dil-Ac-LDL-labeled or green fluorescent protein (GFP)+ EPCs into neovessels of xenograft Lewis lung carcinoma tumors in wild-type- or bone-marrow-transplanted mice. Accordingly, decursin attenuated EPC-derived endothelial cells in neovessels of Lewis lung carcinoma tumor masses grown in mice. Together, decursin likely affects EPC differentiation and function, thereby inhibiting tumor vasculogenesis in early tumorigenesis. Copyright © 2012 Wiley Periodicals, Inc.

The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells

PubMed Central

Xiao, Nengming; Eto, Danelle; Elly, Chris; Peng, Guiying; Crotty, Shane; Liu, Yun-Cai

2014-01-01

Follicular helper T cells (TFH cells) are responsible for effective B cell–mediated immunity, and Bcl-6 is a central factor for the differentiation of TFH cells. However, the molecular mechanisms that regulate the induction of TFH cells remain unclear. Here we found that the E3 ubiquitin ligase Itch was essential for the differentiation of TFH cells, germinal center responses and immunoglobulin G (IgG) responses to acute viral infection. Itch acted intrinsically in CD4+ T cells at early stages of TFH cell development. Itch seemed to act upstream of Bcl-6 expression, as Bcl-6 expression was substantially impaired in Itch−/− cells, and the differentiation of Itch−/− T cells into TFH cells was restored by enforced expression of Bcl-6. Itch associated with the transcription factor Foxo1 and promoted its ubiquitination and degradation. The defective TFH differentiation of Itch−/− T cells was rectified by deletion of Foxo1. Thus, our results indicate that Itch acts as an essential positive regulator in the differentiation of TFH cells. PMID:24859451

Germ layer differentiation during early hindgut and cloaca formation in rabbit and pig embryos

PubMed Central

Hassoun, Romia; Schwartz, Peter; Rath, Detlef; Viebahn, Christoph; Männer, Jörg

2010-01-01

Relative to recent advances in understanding molecular requirements for endoderm differentiation, the dynamics of germ layer morphology and the topographical distribution of molecular factors involved in endoderm formation at the caudal pole of the embryonic disc are still poorly defined. To discover common principles of mammalian germ layer development, pig and rabbit embryos at late gastrulation and early neurulation stages were analysed as species with a human-like embryonic disc morphology, using correlative light and electron microscopy. Close intercellular contact but no direct structural evidence of endoderm formation such as mesenchymal–epithelial transition between posterior primitive streak mesoderm and the emerging posterior endoderm were found. However, a two-step process closely related to posterior germ layer differentiation emerged for the formation of the cloacal membrane: (i) a continuous mesoderm layer and numerous patches of electron-dense flocculent extracellular matrix mark the prospective region of cloacal membrane formation; and (ii) mesoderm cells and all extracellular matrix including the basement membrane are lost locally and close intercellular contact between the endoderm and ectoderm is established. The latter process involves single cells at first and then gradually spreads to form a longitudinally oriented seam-like cloacal membrane. These gradual changes were found from gastrulation to early somite stages in the pig, whereas they were found from early somite to mid-somite stages in the rabbit; in both species cloacal membrane formation is complete prior to secondary neurulation. The results highlight the structural requirements for endoderm formation during development of the hindgut and suggest new mechanisms for the pathogenesis of common urogenital and anorectal malformations. PMID:20874819

Approximation of the Newton Step by a Defect Correction Process

NASA Technical Reports Server (NTRS)

Arian, E.; Batterman, A.; Sachs, E. W.

1999-01-01

In this paper, an optimal control problem governed by a partial differential equation is considered. The Newton step for this system can be computed by solving a coupled system of equations. To do this efficiently with an iterative defect correction process, a modifying operator is introduced into the system. This operator is motivated by local mode analysis. The operator can be used also for preconditioning in Generalized Minimum Residual (GMRES). We give a detailed convergence analysis for the defect correction process and show the derivation of the modifying operator. Numerical tests are done on the small disturbance shape optimization problem in two dimensions for the defect correction process and for GMRES.

Lipoic acid biosynthesis defects.

PubMed

Mayr, Johannes A; Feichtinger, René G; Tort, Frederic; Ribes, Antonia; Sperl, Wolfgang

2014-07-01

Lipoate is a covalently bound cofactor essential for five redox reactions in humans: in four 2-oxoacid dehydrogenases and the glycine cleavage system (GCS). Two enzymes are from the energy metabolism, α-ketoglutarate dehydrogenase and pyruvate dehydrogenase; and three are from the amino acid metabolism, branched-chain ketoacid dehydrogenase, 2-oxoadipate dehydrogenase, and the GCS. All these enzymes consist of multiple subunits and share a similar architecture. Lipoate synthesis in mitochondria involves mitochondrial fatty acid synthesis up to octanoyl-acyl-carrier protein; and three lipoate-specific steps, including octanoic acid transfer to glycine cleavage H protein by lipoyl(octanoyl) transferase 2 (putative) (LIPT2), lipoate synthesis by lipoic acid synthetase (LIAS), and lipoate transfer by lipoyltransferase 1 (LIPT1), which is necessary to lipoylate the E2 subunits of the 2-oxoacid dehydrogenases. The reduced form dihydrolipoate is reactivated by dihydrolipoyl dehydrogenase (DLD). Mutations in LIAS have been identified that result in a variant form of nonketotic hyperglycinemia with early-onset convulsions combined with a defect in mitochondrial energy metabolism with encephalopathy and cardiomyopathy. LIPT1 deficiency spares the GCS, and resulted in a combined 2-oxoacid dehydrogenase deficiency and early death in one patient and in a less severely affected individual with a Leigh-like phenotype. As LIAS is an iron-sulphur-cluster-dependent enzyme, a number of recently identified defects in mitochondrial iron-sulphur cluster synthesis, including NFU1, BOLA3, IBA57, GLRX5 presented with deficiency of LIAS and a LIAS-like phenotype. As in DLD deficiency, a broader clinical spectrum can be anticipated for lipoate synthesis defects depending on which of the affected enzymes is most rate limiting.

An Fgf-Shh signaling hierarchy regulates early specification of the zebrafish skull

PubMed Central

McCarthy, Neil; Sidik, Alfire; Bertrand, Julien Y.; Eberhart, Johann K.

2016-01-01

The neurocranium generates most of the craniofacial skeleton and consists of prechordal and postchordal regions. Although development of the prechordal is well studied, little is known of the postchordal region. Here we characterize a signaling hierarchy necessary for postchordal neurocranial development involving Fibroblast growth factor (Fgf) signaling for early specification of mesodermally-derived progenitor cells. The expression of hyaluron synthetase 2 (has2) in the cephalic mesoderm requires Fgf signaling and Has2 function, in turn, is required for postchordal neurocranial development. While Hedgehog (Hh)-deficient embryos also lack a postchordal neurocranium, this appears primarily due to a later defect in chondrocyte differentiation. Inhibitor studies demonstrate that postchordal neurocranial development requires early Fgf and later Hh signaling. Collectively, our results provide a mechanistic understanding of early postchordal neurocranial development and demonstrate a hierarchy of signaling between Fgf and Hh in the development of this structure. PMID:27060628

Integrated analysis of miRNA and mRNA expression profiles in tilapia gonads at an early stage of sex differentiation.

PubMed

Tao, Wenjing; Sun, Lina; Shi, Hongjuan; Cheng, Yunying; Jiang, Dongneng; Fu, Beide; Conte, Matthew A; Gammerdinger, William J; Kocher, Thomas D; Wang, Deshou

2016-05-04

MicroRNAs (miRNAs) represent a second regulatory network that has important effects on gene expression and protein translation during biological process. However, the possible role of miRNAs in the early stages of fish sex differentiation is not well understood. In this study, we carried an integrated analysis of miRNA and mRNA expression profiles to explore their possibly regulatory patterns at the critical stage of sex differentiation in tilapia. We identified 279 pre-miRNA genes in tilapia genome, which were highly conserved in other fish species. Based on small RNA library sequencing, we identified 635 mature miRNAs in tilapia gonads, in which 62 and 49 miRNAs showed higher expression in XX and XY gonads, respectively. The predicted targets of these sex-biased miRNAs (e.g., miR-9, miR-21, miR-30a, miR-96, miR-200b, miR-212 and miR-7977) included genes encoding key enzymes in steroidogenic pathways (Cyp11a1, Hsd3b, Cyp19a1a, Hsd11b) and key molecules involved in vertebrate sex differentiation (Foxl2, Amh, Star1, Sf1, Dmrt1, and Gsdf). These genes also showed sex-biased expression in tilapia gonads at 5 dah. Some miRNAs (e.g., miR-96 and miR-737) targeted multiple genes involved in steroid synthesis, suggesting a complex miRNA regulatory network during early sex differentiation in this fish. The sequence and expression patterns of most miRNAs in tilapia are conserved in fishes, indicating the basic functions of vertebrate miRNAs might share a common evolutionary origin. This comprehensive analysis of miRNA and mRNA at the early stage of molecular sex differentiation in tilapia XX and XY gonads lead to the discovery of differentially expressed miRNAs and their putative targets, which will facilitate studies of the regulatory network of molecular sex determination and differentiation in fishes.

The use of SHP-2 gene transduced bone marrow mesenchymal stem cells to promote osteogenic differentiation and bone defect repair in rat.

PubMed

Fan, Dapeng; Liu, Shen; Jiang, Shichao; Li, Zhiwei; Mo, Xiumei; Ruan, Hongjiang; Zou, Gang-Ming; Fan, Cunyi

2016-08-01

Bone tissue engineering is a promising approach for bone regeneration, in which growth factors play an important role. The tyrosine phosphatase Src-homology region 2-containing protein tyrosine phosphatase 2 (SHP2), encoded by the PTPN11 gene, is essential for the differentiation, proliferation and metabolism of osteoblasts. However, SHP-2 has never been systematically studied for its effect in osteogenesis. We predicted that overexpression of SHP-2 could promote bone marrow-derived mesenchymal stem cell (BMSC)osteogenic differentiation and SHP-2 transduced BMSCs could enhance new bone formation, determined using the following study groups: (1) BMSCs transduced with SHP-2 and induced with osteoblast-inducing liquid (BMSCs/SHP-2/OL); (2) BMSCs transduced with SHP-2 (BMSCs/-SHP-2); (3) BMSCs induced with osteoblast-inducing liquid (BMSCs/OL) and (4) pure BMSCs. Cells were assessed for osteogenic differentiation by quantitative real-time polymerase chain reaction analysis, western blot analysis, alkaline phosphatase activity and alizarin red S staining. For in vivo assessment, cells were combined with beta-tricalcium phosphate scaffolds and transplanted into rat calvarial defects for 8 weeks. Following euthanasia, skull samples were explanted for osteogenic evaluation, including micro-computed tomography measurement, histology and immunohistochemistry staining. SHP-2 and upregulation of its gene promoted BMSC osteogenic differentiation and therefore represents a potential new therapeutic approach to bone repair. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1871-1881, 2016. © 2016 Wiley Periodicals, Inc.

Detection of small-size solder ball defects through heat conduction analysis

NASA Astrophysics Data System (ADS)

Zhou, Xiuyun; Chen, Yaqiu; Lu, Xiaochuan

2018-02-01

Aiming to solve the defect detection problem of a small-size solder ball in the high density chip, heat conduction analysis based on eddy current pulsed thermography is put forward to differentiate various defects. With establishing the 3D finite element model about induction heating, defects such as cracks and void can be distinguished by temperature difference resulting from heat conduction. Furthermore, the experiment of 0.4 mm-diameter solder balls with different defects is carried out to prove that crack and void solder can be distinguished. Three kinds of crack length on a gull-wing pin are selected, including 0.24 mm, 1.2 mm, and 2.16 mm, to verify that the small defect can be discriminated. Both the simulation study and experiment result show that the heat conduction analysis method is reliable and convenient.

Fibroblast growth factor receptor signaling is essential for lens fiber cell differentiation.

PubMed

Zhao, Haotian; Yang, Tianyu; Madakashira, Bhavani P; Thiels, Cornelius A; Bechtle, Chad A; Garcia, Claudia M; Zhang, Huiming; Yu, Kai; Ornitz, David M; Beebe, David C; Robinson, Michael L

2008-06-15

The vertebrate lens provides an excellent model to study the mechanisms that regulate terminal differentiation. Although fibroblast growth factors (FGFs) are thought to be important for lens cell differentiation, it is unclear which FGF receptors mediate these processes during different stages of lens development. Deletion of three FGF receptors (Fgfr1-3) early in lens development demonstrated that expression of only a single allele of Fgfr2 or Fgfr3 was sufficient for grossly normal lens development, while mice possessing only a single Fgfr1 allele developed cataracts and microphthalmia. Profound defects were observed in lenses lacking all three Fgfrs. These included lack of fiber cell elongation, abnormal proliferation in prospective lens fiber cells, reduced expression of the cell cycle inhibitors p27(kip1) and p57(kip2), increased apoptosis and aberrant or reduced expression of Prox1, Pax6, c-Maf, E-cadherin and alpha-, beta- and gamma-crystallins. Therefore, while signaling by FGF receptors is essential for lens fiber differentiation, different FGF receptors function redundantly.

Surgery for doubly committed ventricular septal defects.

PubMed

Shamsuddin, Ahmad Mahir; Chen, Yen Chuan; Wong, Abdul Rahim; Le, Trong-Phi; Anderson, Robert H; Corno, Antonio F

2016-08-01

Doubly committed ventricular septal defects (VSDs) account for up to almost one-third of isolated ventricular septal defects in Asian countries, compared with only 1/20th in western populations. In our surgical experience, this type of defect accounted for almost three-quarters of our practice. To date, patch closure has been considered the gold standard for surgical treatment of these lesions. Our objectives are to evaluate the indications and examine the outcomes of surgery for doubly committed VSDs. Between October 2013, when our service of paediatric cardiac surgery was opened, and December 2014, 24 patients were referred for surgical closure of VSDs. Among them, 17 patients (71%), with the median age of 6 years, ranging from 2 to 9 years, and with a median body weight of 19 kg, ranging from 11 to 56 kg, underwent surgical repair for doubly committed defects. In terms of size, the defect was considered moderate in 4 and large in 13. Aortic valvular regurgitation (AoVR) was present in 11 patients (65%) preoperatively, with associated malformations found in 14 (82%), with 5 patients (29%) having two or more associated defects. After surgery, there was trivial residual shunting in 2 patients (12%). AoVR persisted in 6 (35%), reducing to trivial in 5 (29%) and mild in 1 (6%). Mean stays in the intensive care unit and hospital were 2.6 ± 1.2 days, ranging from 2 to 7 days, and 6.8 ± 0.8 days, ranging from 6 to 9 days, respectively. The mean follow-up was 14 ± 4 months, ranging from 6 to 20 months, with no early or late deaths and without clinical deterioration. The incidence of doubly committed lesions is high in our experience, frequently associated with AoVR and other associated malformation. Early detection is crucial to prevent further progression of the disease. Patch closure remains the gold standard in management, not least since it allows simultaneous repair of associated intracardiac defects. © The Author 2016. Published by Oxford University Press on

Transplantation of dedifferentiated fat cell-derived micromass pellets contributed to cartilage repair in the rat osteochondral defect model.

PubMed

Shimizu, Manabu; Matsumoto, Taro; Kikuta, Shinsuke; Ohtaki, Munenori; Kano, Koichiro; Taniguchi, Hiroaki; Saito, Shu; Nagaoka, Masahiro; Tokuhashi, Yasuaki

2018-03-20

Mature adipocyte-derived dedifferentiated fat (DFAT) cells possesses the ability to proliferate effectively and the potential to differentiate into multiple linages of mesenchymal tissue; similar to adipose-derived stem cells (ASCs). The purpose of this study is to examine the effects of DFAT cell transplantation on cartilage repair in a rat model of osteochondral defects. Full-thickness osteochondral defects were created in the knees of Sprague-Dawley rats bilaterally. Cartilage-like micromass pellets were prepared from green fluorescent protein (GFP)-labeled rat DFAT cells and subsequently transplanted into the affected right knee of these rats. Defects in the left knee were used as a control. Macroscopic and microscopic changes of treated and control defects were evaluated up to 12 weeks post-treatment with DFAT cells. To observe the transplanted cells, sectioned femurs were immunostained for GFP and type II collagen. DFAT cells formed micromass pellets expressing characteristics of immature cartilage in vitro. In the DFAT cell-transplanted limbs, the defects were completely filled with white micromass pellets as early as 2 weeks post-treatment. These limbs became smooth at 4 weeks. Conversely, the defects in the control limbs were still not repaired by 4 weeks. Macroscopic ICRS scores at 2 and 4 weeks were significantly higher in the DFAT cells-transplanted limbs compared to those of the control limbs. The modified O'Driscol histological scores for the DFAT cell-transplanted limbs were significantly higher than those of the control limbs at corresponding time points. GFP-positive DAFT cells were detected in the transplanted area at 2 weeks but hardly visible at 12 weeks post-operation. Transplantation of DFAT cell-derived micromass pellets contribute to cartilage repair in a rat osteochondral defect model. DFAT cell transplantation may be a viable therapeutic strategy for the repair of osteochondral injuries. Copyright © 2018 The Authors. Published by

The altered expression of perineuronal net elements during neural differentiation.

PubMed

Eskici, Nazli F; Erdem-Ozdamar, Sevim; Dayangac-Erden, Didem

2018-01-01

Perineuronal nets (PNNs), which are localized around neurons during development, are specialized forms of neural extracellular matrix with neuroprotective and plasticity-regulating roles. Hyaluronan and proteoglycan link protein 1 (HAPLN1), tenascin-R (TNR) and aggrecan (ACAN) are key elements of PNNs. In diseases characterized by neuritogenesis defects, the expression of these proteins is known to be downregulated, suggesting that PNNs may have a role in neural differentiation. In this study, the mRNA and protein levels of HAPLN1, TNR and ACAN were determined and compared at specific time points of neural differentiation. We used PC12 cells as the in vitro model because they reflect this developmental process. On day 7, the HAPLN1 mRNA level showed a 2.9-fold increase compared to the non-differentiated state. However, the cellular HAPLN1 protein level showed a decrease, indicating that the protein may have roles in neural differentiation, and may be secreted during the early period of differentiation. By contrast, TNR mRNA and protein levels remained unchanged, and the amount of cellular ACAN protein showed a 3.7-fold increase at day 7. These results suggest that ACAN may be secreted after day 7, possibly due to its large amount of post-translational modifications. Our results provide preliminary data on the expression of PNN elements during neural differentiation. Further investigations will be performed on the role of these elements in neurological disease models.

Differential Network Analyses of Alzheimer’s Disease Identify Early Events in Alzheimer’s Disease Pathology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xia, Jing; Rocke, David M.; Perry, George

In late-onset Alzheimer’s disease (AD), multiple brain regions are not affected simultaneously. Comparing the gene expression of the affected regions to identify the differences in the biological processes perturbed can lead to greater insight into AD pathogenesis and early characteristics. We identified differentially expressed (DE) genes from single cell microarray data of four AD affected brain regions: entorhinal cortex (EC), hippocampus (HIP), posterior cingulate cortex (PCC), and middle temporal gyrus (MTG). We organized the DE genes in the four brain regions into region-specific gene coexpression networks. Differential neighborhood analyses in the coexpression networks were performed to identify genes with lowmore » topological overlap (TO) of their direct neighbors. The low TO genes were used to characterize the biological differences between two regions. Our analyses show that increased oxidative stress, along with alterations in lipid metabolism in neurons, may be some of the very early events occurring in AD pathology. Cellular defense mechanisms try to intervene but fail, finally resulting in AD pathology as the disease progresses. Furthermore, disease annotation of the low TO genes in two independent protein interaction networks has resulted in association between cancer, diabetes, renal diseases, and cardiovascular diseases.« less

Differential Network Analyses of Alzheimer’s Disease Identify Early Events in Alzheimer’s Disease Pathology

DOE PAGES

Xia, Jing; Rocke, David M.; Perry, George; ...

2014-01-01

In late-onset Alzheimer’s disease (AD), multiple brain regions are not affected simultaneously. Comparing the gene expression of the affected regions to identify the differences in the biological processes perturbed can lead to greater insight into AD pathogenesis and early characteristics. We identified differentially expressed (DE) genes from single cell microarray data of four AD affected brain regions: entorhinal cortex (EC), hippocampus (HIP), posterior cingulate cortex (PCC), and middle temporal gyrus (MTG). We organized the DE genes in the four brain regions into region-specific gene coexpression networks. Differential neighborhood analyses in the coexpression networks were performed to identify genes with lowmore » topological overlap (TO) of their direct neighbors. The low TO genes were used to characterize the biological differences between two regions. Our analyses show that increased oxidative stress, along with alterations in lipid metabolism in neurons, may be some of the very early events occurring in AD pathology. Cellular defense mechanisms try to intervene but fail, finally resulting in AD pathology as the disease progresses. Furthermore, disease annotation of the low TO genes in two independent protein interaction networks has resulted in association between cancer, diabetes, renal diseases, and cardiovascular diseases.« less

Problems of interaction longitudinal shear waves with V-shape tunnels defect

NASA Astrophysics Data System (ADS)

Popov, V. G.

2018-04-01

The problem of determining the two-dimensional dynamic stress state near a tunnel defect of V-shaped cross-section is solved. The defect is located in an infinite elastic medium, where harmonic longitudinal shear waves are propagating. The initial problem is reduced to a system of two singular integral or integro-differential equations with fixed singularities. A numerical method for solving these systems with regard to the true asymptotics of the unknown functions is developed.

Successful In Vitro Expansion and Differentiation of Cord Blood Derived CD34+ Cells into Early Endothelial Progenitor Cells Reveals Highly Differential Gene Expression

PubMed Central

Topcic, Denijal; Haviv, Izhak; Merivirta, Ruusu-Maaria; Agrotis, Alexander; Leitner, Ephraem; Jowett, Jeremy B.; Bode, Christoph; Lappas, Martha; Peter, Karlheinz

2011-01-01

Endothelial progenitor cells (EPCs) can be purified from peripheral blood, bone marrow or cord blood and are typically defined by a limited number of cell surface markers and a few functional tests. A detailed in vitro characterization is often restricted by the low cell numbers of circulating EPCs. Therefore in vitro culturing and expansion methods are applied, which allow at least distinguishing two different types of EPCs, early and late EPCs. Herein, we describe an in vitro culture technique with the aim to generate high numbers of phenotypically, functionally and genetically defined early EPCs from human cord blood. Characterization of EPCs was done by flow cytometry, immunofluorescence microscopy, colony forming unit (CFU) assay and endothelial tube formation assay. There was an average 48-fold increase in EPC numbers. EPCs expressed VEGFR-2, CD144, CD18, and CD61, and were positive for acetylated LDL uptake and ulex lectin binding. The cells stimulated endothelial tube formation only in co-cultures with mature endothelial cells and formed CFUs. Microarray analysis revealed highly up-regulated genes, including LL-37 (CAMP), PDK4, and alpha-2-macroglobulin. In addition, genes known to be associated with cardioprotective (GDF15) or pro-angiogenic (galectin-3) properties were also significantly up-regulated after a 72 h differentiation period on fibronectin. We present a novel method that allows to generate high numbers of phenotypically, functionally and genetically characterized early EPCs. Furthermore, we identified several genes newly linked to EPC differentiation, among them LL-37 (CAMP) was the most up-regulated gene. PMID:21858032

Betaine supplementation reduces congenital defects after prenatal alcohol exposure (Conference Presentation)

NASA Astrophysics Data System (ADS)

Karunamuni, Ganga; Gu, Shi; Doughman, Yong Qiu; Sheehan, Megan M.; Ma, Pei; Peterson, Lindsy M.; Linask, Kersti K.; Jenkins, Michael W.; Rollins, Andrew M.; Watanabe, Michiko

2016-03-01

Over 500,000 women per year in the United States drink during pregnancy, and 1 in 5 of this population also binge drink. As high as 20-50% of live-born children with prenatal alcohol exposure (PAE) present with congenital heart defects including outflow and valvuloseptal anomalies that can be life-threatening. Previously we established a model of PAE (modeling a single binge drinking episode) in the avian embryo and used optical coherence tomography (OCT) imaging to assay early-stage cardiac function/structure and late-stage cardiac defects. At early stages, alcohol/ethanol-exposed embryos had smaller cardiac cushions and increased retrograde flow. At late stages, they presented with gross morphological defects in the head and chest wall, and also exhibited smaller or abnormal atrio-ventricular (AV) valves, thinner interventricular septae (IVS), and smaller vessel diameters for the aortic trunk branches. In other animal models, the methyl donor betaine (found naturally in many foods such as wheat bran, quinoa, beets and spinach) ameliorates neurobehavioral deficits associated with PAE but the effects on heart structure are unknown. In our model of PAE, betaine supplementation led to a reduction in gross structural defects and appeared to protect against certain types of cardiac defects such as ventricular septal defects and abnormal AV valvular morphology. Furthermore, vessel diameters, IVS thicknesses and mural AV leaflet volumes were normalized while the septal AV leaflet volume was increased. These findings highlight the importance of betaine and potentially methylation levels in the prevention of PAE-related birth defects which could have significant implications for public health.

Spatiotemporal features of early neuronogenesis differ in wild-type and albino mouse retina

NASA Technical Reports Server (NTRS)

Rachel, Rivka A.; Dolen, Gul; Hayes, Nancy L.; Lu, Alice; Erskine, Lynda; Nowakowski, Richard S.; Mason, Carol A.

2002-01-01

In albino mammals, lack of pigment in the retinal pigment epithelium is associated with retinal defects, including poor visual acuity from a photoreceptor deficit in the central retina and poor depth perception from a decrease in ipsilaterally projecting retinal fibers. Possible contributors to these abnormalities are reported delays in neuronogenesis (Ilia and Jeffery, 1996) and retinal maturation (Webster and Rowe, 1991). To further determine possible perturbations in neuronogenesis and/or differentiation, we used cell-specific markers and refined birth dating methods to examine these events during retinal ganglion cell (RGC) genesis in albino and pigmented mice from embryonic day 11 (E11) to E18. Our data indicate that relative to pigmented mice, more ganglion cells are born in the early stages of neuronogenesis in the albino retina, although the initiation of RGC genesis in the albino is unchanged. The cellular organization of the albino retina is perturbed as early as E12. In addition, cell cycle kinetics and output along the nasotemporal axis differ in retinas of albino and pigmented mice, both absolutely, with the temporal aspect of the retina expanded in albino, and relative to the position of the optic nerve head. Finally, blocking melanin synthesis in pigmented eyecups in culture leads to an increase in RGC differentiation, consistent with a role for melanin formation in regulating RGC neuronogenesis. These results point to spatiotemporal defects in neuronal production in the albino retina, which could perturb expression of genes that specify cell fate, number, and/or projection phenotype.

Characterization of early and late endocytic compartments of the transferrin cycle. Transferrin receptor antibody blocks erythroid differentiation by trapping the receptor in the early endosome.

PubMed

Killisch, I; Steinlein, P; Römisch, K; Hollinshead, R; Beug, H; Griffiths, G

1992-09-01

We describe a detailed morphological characterization of the endocytic pathway in differentiating chicken erythroblasts transformed by a temperature-sensitive mutant of avian erythroblastosis virus (AEV). These cells express high levels of transferrin receptors (TfR) when induced to differentiate at 42 degrees C. Biochemical analysis showed that most (approximately 90%) of the internalized 125I-Tf recycled within approximately 30 min while a smaller fraction of 125I-Tf required up to 2 h for recycling. By immunocytochemistry, the bulk of Tf and TfR was localized at the plasma membrane and in tubuloreticular early endosomes. This structure contained coated buds that labelled with an antibody specific for the clathrin light chain. Decreasing amounts of both Tf and TfR were detected in two distal compartments, spherical endosome vesicles resembling multivesicular bodies and the prelysosomal compartment (PLC) enriched in cation-independent mannose 6-phosphate receptor. As shown by fluorescent (FITC-Tf) labelling of living cells, the movement of Tf/TfR complex into these late structures was accompanied by a significant drop in pH from about 6, the value displayed by early endosomes, to values below pH 5.0. Since no detectable 125I-Tf degradation was observed during a 4 h period we believe that the Tf/TfR detected in these late endocytic structures avoids degradation and recycles back to the cell surface. The addition of an anti-TfR monoclonal antibody to the culture medium of these cells blocks their differentiation. Under this condition the antibody-TfR complex was trapped in an early endosome compartment that enlarged to more than twice its normal size. However, this condition did not affect the transport kinetics of horseradish peroxidase from the medium to the PLC.

Localization of DNA methyltransferase-1 during oocyte differentiation, in vitro maturation and early embryonic development in cow

PubMed Central

Lodde, V.; Modina, S.C.; Franciosi, F.; Zuccari, E.; Tessaro, I.; Luciano, A.M.

2009-01-01

DNA methyltransferase-1 (Dnmt1) is involved in the maintenance of DNA methylation patterns and is crucial for normal mammalian development. The aim of the present study was to assess the localization of Dnmt1 in cow, during the latest phases of oocyte differentiation and during the early stages of segmentation. Dnmt1 expression and localization were assessed in oocytes according to the chromatin configuration, which in turn provides an important epigenetic mechanism for the control of global gene expression and represents a morphological marker of oocyte differentiation. We found that the initial chromatin condensation was accompanied by a slight increase in the level of global DNA methylation, as assessed by 5-methyl-cytosine immunostaining followed by laser scanning confocal microscopy analysis (LSCM). RT-PCR confirmed the presence of Dnmt1 transcripts throughout this phase of oocyte differentiation. Analogously, Dnmt1 immunodetection and LSCM indicated that the protein was always present and localized in the cytoplasm, regardless the chromatin configuration and the level of global DNA methylation. Moreover, our data indicate that while Dnmt1 is retained in the cytoplasm in metaphase II stage oocytes and zygotes, it enters the nuclei of 8–16 cell stage embryos. As suggested in mouse, the functional meaning of the presence of Dnmt1 in the bovine embryo nuclei could be the maintainement of the methylation pattern of imprinted genes. In conclusion, the present work provides useful elements for the study of Dnmt1 function during the late stage of oocyte differentiation, maturation and early embryonic development in mammals. PMID:22073356

An Fgf-Shh signaling hierarchy regulates early specification of the zebrafish skull.

PubMed

McCarthy, Neil; Sidik, Alfire; Bertrand, Julien Y; Eberhart, Johann K

2016-07-15

The neurocranium generates most of the craniofacial skeleton and consists of prechordal and postchordal regions. Although development of the prechordal is well studied, little is known of the postchordal region. Here we characterize a signaling hierarchy necessary for postchordal neurocranial development involving Fibroblast growth factor (Fgf) signaling for early specification of mesodermally-derived progenitor cells. The expression of hyaluron synthetase 2 (has2) in the cephalic mesoderm requires Fgf signaling and Has2 function, in turn, is required for postchordal neurocranial development. While Hedgehog (Hh)-deficient embryos also lack a postchordal neurocranium, this appears primarily due to a later defect in chondrocyte differentiation. Inhibitor studies demonstrate that postchordal neurocranial development requires early Fgf and later Hh signaling. Collectively, our results provide a mechanistic understanding of early postchordal neurocranial development and demonstrate a hierarchy of signaling between Fgf and Hh in the development of this structure. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Smad2 and Smad3 have differential sensitivity in relaying TGFβ signaling and inversely regulate early lineage specification

PubMed Central

Liu, Ling; Liu, Xu; Ren, Xudong; Tian, Yue; Chen, Zhenyu; Xu, Xiangjie; Du, Yanhua; Jiang, Cizhong; Fang, Yujiang; Liu, Zhongliang; Fan, Beibei; Zhang, Quanbin; Jin, Guohua; Yang, Xiao; Zhang, Xiaoqing

2016-01-01

The transforming growth factor beta (TGFβ) related signaling is one of the most important signaling pathways regulating early developmental events. Smad2 and Smad3 are structurally similar and it is mostly considered that they are equally important in mediating TGFβ signals. Here, we show that Smad3 is an insensitive TGFβ transducer as compared with Smad2. Smad3 preferentially localizes within the nucleus and is thus sequestered from membrane signaling. The ability of Smad3 in oligomerization with Smad4 upon agonist stimulation is also impaired given its unique linker region. Smad2 mediated TGFβ signaling plays a crucial role in epiblast development and patterning of three germ layers. However, signaling unrelated nuclear localized Smad3 is dispensable for TGFβ signaling-mediated epiblast specification, but important for early neural development, an event blocked by TGFβ/Smad2 signaling. Both Smad2 and Smad3 bind to the conserved Smads binding element (SBE), but they show nonoverlapped target gene binding specificity and differential transcriptional activity. We conclude that Smad2 and Smad3 possess differential sensitivities in relaying TGFβ signaling and have distinct roles in regulating early developmental events. PMID:26905010

Smad2 and Smad3 have differential sensitivity in relaying TGFβ signaling and inversely regulate early lineage specification.

PubMed

Liu, Ling; Liu, Xu; Ren, Xudong; Tian, Yue; Chen, Zhenyu; Xu, Xiangjie; Du, Yanhua; Jiang, Cizhong; Fang, Yujiang; Liu, Zhongliang; Fan, Beibei; Zhang, Quanbin; Jin, Guohua; Yang, Xiao; Zhang, Xiaoqing

2016-02-24

The transforming growth factor beta (TGFβ) related signaling is one of the most important signaling pathways regulating early developmental events. Smad2 and Smad3 are structurally similar and it is mostly considered that they are equally important in mediating TGFβ signals. Here, we show that Smad3 is an insensitive TGFβ transducer as compared with Smad2. Smad3 preferentially localizes within the nucleus and is thus sequestered from membrane signaling. The ability of Smad3 in oligomerization with Smad4 upon agonist stimulation is also impaired given its unique linker region. Smad2 mediated TGFβ signaling plays a crucial role in epiblast development and patterning of three germ layers. However, signaling unrelated nuclear localized Smad3 is dispensable for TGFβ signaling-mediated epiblast specification, but important for early neural development, an event blocked by TGFβ/Smad2 signaling. Both Smad2 and Smad3 bind to the conserved Smads binding element (SBE), but they show nonoverlapped target gene binding specificity and differential transcriptional activity. We conclude that Smad2 and Smad3 possess differential sensitivities in relaying TGFβ signaling and have distinct roles in regulating early developmental events.

Interleukins 12 and 15 induce cytotoxicity and early NK-cell differentiation in type 3 innate lymphoid cells.

PubMed

Raykova, Ana; Carrega, Paolo; Lehmann, Frank M; Ivanek, Robert; Landtwing, Vanessa; Quast, Isaak; Lünemann, Jan D; Finke, Daniela; Ferlazzo, Guido; Chijioke, Obinna; Münz, Christian

2017-12-26

Type 3 innate lymphoid cells (ILC3s) fulfill protective functions at mucosal surfaces via cytokine production. Although their plasticity to become ILC1s, the innate counterparts of type 1 helper T cells, has been described previously, we report that they can differentiate into cytotoxic lymphocytes with many characteristics of early differentiated natural killer (NK) cells. This transition is promoted by the proinflammatory cytokines interleukin 12 (IL-12) and IL-15, and correlates with expression of the master transcription factor of cytotoxicity, eomesodermin (Eomes). As revealed by transcriptome analysis and flow cytometric profiling, differentiated ILC3s express CD94, NKG2A, NKG2C, CD56, and CD16 among other NK-cell receptors, and possess all components of the cytotoxic machinery. These characteristics allow them to recognize and kill leukemic cells with perforin and granzymes. Therefore, ILC3s can be harnessed for cytotoxic responses via differentiation under the influence of proinflammatory cytokines.

Synergistic promoting effects of bone morphogenetic protein 12/connective tissue growth factor on functional differentiation of tendon derived stem cells and patellar tendon window defect regeneration.

PubMed

Xu, Kang; Sun, Yanjun; Kh Al-Ani, Mohanad; Wang, Chunli; Sha, Yongqiang; Sung, Kl Paul; Dong, Nianguo; Qiu, Xuefeng; Yang, Li

2018-01-03

Current study investigated bone morphogenetic protein 12 (BMP12) and connective tissue growth factor (CTGF) activate tendon derived stem cells (TDSCs) tenogenic differentiation, and promotion of injured tendon regeneration. TDSCs were transfected with BMP12 and CTGF via recombinant adenovirus (Ad) infection. Gene transfection efficiency, cell viability and cytotoxicity, tenogenic gene expression, collagen I/III synthesis were evaluated in vitro. For the in vivo study, the transfected cells were transplanted into the rat patellar tendon window defect. At weeks 2 and 8 of post-surgery, the repaired tendon tissues were harvested for histological and biomechanical examinations. The transfected TDSCs revealed relatively stable transfection efficiency (80-90%) with active cell viability means while rare cytotoxicity in each group. During days 1 and 5, BMP12 and CTGF transfection caused tenogenic differentiation genes activation in TDSCs: type I/III collagen, tenascin-C, and scleraxis were all up-regulated, whereas osteogenic, adipogenic, and chondrogenic markers were all down-regulated respectively. In addition, BMP12 and CTGF overexpression significantly promote type I/III collagen synthesis. After in vivo transplantation, at 2 and 8 weeks post-surgery, BMP12, CTGF and co-transfection groups showed more integrated tendon tissue structure versus control, meanwhile, the ultimate failure loads and Young's were all higher than control. Remarkably, at 8 weeks post-surgery, the biomechanical properties of co-transfection group was approaching to normal rat patellar tendon, moreover, the ratio of type III/I collagen maintained about 20% in each transfection group, meanwhile, the type I collagen were significantly increased with co-transfection treatment. In conclusion, BMP12 and CTGF transfection stimulate tenogenic differentiation of TDSCs. The synergistic effects of simultaneous transfection of both may significantly promoted rat patellar tendon window defect

Osteogenic capability of autologous rabbit adipose-derived stromal cells in repairing calvarial defects.

PubMed

Cheng, Shao-Wen; Lin, Zhong-Qin; Wang, Wei; Zhang, Wei; Kou, Dong-Quan; Ying, Xiao-Zhou; Chen, Qing-Yu; Shen, Yue; Cheng, Xiao-Jie; Peng, Lei; Lv, Chuan-Zhu

2011-01-01

To evaluate the in vitro and in vivo osteogenic capability of adipose-derived stromal cells (ASCs). ASCs were isolated from New Zealand white rabbits and determined by alkaline phosphatase (ALP) staining, von Kossa staining and alizarin red staining. Some specific markers of osteogenic differentiation, including ALP, osteocalcin (OCN), osteopontin (OPN) were examined by reverse transcription-polymerase chain reaction (RT-PCR). In vivo, demineralized bone matrix (DBM)-ASCs composites were implanted into the rabbit calvarial defects created at each side of the longitudinal midline. After 6 weeks, histologic properties of the transplants were analyzed. ASCs were successfully induced into osteogenesis. ALP staining, von Kossa staining and alizarin red staining showed positive results. The expressions of ALP, OCN and OPN were detected in ASCs after cultivation in osteogenic medium. Extensive new bone was observed in the defects transplanted with DBM-ASCs composites. ASCs have the potential to differentiate into osteogenic lineage and DBM-ASCs constructs are a promising method for regeneration in bone defects.

Associations between Maternal Water Consumption and Birth Defects in the National Birth Defects Prevention Study (2000-2005).

PubMed

Alman, Breanna L; Coffman, Evan; Siega-Riz, Anna Maria; Luben, Thomas J

2017-02-15

Water and water-based beverages constitute a major part of daily fluid intake for pregnant women, yet few epidemiologic studies have investigated the role of water consumption on birth outcomes. We used data from the National Birth Defects Prevention Study to conduct a case-control study investigating associations between maternal water consumption during pregnancy and birth defects (BD). We used interview data on water consumption during the first trimester of pregnancy in 14,454 cases (major BDs n ≥ 50) and 5,063 controls. Total water consumption was analyzed as a continuous variable and in quartiles. We evaluated the role of dietary quality and sugar sweetened beverage consumption. Logistic regression models were used to assess effects of water consumption on risk of BDs with adjustment for relevant covariates. Mean daily maternal water consumption among controls was 4.4 eight-ounce glasses. We observed decreases in estimated risk associated with increases in water consumption for several BDs, including neural tube defects (spina bifida), oral clefts (cleft lip), musculoskeletal defects (gastroschisis, limb deficiencies), and congenital heart defects (hypoplastic left heart syndrome, right-sided obstructions, pulmonary valve stenosis). Our results were generally unchanged when an indicator for overall dietary quality was included; however, there was evidence of effect measure modification by heavy consumption of sugar-sweetened beverages for some defects, but not all. These analyses suggest the importance of sufficient water consumption during early pregnancy, above and beyond it being a marker of higher diet quality. Additional analyses are warranted to understand the biological mechanism for this association. Birth Defects Research 109:193-202, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

BM88 is an early marker of proliferating precursor cells that will differentiate into the neuronal lineage.

PubMed

Koutmani, Yassemi; Hurel, Catherine; Patsavoudi, Evangelia; Hack, Michael; Gotz, Magdalena; Thomaidou, Dimitra; Matsas, Rebecca

2004-11-01

Progression of progenitor cells towards neuronal differentiation is tightly linked with cell cycle control and the switch from proliferative to neuron-generating divisions. We have previously shown that the neuronal protein BM88 drives neuroblastoma cells towards exit from the cell cycle and differentiation into a neuronal phenotype in vitro. Here, we explored the role of BM88 during neuronal birth, cell cycle exit and the initiation of differentiation in vivo. By double- and triple-labelling with the S-phase marker BrdU or the late G2 and M-phase marker cyclin B1, antibodies to BM88 and markers of the neuronal or glial cell lineages, we demonstrate that in the rodent forebrain, BM88 is expressed in multipotential progenitor cells before terminal mitosis and in their neuronal progeny during the neurogenic interval, as well as in the adult. Further, we defined at E16 a cohort of proliferative progenitors that exit S phase in synchrony, and by following their fate for 24 h we show that BM88 is associated with the dynamics of neuron-generating divisions. Expression of BM88 was also evident in cycling cortical radial glial cells, which constitute the main neurogenic population in the cerebral cortex. In agreement, BM88 expression was markedly reduced and restricted to a smaller percentage of cells in the cerebral cortex of the Small eye mutant mice, which lack functional Pax6 and exhibit severe neurogenesis defects. Our data show an interesting correlation between BM88 expression and the progression of progenitor cells towards neuronal differentiation during the neurogenic interval.

Investigation of defect modes in a defective photonic crystal with a semiconductor metamaterial defect

NASA Astrophysics Data System (ADS)

Wu, Meng-Ru; Wu, Chien-Jang; Chang, Shoou-Jinn

2014-11-01

In this work, we theoretically investigate the properties of defect modes in a defective photonic crystal containing a semiconductor metamaterial defect. We consider the structure, (LH)N/DP/(LH)N, where N and P are respectively the stack numbers, L is SiO2, H is InP, and defect layer D is a semiconductor metamaterial composed of Al-doped ZnO (AZO) and ZnO. It is found that, within the photonic band gap, the number of defect modes (transmission peaks) will decrease as the defect thickness increases, in sharp contrast to the case of using usual dielectric defect. The peak height and position can be changed by the variation in the thickness of defect layer. In the angle-dependent defect mode, its position is shown to be blue-shifted as the angle of incidence increases for both TE and TM waves. The analysis of defect mode provides useful information for the design of tunable transmission filter in semiconductor optoelectronics.

The Role of Paracrine and Autocrine Signaling in the Early Phase of Adipogenic Differentiation of Adipose-derived Stem Cells

PubMed Central

Hemmingsen, Mette; Vedel, Søren; Skafte-Pedersen, Peder; Sabourin, David; Collas, Philippe; Bruus, Henrik; Dufva, Martin

2013-01-01

Introduction High cell density is known to enhance adipogenic differentiation of mesenchymal stem cells, suggesting secretion of signaling factors or cell-contact-mediated signaling. By employing microfluidic biochip technology, we have been able to separate these two processes and study the secretion pathways. Methods and results Adipogenic differentiation of human adipose-derived stem cells (ASCs) cultured in a microfluidic system was investigated under perfusion conditions with an adipogenic medium or an adipogenic medium supplemented with supernatant from differentiating ASCs (conditioned medium). Conditioned medium increased adipogenic differentiation compared to adipogenic medium with respect to accumulation of lipid-filled vacuoles and gene expression of key adipogenic markers (C/EBPα, C/EBPβ, C/EBPδ, PPARγ, LPL and adiponectin). The positive effects of conditioned medium were observed early in the differentiation process. Conclusions Using different cell densities and microfluidic perfusion cell cultures to suppress the effects of cell-released factors, we have demonstrated the significant role played by auto- or paracrine signaling in adipocyte differentiation. The cell-released factor(s) were shown to act in the recruitment phase of the differentiation process. PMID:23723991

Chemotherapeutic-Induced Cardiovascular Dysfunction: Physiological Effects, Early Detection—The Role of Telomerase to Counteract Mitochondrial Defects and Oxidative Stress

PubMed Central

Quryshi, Nabeel; Norwood Toro, Laura E.; Ait-Aissa, Karima; Kong, Amanda; Beyer, Andreas M.

2018-01-01

Although chemotherapeutics can be highly effective at targeting malignancies, their ability to trigger cardiovascular morbidity is clinically significant. Chemotherapy can adversely affect cardiovascular physiology, resulting in the development of cardiomyopathy, heart failure and microvascular defects. Specifically, anthracyclines are known to cause an excessive buildup of free radical species and mitochondrial DNA damage (mtDNA) that can lead to oxidative stress-induced cardiovascular apoptosis. Therefore, oncologists and cardiologists maintain a network of communication when dealing with patients during treatment in order to treat and prevent chemotherapy-induced cardiovascular damage; however, there is a need to discover more accurate biomarkers and therapeutics to combat and predict the onset of cardiovascular side effects. Telomerase, originally discovered to promote cellular proliferation, has recently emerged as a potential mechanism to counteract mitochondrial defects and restore healthy mitochondrial vascular phenotypes. This review details mechanisms currently used to assess cardiovascular damage, such as C-reactive protein (CRP) and troponin levels, while also unearthing recently researched biomarkers, including circulating mtDNA, telomere length and telomerase activity. Further, we explore a potential role of telomerase in the mitigation of mitochondrial reactive oxygen species and maintenance of mtDNA integrity. Telomerase activity presents a promising indicator for the early detection and treatment of chemotherapy-derived cardiac damage. PMID:29534446

Redundant roles of Sox17 and Sox18 in early cardiovascular development of mouse embryos

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sakamoto, Youhei; Hara, Kenshiro; Kanai-Azuma, Masami

Sox7, -17 and -18 constitute the Sox subgroup F (SoxF) of HMG box transcription factor genes, which all are co-expressed in developing vascular endothelial cells in mice. Here we characterized cardiovascular phenotypes of Sox17/Sox18-double and Sox17-single null embryos during early-somite stages. Whole-mount PECAM staining demonstrated the aberrant heart looping, enlarged cardinal vein and mild defects in anterior dorsal aorta formation in Sox17 single-null embryos. The Sox17/Sox18 double-null embryos showed more severe defects in formation of anterior dorsal aorta and head/cervical microvasculature, and in some cases, aberrant differentiation of endocardial cells and defective fusion of the endocardial tube. However, the posteriormore » dorsal aorta and allantoic microvasculature was properly formed in all of the Sox17/Sox18 double-null embryos. The anomalies in both anterior dorsal aorta and head/cervical vasculature corresponded with the weak Sox7 expression sites. This suggests the region-specific redundant activities of three SoxF members along the anteroposterior axis of embryonic vascular network.« less

Prevention of congenital defects induced by prenatal alcohol exposure (Conference Presentation)

NASA Astrophysics Data System (ADS)

Sheehan, Megan M.; Karunamuni, Ganga; Pedersen, Cameron J.; Gu, Shi; Doughman, Yong Qiu; Jenkins, Michael W.; Watanabe, Michiko; Rollins, Andrew M.

2017-02-01

Over 500,000 women per year in the United States drink during pregnancy, and 1 in 5 of this population also binge drink. Up to 40% of live-born children with prenatal alcohol exposure (PAE) present with congenital heart defects (CHDs) including life-threatening outflow and valvuloseptal anomalies. Previously we established a PAE model in the avian embryo and used optical coherence tomography (OCT) imaging to assay looping-stage (early) cardiac function/structure and septation-stage (late) cardiac defects. Early-stage ethanol-exposed embryos had smaller cardiac cushions (valve precursors) and increased retrograde flow, while late-stage embryos presented with gross head/body defects, and exhibited smaller atrio-ventricular (AV) valves, interventricular septae, and aortic vessels. However, supplementation with the methyl donor betaine reduced gross defects, prevented cardiac defects such as ventricular septal defects and abnormal AV valves, and normalized cardiac parameters. Immunofluorescent staining for 5-methylcytosine in transverse embryo sections also revealed that DNA methylation levels were reduced by ethanol but normalized by co-administration of betaine. Furthermore, supplementation with folate, another methyl donor, in the PAE model appeared to normalize retrograde flow levels which are typically elevated by ethanol exposure. Studies are underway to correlate retrograde flow numbers for folate with associated cushion volumes. Finally, preliminary findings have revealed that glutathione, a key endogenous antioxidant which also regulates methyl group donation, is particularly effective in improving alcohol-impacted survival and gross defect rates. Current investigations will determine whether glutathione has any positive effect on PAE-related CHDs. Our studies could have significant implications for public health, especially related to prenatal nutrition recommendations.

Interpersonal differentiation within depression diagnosis: relating interpersonal subgroups to symptom load and the quality of the early therapeutic alliance.

PubMed

Grosse Holtforth, Martin; Altenstein, David; Krieger, Tobias; Flückiger, Christoph; Wright, Aidan G C; Caspar, Franz

2014-01-01

We examined interpersonal problems in psychotherapy outpatients with a principal diagnosis of a depressive disorder in routine care (n=361). These patients were compared to a normative non-clinical sample and to outpatients with other principal diagnoses (n=959). Furthermore, these patients were statistically assigned to interpersonally defined subgroups that were compared regarding symptoms and the quality of the early alliance. The sample of depressive patients reported higher levels of interpersonal problems than the normative sample and the sample of outpatients without a principal diagnosis of depression. Latent Class Analysis identified eight distinct interpersonal subgroups, which differed regarding self-reported symptom load and the quality of the early alliance. However, therapists' alliance ratings did not differentiate between the groups. This interpersonal differentiation within the group of patients with a principal diagnosis of depression may add to a personalized psychotherapy based on interpersonal profiles.

Circuit Motifs for Contrast-Adaptive Differentiation in Early Sensory Systems: The Role of Presynaptic Inhibition and Short-Term Plasticity

PubMed Central

Zhang, Danke; Wu, Si; Rasch, Malte J.

2015-01-01

In natural signals, such as the luminance value across of a visual scene, abrupt changes in intensity value are often more relevant to an organism than intensity values at other positions and times. Thus to reduce redundancy, sensory systems are specialized to detect the times and amplitudes of informative abrupt changes in the input stream rather than coding the intensity values at all times. In theory, a system that responds transiently to fast changes is called a differentiator. In principle, several different neural circuit mechanisms exist that are capable of responding transiently to abrupt input changes. However, it is unclear which circuit would be best suited for early sensory systems, where the dynamic range of the natural input signals can be very wide. We here compare the properties of different simple neural circuit motifs for implementing signal differentiation. We found that a circuit motif based on presynaptic inhibition (PI) is unique in a sense that the vesicle resources in the presynaptic site can be stably maintained over a wide range of stimulus intensities, making PI a biophysically plausible mechanism to implement a differentiator with a very wide dynamical range. Moreover, by additionally considering short-term plasticity (STP), differentiation becomes contrast adaptive in the PI-circuit but not in other potential neural circuit motifs. Numerical simulations show that the behavior of the adaptive PI-circuit is consistent with experimental observations suggesting that adaptive presynaptic inhibition might be a good candidate neural mechanism to achieve differentiation in early sensory systems. PMID:25723493

Circuit motifs for contrast-adaptive differentiation in early sensory systems: the role of presynaptic inhibition and short-term plasticity.

PubMed

Zhang, Danke; Wu, Si; Rasch, Malte J

2015-01-01

In natural signals, such as the luminance value across of a visual scene, abrupt changes in intensity value are often more relevant to an organism than intensity values at other positions and times. Thus to reduce redundancy, sensory systems are specialized to detect the times and amplitudes of informative abrupt changes in the input stream rather than coding the intensity values at all times. In theory, a system that responds transiently to fast changes is called a differentiator. In principle, several different neural circuit mechanisms exist that are capable of responding transiently to abrupt input changes. However, it is unclear which circuit would be best suited for early sensory systems, where the dynamic range of the natural input signals can be very wide. We here compare the properties of different simple neural circuit motifs for implementing signal differentiation. We found that a circuit motif based on presynaptic inhibition (PI) is unique in a sense that the vesicle resources in the presynaptic site can be stably maintained over a wide range of stimulus intensities, making PI a biophysically plausible mechanism to implement a differentiator with a very wide dynamical range. Moreover, by additionally considering short-term plasticity (STP), differentiation becomes contrast adaptive in the PI-circuit but not in other potential neural circuit motifs. Numerical simulations show that the behavior of the adaptive PI-circuit is consistent with experimental observations suggesting that adaptive presynaptic inhibition might be a good candidate neural mechanism to achieve differentiation in early sensory systems.

Understanding and reduction of defects on finished EUV masks

NASA Astrophysics Data System (ADS)

Liang, Ted; Sanchez, Peter; Zhang, Guojing; Shu, Emily; Nagpal, Rajesh; Stivers, Alan

2005-05-01

To reduce the risk of EUV lithography adaptation for the 32nm technology node in 2009, Intel has operated a EUV mask Pilot Line since early 2004. The Pilot Line integrates all the necessary process modules including common tool sets shared with current photomask production as well as EUV specific tools. This integrated endeavor ensures a comprehensive understanding of any issues, and development of solutions for the eventual fabrication of defect-free EUV masks. Two enabling modules for "defect-free" masks are pattern inspection and repair, which have been integrated into the Pilot Line. This is the first time we are able to look at real defects originated from multilayer blanks and patterning process on finished masks over entire mask area. In this paper, we describe our efforts in the qualification of DUV pattern inspection and electron beam mask repair tools for Pilot Line operation, including inspection tool sensitivity, defect classification and characterization, and defect repair. We will discuss the origins of each of the five classes of defects as seen by DUV pattern inspection tool on finished masks, and present solutions of eliminating and mitigating them.

Early In Vitro Differentiation of Mouse Definitive Endoderm Is Not Correlated with Progressive Maturation of Nuclear DNA Methylation Patterns

PubMed Central

Tajbakhsh, Jian; Gertych, Arkadiusz; Fagg, W. Samuel; Hatada, Seigo; Fair, Jeffrey H.

2011-01-01

The genome organization in pluripotent cells undergoing the first steps of differentiation is highly relevant to the reprogramming process in differentiation. Considering this fact, chromatin texture patterns that identify cells at the very early stage of lineage commitment could serve as valuable tools in the selection of optimal cell phenotypes for regenerative medicine applications. Here we report on the first-time use of high-resolution three-dimensional fluorescence imaging and comprehensive topological cell-by-cell analyses with a novel image-cytometrical approach towards the identification of in situ global nuclear DNA methylation patterns in early endodermal differentiation of mouse ES cells (up to day 6), and the correlations of these patterns with a set of putative markers for pluripotency and endodermal commitment, and the epithelial and mesenchymal character of cells. Utilizing this in vitro cell system as a model for assessing the relationship between differentiation and nuclear DNA methylation patterns, we found that differentiating cell populations display an increasing number of cells with a gain in DNA methylation load: first within their euchromatin, then extending into heterochromatic areas of the nucleus, which also results in significant changes of methylcytosine/global DNA codistribution patterns. We were also able to co-visualize and quantify the concomitant stochastic marker expression on a per-cell basis, for which we did not measure any correlation to methylcytosine loads or distribution patterns. We observe that the progression of global DNA methylation is not correlated with the standard transcription factors associated with endodermal development. Further studies are needed to determine whether the progression of global methylation could represent a useful signature of cellular differentiation. This concept of tracking epigenetic progression may prove useful in the selection of cell phenotypes for future regenerative medicine

Fos Promotes Early Stage Teno-Lineage Differentiation of Tendon Stem/Progenitor Cells in Tendon.

PubMed

Chen, Jialin; Zhang, Erchen; Zhang, Wei; Liu, Zeyu; Lu, Ping; Zhu, Ting; Yin, Zi; Backman, Ludvig J; Liu, Huanhuan; Chen, Xiao; Ouyang, Hongwei

2017-11-01

Stem cells have been widely used in tendon tissue engineering. The lack of refined and controlled differentiation strategy hampers the tendon repair and regeneration. This study aimed to find new effective differentiation factors for stepwise tenogenic differentiation. By microarray screening, the transcript factor Fos was found to be expressed in significantly higher amounts in postnatal Achilles tendon tissue derived from 1 day as compared with 7-days-old rats. It was further confirmed that expression of Fos decreased with time in postnatal rat Achilles tendon, which was accompanied with the decreased expression of multiply tendon markers. The expression of Fos also declined during regular in vitro cell culture, which corresponded to the loss of tendon phenotype. In a cell-sheet and a three-dimensional cell culture model, the expression of Fos was upregulated as compared with in regular cell culture, together with the recovery of tendon phenotype. In addition, significant higher expression of tendon markers was found in Fos-overexpressed tendon stem/progenitor cells (TSPCs), and Fos knock-down gave opposite results. In situ rat tendon repair experiments found more normal tendon-like tissue formed and higher tendon markers expression at 4 weeks postimplantation of Fos-overexpressed TSPCs derived nonscaffold engineering tendon (cell-sheet), as compared with the control group. This study identifies Fos as a new marker and functional driver in the early stage teno-lineage differentiation of tendon, which paves the way for effective stepwise tendon differentiation and future tendon regeneration. Stem Cells Translational Medicine 2017;6:2009-2019. © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Identification of nickel response genes in abnormal early developments of sea urchin by differential display polymerase chain reaction.

PubMed

Ryu, Tae Kwon; Lee, Gunsup; Rhee, Yong; Park, Heung-Sik; Chang, Man; Lee, Sukchan; Lee, Jaean; Lee, Taek-Kyun

2012-10-01

Bioassays and biomarkers have been previously developed to assess the effects of heavy metal contaminants on the early life stages of the sea urchin. In this study, malformation in the early developmental processes was observed in sea urchin (Strongylocentrotus intermedius) larvae exposed to 10 ppm Ni for over 30 h. The most critical stage at which the triggering of nickel effects takes place is thought to be the blastula stage, which occurs after fertilization in larval development. To investigate the molecular-level responses of sea urchin exposed to heavy metal stress and to explore the differentially expressed genes that are induced or repressed by nickel, differential display polymerase chain reaction (DD-PCR) was used with sea urchin mRNAs. The malformation-related genes expressed in the early life stages of the sea urchin were cloned from larvae exposed to 10 ppm of nickel for 15 h, and accessed via DD-PCR. Sequence analysis results revealed that each of the genes evidenced high homology with EGF2, PCSK9, serine/threonine protein kinase, apolipophorin precursor protein, and MGC80921 protein/transcript variant 2. This result may prove useful in the development of novel biomarkers for the assessment of heavy metal stresses on sea urchin embryos. Copyright © 2012 Elsevier Inc. All rights reserved.

Stromal cell markers are differentially expressed in the synovial tissue of patients with early arthritis.

PubMed

Choi, Ivy Y; Karpus, Olga N; Turner, Jason D; Hardie, Debbie; Marshall, Jennifer L; de Hair, Maria J H; Maijer, Karen I; Tak, Paul P; Raza, Karim; Hamann, Jörg; Buckley, Christopher D; Gerlag, Danielle M; Filer, Andrew

2017-01-01

Previous studies have shown increased expression of stromal markers in synovial tissue (ST) of patients with established rheumatoid arthritis (RA). Here, ST expression of stromal markers in early arthritis in relationship to diagnosis and prognostic outcome was studied. ST from 56 patients included in two different early arthritis cohorts and 7 non-inflammatory controls was analysed using immunofluorescence to detect stromal markers CD55, CD248, fibroblast activation protein (FAP) and podoplanin. Diagnostic classification (gout, psoriatic arthritis, unclassified arthritis (UA), parvovirus associated arthritis, reactive arthritis and RA), disease outcome (resolving vs persistent) and clinical variables were determined at baseline and after follow-up, and related to the expression of stromal markers. We observed expression of all stromal markers in ST of early arthritis patients, independent of diagnosis or prognostic outcome. Synovial expression of FAP was significantly higher in patients developing early RA compared to other diagnostic groups and non-inflammatory controls. In RA FAP protein was expressed in both lining and sublining layers. Podoplanin expression was higher in all early inflammatory arthritis patients than controls, but did not differentiate diagnostic outcomes. Stromal marker expression was not associated with prognostic outcomes of disease persistence or resolution. There was no association with clinical or sonographic variables. Stromal cell markers CD55, CD248, FAP and podoplanin are expressed in ST in the earliest stage of arthritis. Baseline expression of FAP is higher in early synovitis patients who fulfil classification criteria for RA over time. These results suggest that significant fibroblast activation occurs in RA in the early window of disease.

Perfusion defects in pulmonary perfusion iodine maps: causes and semiology.

PubMed

Bustos Fiore, A; González Vázquez, M; Trinidad López, C; Mera Fernández, D; Costas Álvarez, M

2017-12-14

to describe the usefulness of dual-energy CT for obtaining pulmonary perfusion maps to provide morphological and functional information in patients with pulmonary embolisms. To review the semiology of perfusion defects due to pulmonary embolism so they can be differentiated from perfusion defects due to other causes: alterations outside the range used in the iodine map caused by other diseases of the lung parenchyma or artifacts. CT angiography of the pulmonary arteries is the technique of choice for the diagnosis of pulmonary embolisms. New dual-energy CT scanners are useful for detecting perfusion defects secondary to complete or partial obstruction of pulmonary arteries and is most useful for detecting pulmonary embolisms in subsegmental branches. Copyright © 2017 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

Cor triatriatum dexter associated with atrial septal defect: Management in a complex clinical case.

PubMed

Sozzi, Fabiola B; Montanaro, Claudia; Bacà, Laura; Viani, Giacomo M; Zilocchi, Massimo; Canetta, Ciro; Meazza, Roberto; Pavone, Laura; Lombardi, Federico

2017-11-01

The coexistence of an atrial septal defect and a prominent eustachian valve is a rare congenital anomaly, rarely reported in literature. Differentiation between a giant eustachian valve and cor triatriatum dexter can be difficult. A case of a large atrial septal defect associated with cor triatriatum dexter diagnosed by echocardiography in an asymptomatic woman is reported. A watchful waiting strategy was adopted. © 2017, Wiley Periodicals, Inc.

Large-scale generation of human iPSC-derived neural stem cells/early neural progenitor cells and their neuronal differentiation.

PubMed

D'Aiuto, Leonardo; Zhi, Yun; Kumar Das, Dhanjit; Wilcox, Madeleine R; Johnson, Jon W; McClain, Lora; MacDonald, Matthew L; Di Maio, Roberto; Schurdak, Mark E; Piazza, Paolo; Viggiano, Luigi; Sweet, Robert; Kinchington, Paul R; Bhattacharjee, Ayantika G; Yolken, Robert; Nimgaonka, Vishwajit L; Nimgaonkar, Vishwajit L

2014-01-01

Induced pluripotent stem cell (iPSC)-based technologies offer an unprecedented opportunity to perform high-throughput screening of novel drugs for neurological and neurodegenerative diseases. Such screenings require a robust and scalable method for generating large numbers of mature, differentiated neuronal cells. Currently available methods based on differentiation of embryoid bodies (EBs) or directed differentiation of adherent culture systems are either expensive or are not scalable. We developed a protocol for large-scale generation of neuronal stem cells (NSCs)/early neural progenitor cells (eNPCs) and their differentiation into neurons. Our scalable protocol allows robust and cost-effective generation of NSCs/eNPCs from iPSCs. Following culture in neurobasal medium supplemented with B27 and BDNF, NSCs/eNPCs differentiate predominantly into vesicular glutamate transporter 1 (VGLUT1) positive neurons. Targeted mass spectrometry analysis demonstrates that iPSC-derived neurons express ligand-gated channels and other synaptic proteins and whole-cell patch-clamp experiments indicate that these channels are functional. The robust and cost-effective differentiation protocol described here for large-scale generation of NSCs/eNPCs and their differentiation into neurons paves the way for automated high-throughput screening of drugs for neurological and neurodegenerative diseases.

Differanisole A, an inducer of the differentiation of Friend leukemic cells, induces stalk cell differentiation in Dictyostelium discoideum.

PubMed

Kubohara, Y; Okamoto, K; Tanaka, Y; Asahi, K; Sakurai, A; Takahashi, N

1993-05-03

Differanisole A isolated from the conditioned medium of a soil microorganism, Chaetomium strain RB-001, is an inducer of the differentiation of the Friend leukemic cells (mouse leukemia cells). The chemical structure of this substance is very similar to that of stalk cell differentiation-inducing factor (DIF) isolated from the cellular slime mould, Dictyostelium discoideum. We examined the effects of differanisole A on Dictyostelium HM44 cells, a mutant strain which is defective in DIF production, and found this substance to be an inducer of stalk cell differentiation in D. discoideum.

High Cycle Fatigue Properties Of Electron Beam Melted TI-6AL-4V Samples Without And With Integrated Defects ("Effects Of Defects")

NASA Astrophysics Data System (ADS)

Brandl, Erhard; Greitemeier, Daniel; Maier, Hans Jurgen; Syassen, Freerk

2012-07-01

The understanding of additive manufactured material properties is still at an early stage and mostly not profound. Nowadays, there is only little experience in predicting the effect of defects (e.g. porosity, unmelted spots, insufficient bonding between the layers) on the fatigue behaviour. In this paper, some of these questions are adressed. An electron beam melting process is used to manufacture Ti-6Al-4V high cycle fatigue samples without and with intentionally integrated defects inside of the samples. The samples were annealed or hot isostatically pressed. The defects were analysed by non- destructive methods before and by light/electron microscopy after the tests. In order to predict the high cycle fatigue properties, the crack propagation properties of the material (da/dN - ΔK curve) were tested and AFGROW simulation was used.

Bendectin and birth defects. II: Ecological analyses.

PubMed

Kutcher, Jeffrey S; Engle, Arnold; Firth, Jacqueline; Lamm, Steven H

2003-02-01

Bendectin was the primary pharmaceutical treatment of nausea and vomiting of pregnancy (NVP) in the United States until the early 1980s. Its manufacture was then discontinued after public allegations that it was causing birth defects. Subsequently, meta-analyses of the many epidemiological cohort and case/control studies used to examine that hypothesis have demonstrated the absence of a detectable teratogenic effect. This study presents an ecological analysis of the same hypothesis that examines specific malformations. Annual birth defect prevalence data for the 1970s to the 1990s have been obtained for specific birth defects from the Center for Disease Control's nationwide Birth Defect Monitoring Program. These data for the US have been compared graphically to the annual US Bendectin sales for the treatment of NVP. Data have also been obtained for annual US rates for hospitalization for NVP. The three data sets have been temporally compared in graphic analysis. The temporal trends in prevalence rates for specific birth defects examined from 1970 through 1992 did not show changes that reflected the cessation of Bendectin use over the 1980-84 period. Further, the NVP hospitalization rate doubled when Bendectin use ceased. The population results of the ecological analyses complement the person-specific results of the epidemiological analyses in finding no evidence of a teratogenic effect from the use of Bendectin.

Early detection of myocardial infarction following blunt chest trauma by computed tomography: a case report.

PubMed

Lee, Thung-Lip; Hsuan, Chin-Feng; Shih, Chen-Hsiang; Liang, Huai-Wen; Tsai, Hsing-Shan; Tseng, Wei-Kung; Hsu, Kwan-Lih

2017-02-10

Blunt cardiac trauma encompasses a wide range of clinical entities, including myocardial contusion, cardiac rupture, valve avulsion, pericardial injuries, arrhythmia, and even myocardial infarction. Acute myocardial infarction due to coronary artery dissection after blunt chest trauma is rare and may be life threatening. Differential diagnosis of acute myocardial infarction from cardiac contusion at this setting is not easy. Here we demonstrated a case of blunt chest trauma, with computed tomography detected myocardium enhancement defect early at emergency department. Under the impression of acute myocardial infarction, emergent coronary angiography revealed left anterior descending artery occlusion. Revascularization was performed and coronary artery dissection was found after thrombus aspiration. Finally, the patient survived after coronary stenting. Perfusion defects of myocardium enhancement on CT after blunt chest trauma can be very helpful to suggest myocardial infarction and facilitate the decision making of emergent procedure. This valuable sign should not be missed during the initial interpretation.

Bad habits and bad genes: early 20th-century eugenic attempts to eliminate syphilis and associated "defects" from the United States.

PubMed

Wilson, Philip K

2003-01-01

American eugenists in the early 20th century distinguished "degenerates," including syphilitics, prostitutes, alcoholics and criminals, from the "normal" population by their particular bad habits. From eugenists' viewpoint, these bad habits were derived from bad character, a flaw that stemmed from an individual's bad genes. This essay explores how eugenists during this period characterized syphilitics and those with associated character "defects" in terms of heredity. Additionally, it examines the methods eugenists most frequently advocated to rectify these bad habits. These methods included marriage restriction, immigration control and reproductive sterilization. Overall, eugenists directed their efforts not so much at the "degenerate" as at his or her germ line.

Early exposure to interleukin-21 limits rapidly generated anti-Epstein-Barr virus T-cell line differentiation.

PubMed

Orio, Julie; Carli, Cédric; Janelle, Valérie; Giroux, Martin; Taillefer, Julie; Goupil, Mathieu; Richaud, Manon; Roy, Denis-Claude; Delisle, Jean-Sébastien

2015-04-01

The adoptive transfer of ex vivo-expanded Epstein-Barr virus (EBV)-specific T-cell lines is an attractive strategy to treat EBV-related neoplasms. Current evidence suggests that for adoptive immunotherapy in general, clinical responses are superior if the transferred cells have not reached a late or terminal effector differentiation phenotype before infusion. The cytokine interleukin (IL)-21 has shown great promise at limiting late T-cell differentiation in vitro, but this remains to be demonstrated in anti-viral T-cell lines. We adapted a clinically validated protocol to rapidly generate EBV-specific T-cell lines in 12 to 14 days and tested whether the addition of IL-21 at the initiation of the culture would affect T-cell expansion and differentiation. We generated clinical-scale EBV-restricted T-cell line expansion with balanced T-cell subset ratios. The addition of IL-21 at the beginning of the culture decreased both T-cell expansion and effector memory T-cell accumulation, with a relative increase in less-differentiated T cells. Within CD4 T-cell subsets, exogenous IL-21 was notably associated with the cell surface expression of CD27 and high KLF2 transcript levels, further arguing for a role of IL-21 in the control of late T-cell differentiation. Our results show that IL-21 has profound effects on T-cell differentiation in a rapid T-cell line generation protocol and as such should be further explored as a novel approach to program anti-viral T cells with features associated with early differentiation and optimal therapeutic efficacy. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Birth Defects

MedlinePlus

... both. Some birth defects like cleft lip or neural tube defects are structural problems that can be ... during pregnancy is a key factor in causing neural tube defects. For most birth defects, the cause ...

Definition of a new thermal contrast and pulse correction for defect quantification in pulsed thermography

NASA Astrophysics Data System (ADS)

Benítez, Hernán D.; Ibarra-Castanedo, Clemente; Bendada, AbdelHakim; Maldague, Xavier; Loaiza, Humberto; Caicedo, Eduardo

2008-01-01

It is well known that the methods of thermographic non-destructive testing based on the thermal contrast are strongly affected by non-uniform heating at the surface. Hence, the results obtained from these methods considerably depend on the chosen reference point. The differential absolute contrast (DAC) method was developed to eliminate the need of determining a reference point that defined the thermal contrast with respect to an ideal sound area. Although, very useful at early times, the DAC accuracy decreases when the heat front approaches the sample rear face. We propose a new DAC version by explicitly introducing the sample thickness using the thermal quadrupoles theory and showing that the new DAC range of validity increases for long times while preserving the validity for short times. This new contrast is used for defect quantification in composite, Plexiglas™ and aluminum samples.

Triple DMARD treatment in early rheumatoid arthritis modulates synovial T cell activation and plasmablast/plasma cell differentiation pathways

PubMed Central

Wechalekar, Mihir D.; Guo, Yanxia; Yin, Xuefeng; Weedon, Helen; Proudman, Susanna M.; Smith, Malcolm D.; Nagpal, Sunil

2017-01-01

Objectives This study sought to investigate the genome-wide transcriptional effects of a combination of disease modifying anti-rheumatic drugs (tDMARD; methotrexate, sulfasalazine and hydroxychloroquine) in synovial tissues obtained from early rheumatoid arthritis (RA) patients. While combination DMARD strategies have been investigated for clinical efficacy, very little data exists on the potential molecular mechanism of action. We hypothesized that tDMARD would impact multiple biological pathways, but the specific pathways were unknown. Methods Paired synovial biopsy samples from early RA patients before and after 6 months of tDMARD therapy were collected by arthroscopy (n = 19). These biopsies as well as those from subjects with normal synovium (n = 28) were profiled by total RNA sequencing. Results Large differences in gene expression between RA and control biopsies (over 5000 genes) were identified. Despite clinical efficacy, the expression of a restricted set of less than 300 genes was reversed after 6 months of treatment. Many genes remained elevated, even in patients who achieved low disease activity. Interestingly, tDMARD downregulated genes included those involved in T cell activation and signaling and plasmablast/plasma cell differentiation and function. Conclusions We have identified transcriptomic signatures that characterize synovial tissue from RA patients with early disease. Analysis after 6 months of tDMARD treatment highlight consistent alterations in expression of genes related to T cell activation and plasmablast/plasma cell differentiation. These results provide novel insight into the biology of early RA and the mechanism of tDMARD action and may help identify novel drug targets to improve rates of treatment-induced disease remission. PMID:28863153

Triple DMARD treatment in early rheumatoid arthritis modulates synovial T cell activation and plasmablast/plasma cell differentiation pathways.

PubMed

Walsh, Alice M; Wechalekar, Mihir D; Guo, Yanxia; Yin, Xuefeng; Weedon, Helen; Proudman, Susanna M; Smith, Malcolm D; Nagpal, Sunil

2017-01-01

This study sought to investigate the genome-wide transcriptional effects of a combination of disease modifying anti-rheumatic drugs (tDMARD; methotrexate, sulfasalazine and hydroxychloroquine) in synovial tissues obtained from early rheumatoid arthritis (RA) patients. While combination DMARD strategies have been investigated for clinical efficacy, very little data exists on the potential molecular mechanism of action. We hypothesized that tDMARD would impact multiple biological pathways, but the specific pathways were unknown. Paired synovial biopsy samples from early RA patients before and after 6 months of tDMARD therapy were collected by arthroscopy (n = 19). These biopsies as well as those from subjects with normal synovium (n = 28) were profiled by total RNA sequencing. Large differences in gene expression between RA and control biopsies (over 5000 genes) were identified. Despite clinical efficacy, the expression of a restricted set of less than 300 genes was reversed after 6 months of treatment. Many genes remained elevated, even in patients who achieved low disease activity. Interestingly, tDMARD downregulated genes included those involved in T cell activation and signaling and plasmablast/plasma cell differentiation and function. We have identified transcriptomic signatures that characterize synovial tissue from RA patients with early disease. Analysis after 6 months of tDMARD treatment highlight consistent alterations in expression of genes related to T cell activation and plasmablast/plasma cell differentiation. These results provide novel insight into the biology of early RA and the mechanism of tDMARD action and may help identify novel drug targets to improve rates of treatment-induced disease remission.

Scanning electron microscope automatic defect classification of process induced defects

NASA Astrophysics Data System (ADS)

Wolfe, Scott; McGarvey, Steve

2017-03-01

With the integration of high speed Scanning Electron Microscope (SEM) based Automated Defect Redetection (ADR) in both high volume semiconductor manufacturing and Research and Development (R and D), the need for reliable SEM Automated Defect Classification (ADC) has grown tremendously in the past few years. In many high volume manufacturing facilities and R and D operations, defect inspection is performed on EBeam (EB), Bright Field (BF) or Dark Field (DF) defect inspection equipment. A comma separated value (CSV) file is created by both the patterned and non-patterned defect inspection tools. The defect inspection result file contains a list of the inspection anomalies detected during the inspection tools' examination of each structure, or the examination of an entire wafers surface for non-patterned applications. This file is imported into the Defect Review Scanning Electron Microscope (DRSEM). Following the defect inspection result file import, the DRSEM automatically moves the wafer to each defect coordinate and performs ADR. During ADR the DRSEM operates in a reference mode, capturing a SEM image at the exact position of the anomalies coordinates and capturing a SEM image of a reference location in the center of the wafer. A Defect reference image is created based on the Reference image minus the Defect image. The exact coordinates of the defect is calculated based on the calculated defect position and the anomalies stage coordinate calculated when the high magnification SEM defect image is captured. The captured SEM image is processed through either DRSEM ADC binning, exporting to a Yield Analysis System (YAS), or a combination of both. Process Engineers, Yield Analysis Engineers or Failure Analysis Engineers will manually review the captured images to insure that either the YAS defect binning is accurately classifying the defects or that the DRSEM defect binning is accurately classifying the defects. This paper is an exploration of the feasibility of the

Dictyostelium discoideum mutants with conditional defects in phagocytosis

PubMed Central

1994-01-01

We have isolated and characterized Dictyostelium discoideum mutants with conditional defects in phagocytosis. Under suspension conditions, the mutants exhibited dramatic reductions in the uptake of bacteria and polystyrene latex beads. The initial binding of these ligands was unaffected, however, indicating that the defect was not in a plasma membrane receptor: Because of the phagocytosis defect, the mutants were unable to grow when cultured in suspensions of heat-killed bacteria. The mutants exhibited normal capacities for fluid phase endocytosis and grew as rapidly as parental (AX4) cells in axenic medium. Both the defects in phagocytosis and growth on bacteria were corrected when the mutant Dictyostelium cells were cultured on solid substrates. Reversion and genetic complementation analysis suggested that the mutant phenotypes were caused by single gene defects. While the precise site of action of the mutations was not established, the mutations are likely to affect an early signaling event because the binding of bacteria to mutant cells in suspension was unable to trigger the localized polymerization of actin filaments required for ingestion; other aspects of actin function appeared normal. This class of conditional phagocytosis mutant should prove to be useful for the expression cloning of the affected gene(s). PMID:7519624

The differential effect of basic fibroblast growth factor and stromal cell‑derived factor‑1 pretreatment on bone morrow mesenchymal stem cells osteogenic differentiation potency.

PubMed

Wang, Ruolin; Liu, Wenhua; Du, Mi; Yang, Chengzhe; Li, Xuefen; Yang, Pishan

2018-03-01

In situ tissue engineering has become a novel strategy to repair periodontal/bone tissue defects. The choice of cytokines that promote the recruitment and proliferation, and potentiate and maintain the osteogenic differentiation ability of mesenchymal stem cells (MSCs) is the key point in this technique. Stromal cell‑derived factor‑1 (SDF‑1) and basic fibroblast growth factor (bFGF) have the ability to promote the recruitment, and proliferation of MSCs; however, the differential effect of SDF‑1 and bFGF pretreatment on MSC osteogenic differentiation potency remains to be explored. The present study comparatively observed osteogenic differentiation of bone morrow MSCs (BMMSCs) pretreated by bFGF or SDF‑1 in vitro. The gene and protein expression levels of alkaline phosphatase (ALP), runt related transcription factor 2 (Runx‑2) and bone sialoprotein (BSP) were detected using reverse transcription‑quantitative polymerase chain reaction and western blotting. The results showed that the expression of ALP mRNA on day 3, and BSP and Runx‑2 mRNA on day 7 in the bFGF pretreatment group was significantly higher than those in SDF‑1 pretreatment group. Expression levels of Runx‑2 mRNA, and ALP and Runx‑2 protein on day 3 in the SDF‑1 pretreatment group were higher than those in the bFGF pretreatment group. However, there was no significant difference in osteogenic differentiation ability on day 14 and 28 between the bFGF‑ or SDF‑1‑pretreatment groups and the control. In conclusion, bFGF and SDF‑1 pretreatment inhibits osteogenic differentiation of BMMSCs at the early stage, promotes it in the medium phase, and maintains it in the later stage during osteogenic induction, particularly at the mRNA level. Out of the two cytokines, bFGF appeared to have a greater effect on osteogenic differentiation.

Deformation of a crystalline olivine aggregate containing two immiscible liquids: Implications for early core-mantle differentiation

NASA Astrophysics Data System (ADS)

Cerantola, V.; Walte, N. P.; Rubie, D. C.

2015-05-01

Deformation-assisted segregation of metallic and sulphidic liquid from a solid peridotitic matrix is a process that may contribute to the early differentiation of small planetesimals into a metallic core and a silicate mantle. Here we present results of an experimental study using a simplified system consisting of a polycrystalline Fo90-olivine matrix containing a small percentage of iron sulphide and a synthetic primitive MORB melt, in order to investigate whether the silicate melt enhances the interconnection and segregation of FeS liquid under deformation conditions at varying strain rates. The experiments have been performed at 2 GPa, 1450 °C and strain rates between 1 ×10-3s-1 to 1 ×10-5s-1. Our results show that the presence of silicate melt actually hinders the migration and segregation of sulphide liquid by reducing its interconnectivity. At low to moderate strain rates the sulphide liquid pockets preserved a roundish shape, showing the liquid behavior is governed mainly by surface tension rather than by differential stress. Even at the highest strain rates, insignificant FeS segregation and interconnection were observed. On the other hand the basaltic melt was very mobile during deformation, accommodating part of the strain, which led to its segregation from the matrix at high bulk strains leaving the sulphide liquid stranded in the olivine matrix. Hence, we conclude that deformation-induced percolation of sulphide liquid does not contribute to the formation of planetary cores after the silicate solidus is overstepped. A possible early deformation enhanced core-mantle differentiation after overstepping the Fe-S solidus is not possible between the initial formation of silicate melt and the formation of a widespread magma ocean.

Investigation of intrinsic and extrinsic defects effective role on producing intense red emission in ZnO:Eu nanostructures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Najafi, Mehrdad, E-mail: najafi@shahroodut.ac.ir; Haratizadeh, Hamid

2015-05-15

Highlights: • Effective role of defects on producing red emission at indirect excitation. • V{sub Zn} and V{sub O} defects have important role on energy transfer. • Mg related defects and Zn{sub i} defects were responsible for blue emission. • Extrinsic and intrinsic defects mediated energy transfer to sensitize Eu{sup 3+} ions. • Decrease of red emission because of diminishing in oxygen vacancy. - Abstract: Europium doped ZnO nanorads and nanosheets were synthesized by hydrothermal method. Effects of Mg doping, morphology and annealing in oxygen ambient on structural and optical properties of ZnO nanostructures were investigated using X-ray diffraction (XRD),more » particle size analysis (PSA), thermo gravimetric analysis (TGA), differential thermal analysis (DTA), differential thermo gravimetry (DTG), scanning electron microscopy (SEM) and photoluminescence spectroscopy (PL). This study recommends that both of intrinsic and extrinsic defects facilitate energy transfer (ET) from the ZnO host to Eu{sup 3+} ions and consequently have efficient role on producing intense red emission at indirect excitation. The results also showed that annealing process improved the crystal structure of ZnO nanosheets due to decrease of surface defects; however decreased ET and red emission because of diminishing in oxygen vacancy. In addition in ZnO nanorods sample with more surface area in comparison with ZnO nanosheets sample deep level emissions are enhanced.« less

Differential Training Facilitates Early Consolidation in Motor Learning

PubMed Central

Henz, Diana; Schöllhorn, Wolfgang I.

2016-01-01

Current research demonstrates increased learning rates in differential learning (DL) compared to repetitive training. To date, little is known on the underlying neurophysiological processes in DL that contribute to superior performance over repetitive practice. In the present study, we measured electroencephalographic (EEG) brain activation patterns after DL and repetitive badminton serve training. Twenty-four semi-professional badminton players performed badminton serves in a DL and repetitive training schedule in a within-subjects design. EEG activity was recorded from 19 electrodes according to the 10–20 system before and immediately after each 20-min exercise. Increased theta activity was obtained in contralateral parieto-occipital regions after DL. Further, increased posterior alpha activity was obtained in DL compared to repetitive training. Results indicate different underlying neuronal processes in DL and repetitive training with a higher involvement of parieto-occipital areas in DL. We argue that DL facilitates early consolidation in motor learning indicated by post-training increases in theta and alpha activity. Further, brain activation patterns indicate somatosensory working memory processes where attentional resources are allocated in processing of somatosensory information in DL. Reinforcing a somatosensory memory trace might explain increased motor learning rates in DL. Finally, this memory trace is more stable against interference from internal and external disturbances that afford executively controlled processing such as attentional processes. PMID:27818627

Impact of interstitial iron on the study of meta-stable B-O defects in Czochralski silicon: Further evidence of a single defect

NASA Astrophysics Data System (ADS)

Kim, Moonyong; Chen, Daniel; Abbott, Malcolm; Nampalli, Nitin; Wenham, Stuart; Stefani, Bruno; Hallam, Brett

2018-04-01

We explore the influence of interstitial iron (Fei) on lifetime spectroscopy of boron-oxygen (B-O) related degradation in p-type Czochralski silicon. Theoretical and experimental evidence presented in this study indicate that iron-boron pair (Fe-B) related reactions could have influenced several key experimental results used to derive theories on the fundamental properties of the B-O defect. Firstly, the presence of Fei can account for higher apparent capture cross-section ratios (k) of approximately 100 observed in previous studies during early stages of B-O related degradation. Secondly, the association of Fe-B pairs can explain the initial stage of a two-stage recovery of carrier lifetime with dark annealing after partial degradation. Thirdly, Fei can result in high apparent k values after the permanent deactivation of B-O defects. Subsequently, we show that a single k value can describe the recombination properties associated with B-O defects throughout degradation, that the recovery during dark annealing occurs with a single-stage, and both the fast- and slow-stage B-O related degradation can be permanently deactivated during illuminated annealing. Accounting for the recombination activity of Fei provides further evidence that the B-O defect is a single defect, rather than two separate defects normally attributed to fast-forming recombination centers and slow-forming recombination centers. Implications of this finding for the nature of the B-O defect are also discussed.

Atomistic investigation on the detachment of oil molecules from defective alumina surface

NASA Astrophysics Data System (ADS)

Xie, W. K.; Sun, Y. Z.; Liu, H. T.

2017-12-01

The mechanism of oil detachment from defective alumina surface in aqueous solution was investigated via atomistic molecular dynamics (MD) simulations. Special attention was focused on the effect of surface defect on the oil detachment. Our simulation results suggest that compared with perfect Al2O3 surface, defective substrate surface provides much more sites for the adsorption of oil molecules, thus it has higher oil adsorption energy. However, higher oil-solid adsorption energy does not mean that oil contaminants are much more difficult to be detached. It is found that surface defect could induce the spontaneous imbibition of water molecules, effectively promoting the detachment of oil molecules. Thus, compared with perfect alumina surface, the detachment of oil molecules from defective alumina surface tends to be much easier. Moreover, surface defect could lead to the oil residues inside surface defect. In water solution, the entire detachment process of oil molecules on defective surface consists of following stages, including the early detachment of oil molecules inside surface defect induced by capillary-driven spontaneous imbibition of water molecules, the following conformational change of oil molecules on topmost surface and the final migration of detached oil molecules from solid surface. These findings may help to sufficiently enrich the removal mechanism of oil molecules adhered onto defective solid surface.

Kibble-Zurek Scaling during Defect Formation in a Nematic Liquid Crystal.

PubMed

Fowler, Nicholas; Dierking, Dr Ingo

2017-04-05

Symmetry-breaking phase transitions are often accompanied by the formation of topological defects, as in cosmological theories of the early universe, superfluids, liquid crystals or solid-state systems. This scenario is described by the Kibble-Zurek mechanism, which predicts corresponding scaling laws for the defect density ρ. One such scaling law suggests a relation ρ≈τ Q -1/2 with τ Q the change of rate of a control parameter. In contrast to the scaling of the defect density during annihilation with ρ≈t -1 , which is governed by the attraction of defects of the same strength but opposite sign, the defect formation process, which depends on the rate of change of a physical quantity initiating the transition, has only rarely been investigated. Herein, we use nematic liquid crystals as a different system to demonstrate the validity of the predicted scaling relation for defect formation. It is found that the scaling exponent is independent of temperature and material employed, thus universal, as predicted. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Early-onset pediatric atopic dermatitis is characterized by TH2/TH17/TH22-centered inflammation and lipid alterations.

PubMed

Brunner, Patrick M; Israel, Ariel; Zhang, Ning; Leonard, Alexandra; Wen, Huei-Chi; Huynh, Thy; Tran, Gary; Lyon, Sarah; Rodriguez, Giselle; Immaneni, Supriya; Wagner, Annette; Zheng, Xiuzhong; Estrada, Yeriel D; Xu, Hui; Krueger, James G; Paller, Amy S; Guttman-Yassky, Emma

2018-06-01

Although atopic dermatitis (AD) often starts in early childhood, detailed tissue profiling of early-onset AD in children is lacking, hindering therapeutic development for this patient population with a particularly high unmet need for better treatments. We sought to globally profile the skin of infants with AD compared with that of adults with AD and healthy control subjects. We performed microarray, RT-PCR, and fluorescence microscopy studies in infants and young children (<5 years old) with early-onset AD (<6 months disease duration) compared with age-matched control subjects and adults with longstanding AD. Transcriptomic analyses revealed profound differences between pediatric patients with early-onset versus adult patients with longstanding AD in not only lesional but also nonlesional tissues. Although both patient populations harbored T H 2-centered inflammation, pediatric AD also showed significant T H 17/T H 22 skewing but lacked the T H 1 upregulation that characterizes adult AD. Pediatric AD exhibited relatively normal expression of epidermal differentiation and cornification products, which is downregulated in adults with AD. Defects in the lipid barrier (eg, ELOVL fatty acid elongase 3 [ELOVL3] and diacylglycerol o-acyltransferase 2 [DGAT2]) and tight junction regulation (eg, claudins 8 and 23) were evident in both groups. However, some lipid-associated mediators (eg, fatty acyl-CoA reductase 2 and fatty acid 2-hydroxylase) showed preferential downregulation in pediatric AD, and lipid barrier genes (FA2H and DGAT2) showed inverse correlations with transepidermal water loss, a functional measure of the epidermal barrier. Skin samples from children and adult patients with AD share lipid metabolism and tight junction alterations, but epidermal differentiation complex defects are only present in adult AD, potentially resulting from chronic immune aberration that is not yet present in early-onset disease. Copyright © 2018 American Academy of Allergy

Heat shock during early somitogenesis induces caudal vertebral column defects in Atlantic salmon (Salmo salar).

PubMed

Wargelius, Anna; Fjelldal, Per Gunnar; Hansen, Tom

2005-07-01

In several terrestrial vertebrates, heat shock (HS) during somitogenesis causes vertebral deformities. To determine if vertebral deformities can occur due to sudden temperature changes during early development in fish, Atlantic salmon embryos were HS treated during somitogenesis. Ten months later these individuals displayed a high prevalence of caudal vertebral column condensations (27-34%). The defects were located caudally of the abdominal cavity, displaying an even distribution in this region independent of time of HS. To determine if HS disturbed vertebral development during somitogenesis, two genes coding for markers of skeletal development were identified, namely, the secreted protein Shh (Sashh) and the transcription factor Twist (Satwist). These proteins are involved in the proliferation and specification of presumptive skeletal cells (sclerotome) in vertebrates. The spatial expression pattern of sashh and satwist in salmon indicated a functional conservation of these proteins. Furthermore, HS embryos displayed expressional disturbance in both sashh and satwist, indicating an effect of HS on sclerotomal cell patterning. However, the HS-protecting ability in embryos seems to be individually regulated because reduction in gene expression was not detected at all stages; in addition, HS did not induce somitic disturbance and vertebral deformity in all embryos.

Skull Defects in Finite Element Head Models for Source Reconstruction from Magnetoencephalography Signals

PubMed Central

Lau, Stephan; Güllmar, Daniel; Flemming, Lars; Grayden, David B.; Cook, Mark J.; Wolters, Carsten H.; Haueisen, Jens

2016-01-01

Magnetoencephalography (MEG) signals are influenced by skull defects. However, there is a lack of evidence of this influence during source reconstruction. Our objectives are to characterize errors in source reconstruction from MEG signals due to ignoring skull defects and to assess the ability of an exact finite element head model to eliminate such errors. A detailed finite element model of the head of a rabbit used in a physical experiment was constructed from magnetic resonance and co-registered computer tomography imaging that differentiated nine tissue types. Sources of the MEG measurements above intact skull and above skull defects respectively were reconstructed using a finite element model with the intact skull and one incorporating the skull defects. The forward simulation of the MEG signals reproduced the experimentally observed characteristic magnitude and topography changes due to skull defects. Sources reconstructed from measured MEG signals above intact skull matched the known physical locations and orientations. Ignoring skull defects in the head model during reconstruction displaced sources under a skull defect away from that defect. Sources next to a defect were reoriented. When skull defects, with their physical conductivity, were incorporated in the head model, the location and orientation errors were mostly eliminated. The conductivity of the skull defect material non-uniformly modulated the influence on MEG signals. We propose concrete guidelines for taking into account conducting skull defects during MEG coil placement and modeling. Exact finite element head models can improve localization of brain function, specifically after surgery. PMID:27092044

Detection of retinal nerve fiber layer defects on retinal fundus images for early diagnosis of glaucoma

NASA Astrophysics Data System (ADS)

Muramatsu, Chisako; Hayashi, Yoshinori; Sawada, Akira; Hatanaka, Yuji; Hara, Takeshi; Yamamoto, Tetsuya; Fujita, Hiroshi

2010-01-01

Retinal nerve fiber layer defect (NFLD) is a major sign of glaucoma, which is the second leading cause of blindness in the world. Early detection of NFLDs is critical for improved prognosis of this progressive, blinding disease. We have investigated a computerized scheme for detection of NFLDs on retinal fundus images. In this study, 162 images, including 81 images with 99 NFLDs, were used. After major blood vessels were removed, the images were transformed so that the curved paths of retinal nerves become approximately straight on the basis of ellipses, and the Gabor filters were applied for enhancement of NFLDs. Bandlike regions darker than the surrounding pixels were detected as candidates of NFLDs. For each candidate, image features were determined and the likelihood of a true NFLD was determined by using the linear discriminant analysis and an artificial neural network (ANN). The sensitivity for detecting the NFLDs was 91% at 1.0 false positive per image by using the ANN. The proposed computerized system for the detection of NFLDs can be useful to physicians in the diagnosis of glaucoma in a mass screening.

Differential gene expression during early embryonic development in diapause and non-diapause eggs of multivoltine silkworm Bombyx mori.

PubMed

Ponnuvel, Kangayam M; Murthy, Geetha N; Awasthi, Arvind K; Rao, Guruprasad; Vijayaprakash, Nanjappa B

2010-11-01

Quantification of the differential expression of metabolic enzyme and heat-shock protein genes (Hsp) during early embryogenesis in diapause and non-diapause eggs of the silkworm B. mori was carried out by semi-quantitative RT-PCR. Data analysis revealed that, the phosphofructokinase (PFK) expression started at a higher level in the early stage (6 h after oviposition) in non-diapause eggs, while in diapause induced eggs, it started at a lower level. However, the PFK gene expression in diapause eggs was comparatively higher than in non-diapause eggs. PFK facilitates use of carbohydrate reserves. The lower level of PFK gene expression in the early stage of diapause induced eggs but comparatively higher level of expression than in non-diapause eggs is due to enzyme inactivation via protein phosphorylation during early embryogenesis followed by de-phosphorylation in later stage. The sorbitol dehydrogenase-2 (SDH-2) gene was down regulated in diapause induced eggs up to 24 h and its expression levels in diapause induced eggs coincided with that of PFK gene at 48h in non-diapause eggs. During carbohydrate metabolism, there is an initial temporary accumulation of sorbitol which acts as protectant. The down regulation of SDH-2 gene during the first 24 hours in diapause induced eggs was due to the requirement of sorbitol as protectant. However, since the diapause process culminates by 48 h, the SDH-2 gene expression increased and coincided with that of PFK gene expression. The trehalase (Tre) gene expression was at a lower level in diapause induced eggs compared to non-diapausing eggs. The induction of Tre activity is to regulate uptake and use of sugar by the tissues. The non-diapause eggs revealed maximum expression of GPase gene with major fluctuations as well as an overall higher expression compared to diapause induced eggs. The diapause process requires less energy source which reflects lower activity of the gene. Heat shock protein (Hsp) genes (Hsp20.4, 40, 70, and 90

Origins and consequences of congenital heart defects affecting the right ventricle.

PubMed

Woudstra, Odilia I; Ahuja, Suchit; Bokma, Jouke P; Bouma, Berto J; Mulder, Barbara J M; Christoffels, Vincent M

2017-10-01

Congenital heart disease is a major health issue, accounting for a third of all congenital defects. Improved early surgical management has led to a growing population of adults with congenital heart disease, including patients with defects affecting the right ventricle, which are often classified as severe. Defects affecting the right ventricle often cause right ventricular volume or pressure overload and affected patients are at high risk for complications such as heart failure and sudden death. Recent insights into the developmental mechanisms and distinct developmental origins of the left ventricle, right ventricle, and the outflow tract have shed light on the common features and distinct problems arising in specific defects. Here, we provide a comprehensive overview of the current knowledge on the development into the normal and congenitally malformed right heart and the clinical consequences of several congenital heart defects affecting the right ventricle. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Early differentiation and volatile accretion recorded in deep-mantle neon and xenon.

PubMed

Mukhopadhyay, Sujoy

2012-06-06

The isotopes (129)Xe, produced from the radioactive decay of extinct (129)I, and (136)Xe, produced from extinct (244)Pu and extant (238)U, have provided important constraints on early mantle outgassing and volatile loss from Earth. The low ratios of radiogenic to non-radiogenic xenon ((129)Xe/(130)Xe) in ocean island basalts (OIBs) compared with mid-ocean-ridge basalts (MORBs) have been used as evidence for the existence of a relatively undegassed primitive deep-mantle reservoir. However, the low (129)Xe/(130)Xe ratios in OIBs have also been attributed to mixing between subducted atmospheric Xe and MORB Xe, which obviates the need for a less degassed deep-mantle reservoir. Here I present new noble gas (He, Ne, Ar, Xe) measurements from an Icelandic OIB that reveal differences in elemental abundances and (20)Ne/(22)Ne ratios between the Iceland mantle plume and the MORB source. These observations show that the lower (129)Xe/(130)Xe ratios in OIBs are due to a lower I/Xe ratio in the OIB mantle source and cannot be explained solely by mixing atmospheric Xe with MORB-type Xe. Because (129)I became extinct about 100 million years after the formation of the Solar System, OIB and MORB mantle sources must have differentiated by 4.45 billion years ago and subsequent mixing must have been limited. The Iceland plume source also has a higher proportion of Pu- to U-derived fission Xe, requiring the plume source to be less degassed than MORBs, a conclusion that is independent of noble gas concentrations and the partitioning behaviour of the noble gases with respect to their radiogenic parents. Overall, these results show that Earth's mantle accreted volatiles from at least two separate sources and that neither the Moon-forming impact nor 4.45 billion years of mantle convection has erased the signature of Earth's heterogeneous accretion and early differentiation.

Assessment of dynamic properties and stiffness of composite bridges with pavement defects

NASA Astrophysics Data System (ADS)

Kartopol'tsev, Vladimir; Kartopol'tsev, Andrei; Kolmakov, Boris

2017-01-01

This paper is aimed at assessing the dynamic properties and stiffness of the reinforced concrete roadway slab under live loads that impact composite bridge girders considering pavement defects. A special attention is paid to the reinforced concrete roadway slab as a transfer member of forced oscillations. The test results obtained for bridges with different spans ranging from 24 to 110 m are presented to assess the behavior of the reinforced concrete roadway slab and the dynamic stiffness of bridge span allowed for the pavement defects. Dynamic tests are carried out under controlled and random loads that simulate live load interaction with the span and the pavement with defects. The differential equations are presented for vertical oscillations of spans, pavement defect parameter, Eigen frequency and others. As a result of the experimental research the equation is derived to ascertain the dynamic stiffness of the vehicle-span system.

An experimental study on the application of radionuclide imaging in repair of the bone defect

PubMed Central

Zhu, Weimin; Wang, Daping; Zhang, Xiaojun; Lu, Wei; Liu, Jianquan; Peng, Liangquan; Li, Hao; Han, Yun; Zeng, Yanjun

2011-01-01

The aim of our study was to validate the effect of radionuclide imaging in early monitoring of the bone’s reconstruction, the animal model of bone defect was made on the rabbits repaired with HA artificial bone. The ability of bone defect repair was evaluated by using radionuclide bone imaging at 2, 4, 8 and 12 weeks postoperatively. The results indicate that the experimental group stimulated more bone formation than that of the control group. The differences of the bone reconstruction ability were statistically significant (p<0.05). The nano-HA artificial has good bone conduction, and it can be used for the treatment of bone defects. Radionuclide imaging may be an effective and first choice method for the early monitoring of the bone’s reconstruction. PMID:21875418

Expression of polysialylated neural cell adhesion molecules on adult stem cells after neuronal differentiation of inner ear spiral ganglion neurons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Kyoung Ho; Yeo, Sang Won, E-mail: swyeo@catholic.ac.kr; Troy, Frederic A., E-mail: fatroy@ucdavis.edu

Highlights: • PolySia expressed on neurons primarily during early stages of neuronal development. • PolySia–NCAM is expressed on neural stem cells from adult guinea pig spiral ganglion. • PolySia is a biomarker that modulates neuronal differentiation in inner ear stem cells. - Abstract: During brain development, polysialylated (polySia) neural cell adhesion molecules (polySia–NCAMs) modulate cell–cell adhesive interactions involved in synaptogenesis, neural plasticity, myelination, and neural stem cell (NSC) proliferation and differentiation. Our findings show that polySia–NCAM is expressed on NSC isolated from adult guinea pig spiral ganglion (GPSG), and in neurons and Schwann cells after differentiation of the NSC withmore » epidermal, glia, fibroblast growth factors (GFs) and neurotrophins. These differentiated cells were immunoreactive with mAb’s to polySia, NCAM, β-III tubulin, nestin, S-100 and stained with BrdU. NSC could regenerate and be differentiated into neurons and Schwann cells. We conclude: (1) polySia is expressed on NSC isolated from adult GPSG and on neurons and Schwann cells differentiated from these NSC; (2) polySia is expressed on neurons primarily during the early stage of neuronal development and is expressed on Schwann cells at points of cell–cell contact; (3) polySia is a functional biomarker that modulates neuronal differentiation in inner ear stem cells. These new findings suggest that replacement of defective cells in the inner ear of hearing impaired patients using adult spiral ganglion neurons may offer potential hope to improve the quality of life for patients with auditory dysfunction and impaired hearing disorders.« less

Plasma-Sprayed Titanium Patterns for Enhancing Early Cell Responses

NASA Astrophysics Data System (ADS)

Shi, Yunqi; Xie, Youtao; Pan, Houhua; Zheng, Xuebin; Huang, Liping; Ji, Fang; Li, Kai

2016-06-01

Titanium coating has been widely used as a biocompatible metal in biomedical applications. However, the early cell responses and long-term fixation of titanium implants are not satisfied. To obviate these defects, in this paper, micro-post arrays with various widths (150-1000 μm) and intervals (100-300 μm) were fabricated on the titanium substrate by template-assisted plasma spraying technology. In vitro cell culture experiments showed that MC3T3-E1 cells exhibited significantly higher osteogenic differentiation as well as slightly improved adhesion and proliferation on the micro-patterned coatings compared with the traditional one. The cell number on the pattern with 1000 µm width reached 130% after 6 days of incubation, and the expressions of osteopontin (OPN) as well as osteocalcin (OC) were doubled. No obvious difference was found in cell adhesion on various size patterns. The present micro-patterned coatings proposed a new modification method for the traditional plasma spraying technology to enhance the early cell responses and convenience for the bone in-growth.

Early transcriptional and epigenetic regulation of CD8+ T cell differentiation revealed by single-cell RNA-seq

PubMed Central

Kakaradov, Boyko; Arsenio, Janilyn; Widjaja, Christella E.; He, Zhaoren; Aigner, Stefan; Metz, Patrick J.; Yu, Bingfei; Wehrens, Ellen J.; Lopez, Justine; Kim, Stephanie H.; Zuniga, Elina I.; Goldrath, Ananda W.; Chang, John T.; Yeo, Gene W.

2017-01-01

SUMMARY During microbial infection, responding CD8+ T lymphocytes differentiate into heterogeneous subsets that together provide immediate and durable protection. To elucidate the dynamic transcriptional changes that underlie this process, we applied a single-cell RNA sequencing approach and analyzed individual CD8+ T lymphocytes sequentially throughout the course of a viral infection in vivo. Our analyses revealed a striking transcriptional divergence among cells that had undergone their first division and identified previously unknown molecular determinants controlling CD8+ T lymphocyte fate specification. These findings suggest a model of terminal effector cell differentiation initiated by an early burst of transcriptional activity and subsequently refined by epigenetic silencing of transcripts associated with memory lymphocytes, highlighting the power and necessity of single-cell approaches. PMID:28218746

Dual delivery of rhPDGF-BB and bone marrow mesenchymal stromal cells expressing the BMP2 gene enhance bone formation in a critical-sized defect model.

PubMed

Park, Shin-Young; Kim, Kyoung-Hwa; Shin, Seung-Yun; Koo, Ki-Tae; Lee, Yong-Moo; Seol, Yang-Jo

2013-11-01

Bone tissue healing is a dynamic, orchestrated process that relies on multiple growth factors and cell types. Platelet-derived growth factor-BB (PDGF-BB) is released from platelets at wound sites and induces cellular migration and proliferation necessary for bone regeneration in the early healing process. Bone morphogenetic protein-2 (BMP-2), the most potent osteogenic differentiation inducer, directs new bone formation at the sites of bone defects. This study evaluated a combinatorial treatment protocol of PDGF-BB and BMP-2 on bone healing in a critical-sized defect model. To mimic the bone tissue healing process, a dual delivery approach was designed to deliver the rhPDGF-BB protein transiently during the early healing phase, whereas BMP-2 was supplied by rat bone marrow stromal cells (BMSCs) transfected with an adenoviral vector containing the BMP2 gene (AdBMP2) for prolonged release throughout the healing process. In in vitro experiments, the dual delivery of rhPDGF-BB and BMP2 significantly enhanced cell proliferation. However, the osteogenic differentiation of BMSCs was significantly suppressed even though the amount of BMP-2 secreted by the AdBMP2-transfected BMSCs was not significantly affected by the rhPDGF-BB treatment. In addition, dual delivery inhibited the mRNA expression of BMP receptor type II and Noggin in BMSCs. In in vivo experiments, critical-sized calvarial defects in rats showed enhanced bone regeneration by dual delivery of autologous AdBMP2-transfected BMSCs and rhPDGF-BB in both the amount of new bone formed and the bone mineral density. These enhancements in bone regeneration were greater than those observed in the group treated with AdBMP2-transfected BMSCs alone. In conclusion, the dual delivery of rhPDGF-BB and AdBMP2-transfected BMSCs improved the quality of the regenerated bone, possibly due to the modulation of PDGF-BB on BMP-2-induced osteogenesis.

Early-stage detection of VE-cadherin during endothelial differentiation of human mesenchymal stem cells using SPR biosensor.

PubMed

Fathi, Farzaneh; Rezabakhsh, Aysa; Rahbarghazi, Reza; Rashidi, Mohammad-Reza

2017-10-15

Surface plasmon resonance (SPR) biosensors are most commonly applied for real-time dynamic analysis and measurement of interactions in bio-molecular studies and cell-surface analysis without the need for labeling processes. Up to present, SPR application in stem cell biology and biomedical sciences was underused. Herein, a very simple and sensitive method was developed to evaluate human mesenchymal stem cells trans-differentiation to endothelial lineage of over a period of 14 days based on VE-cadherin biomarker. The SPR signals increased with the increase of the amount of VE-cadherin expression on the cell surface during cell differentiation process. The method was able to detect ≈27 cells permm 2 . No significant effect was observed on the cell viability during the cell attachment to the surface of immune-reactive biochips and during the SPR analysis. Using this highly sensitive SPR method, it was possible to sense the early stage of endothelial differentiation on day 3 in label-free form, whereas flow cytometry and fluorescent microscopy methods were found unable to detect the cell differentiation at the same time. Therefore, the proposed method can rapidly and accurately detect cell differentiation in live cells and label-free manner without any need of cell breakage and has great potential for both diagnostic and experimental approaches. Copyright © 2017. Published by Elsevier B.V.

PTH promotes allograft integration in a calvarial bone defect

PubMed Central

Sheyn, Dmitriy; Yakubovich, Doron Cohn; Kallai, Ilan; Su, Susan; Da, Xiaoyu; Pelled, Gadi; Tawackoli, Wafa; Cook-Weins, Galen; Schwarz, Edward M.; Gazit, Dan; Gazit, Zulma

2013-01-01

Allografts may be useful in craniofacial bone repair, although they often fail to integrate with the host bone. We hypothesized that intermittent administration of parathyroid hormone (PTH) would enhance mesenchymal stem cell recruitment and differentiation, resulting in allograft osseointegration in cranial membranous bones. Calvarial bone defects were created in transgenic mice, in which luciferase is expressed under the control of the osteocalcin promoter. The mice were given implants of allografts with or without daily PTH treatment. Bioluminescence imaging (BLI) was performed to monitor host osteprogenitor differentiation at the implantation site. Bone formation was evaluated with the aid of fluorescence imaging (FLI) and micro–computed tomography (μCT) as well as histological analyses. Reverse transcription polymerase chain reaction (RT-PCR) was performed to evaluate the expression of key osteogenic and angiogenic genes. Osteoprogenitor differentiation, as detected by BLI, in mice treated with an allograft implant and PTH was over 2-fold higher than those in mice treated with an allograft implant without PTH. FLI also demonstrated that the bone mineralization process in PTH-treated allografts was significantly higher than that in untreated allografts. The μCT scans revealed a significant increase in bone formation in Allograft + PTH–treated mice comparing to Allograft + PBS treated mice. The osteogenic genes osteocalcin (Oc/Bglap) and integrin binding sialoprotein (Ibsp) were upregulated in the Allograft + PTH–treated animals. In summary, PTH treatment enhances osteoprogenitor differentiation and augments bone formation around structural allografts. The precise mechanism is not clear, but we show that infiltration pattern of mast cells, associated with the formation of fibrotic tissue, in the defect site is significantly affected by the PTH treatment. PMID:24131143

PTH promotes allograft integration in a calvarial bone defect.

PubMed

Sheyn, Dmitriy; Cohn Yakubovich, Doron; Kallai, Ilan; Su, Susan; Da, Xiaoyu; Pelled, Gadi; Tawackoli, Wafa; Cook-Weins, Galen; Schwarz, Edward M; Gazit, Dan; Gazit, Zulma

2013-12-02

Allografts may be useful in craniofacial bone repair, although they often fail to integrate with the host bone. We hypothesized that intermittent administration of parathyroid hormone (PTH) would enhance mesenchymal stem cell recruitment and differentiation, resulting in allograft osseointegration in cranial membranous bones. Calvarial bone defects were created in transgenic mice, in which luciferase is expressed under the control of the osteocalcin promoter. The mice were given implants of allografts with or without daily PTH treatment. Bioluminescence imaging (BLI) was performed to monitor host osteprogenitor differentiation at the implantation site. Bone formation was evaluated with the aid of fluorescence imaging (FLI) and microcomputed tomography (μCT) as well as histological analyses. Reverse transcription polymerase chain reaction (RT-PCR) was performed to evaluate the expression of key osteogenic and angiogenic genes. Osteoprogenitor differentiation, as detected by BLI, in mice treated with an allograft implant and PTH was over 2-fold higher than those in mice treated with an allograft implant without PTH. FLI also demonstrated that the bone mineralization process in PTH-treated allografts was significantly higher than that in untreated allografts. The μCT scans revealed a significant increase in bone formation in allograft + PTH treated mice comparing to allograft + PBS treated mice. The osteogenic genes osteocalcin (Oc/Bglap) and integrin binding sialoprotein (Ibsp) were upregulated in the allograft + PTH treated animals. In summary, PTH treatment enhances osteoprogenitor differentiation and augments bone formation around structural allografts. The precise mechanism is not clear, but we show that infiltration pattern of mast cells, associated with the formation of fibrotic tissue, in the defect site is significantly affected by the PTH treatment.

Essential Role of Chromatin Remodeling Protein Bptf in Early Mouse Embryos and Embryonic Stem Cells

PubMed Central

Landry, Joseph; Sharov, Alexei A.; Piao, Yulan; Sharova, Lioudmila V.; Xiao, Hua; Southon, Eileen; Matta, Jennifer; Tessarollo, Lino; Zhang, Ying E.; Ko, Minoru S. H.; Kuehn, Michael R.; Yamaguchi, Terry P.; Wu, Carl

2008-01-01

We have characterized the biological functions of the chromatin remodeling protein Bptf (Bromodomain PHD-finger Transcription Factor), the largest subunit of NURF (Nucleosome Remodeling Factor) in a mammal. Bptf mutants manifest growth defects at the post-implantation stage and are reabsorbed by E8.5. Histological analyses of lineage markers show that Bptf−/− embryos implant but fail to establish a functional distal visceral endoderm. Microarray analysis at early stages of differentiation has identified Bptf-dependent gene targets including homeobox transcriptions factors and genes essential for the development of ectoderm, mesoderm, and both definitive and visceral endoderm. Differentiation of Bptf−/− embryonic stem cell lines into embryoid bodies revealed its requirement for development of mesoderm, endoderm, and ectoderm tissue lineages, and uncovered many genes whose activation or repression are Bptf-dependent. We also provide functional and physical links between the Bptf-containing NURF complex and the Smad transcription factors. These results suggest that Bptf may co-regulate some gene targets of this pathway, which is essential for establishment of the visceral endoderm. We conclude that Bptf likely regulates genes and signaling pathways essential for the development of key tissues of the early mouse embryo. PMID:18974875

Magnetic Resonance Imaging Diagnosis of Volvulus through Mesenteric Defect in Neonate

PubMed Central

Leopold, Scott; Al-Qaraghouli, Mohammed; Hussain, Naveed; Finck, Christine

2016-01-01

Antenatal midgut volvulus is a rare surgical emergency in which bowel is severely compromised. Rarely the etiology is a mesenteric defect. Early diagnosis is essential and lifesaving in the immediate newborn period. Typically upper gastrointestinal or ultrasound imaging can be suggestive of the diagnosis of volvulus in the neonate. Sometimes, however, the diagnosis may be elusive. Herein, we report on the use of neonatal magnetic resonance imaging to diagnose a midgut volvulus that occurred through a congenital mesenteric defect. PMID:27551577

Differential diagnostic perspectives provided by en face microscopic examination of articular surface defects.

PubMed

Rothschild, Bruce M

2018-03-01

Surface defects have a central position in diagnosis of articular pathology. Recognizing the limitations of standard radiologic techniques and those imposed by positioning and averaging artifacts on CT evaluation, direct visualization of surface defects was pursued to identify disease characteristics that would facilitate interpretation of radiologic findings. Epi-illumination surface microscopy was utilized to examine macroscopically recognized articular surface defects in individuals in the Hamann-Todd, Terry, and Huntington human skeletal collections with previously verified diagnoses of rheumatoid arthritis, spondyloarthropathy, juvenile inflammatory arthritis (JIA), calcium pyrophosphate deposition disease (CPPD), gout, metastatic cancer, multiple myeloma, septic arthritis, tuberculosis, fungal arthritis, histiocytosis and sickle cell anemia (Rothschild and Rothschild Clin Infect Dis 20(5):1402-1408, 1995; Rothschild et al. Amer J Phys Anthropol 82(4):441-449, 1990; Rothschild and Rothschild Amer J Phys Anthropol 96(4):357-563, 1995; Rothschild and Woods Clin Exp Rheumatol 10(2):117-122, 1992; Barrett and Keat Radiographics 24(6):1679-1691, 2004; Rothschild and Heathcote Amer J Phys Anthropol 98(4):519-525, 1995; Rothschild and Woods Am J Phys Anthropol 85:25-34, 1991; Hershkovitz et al. Amer J Phys Anthropol 106(1):47-60, 1998; Winland et al. Amer J Phys Anthropol 24:S243, 1997; Rothschild et al. Clin Exp Rheumatol 10(6):557-564, 1992; Rothschild and Martin , 2006; Rothschild et al. Amer J Phys Anthropol 102(2):249-264, 1997). Observed alterations were compared with standard radiographs. Fronts of resorption distinguished inflammatory arthritis from those caused by the other disorders studied. Multiple myeloma, fungal disease, and gout are expansile character; the latter accompanied by reactive new bone formation more prominent than that noted with spondyloarthropathy and JIA. Those were clearly distinguished from the crumbling alterations found with CPPD

Antithyroid Drug Use in Pregnancy and Birth Defects: Why Some Studies Find Clear Associations, and Some Studies Report None.

PubMed

Laurberg, Peter; Andersen, Stine Linding

2015-11-01

Rare cases of birth defects after the use of methimazole (MMI) or carbimazole to treat hyperthyroidism in early pregnancy have been reported since 1972, whereas propylthiouracil (PTU) has not been considered teratogenic. Recently, two studies reported birth defects after the use of MMI in early pregnancy to affect 2-4% of exposed children, and one study also found birth defects after the use of PTU. On the other hand, some published studies did not find associations between the use of thionamides and birth defects. The methods used in the two positive and the four negative reports are reviewed. The two positive studies included a sufficient number of children exposed to MMI (n = 1231 and 1097) to evaluate the studied outcomes, whereas the four negative studies included a much lower number of exposed children (n = 73, 108, 30, and 124). Considering PTU, the birth defects observed in one study were in general milder and tended to be diagnosed and registered only when they resulted in complications and led to surgery after one year of age. None of the negative studies has investigated outcomes after one year of age. Studies finding no associations between early pregnancy exposure to antithyroid drugs and birth defects were either not sufficiently powered or did not study outcomes at optimal ages.

Xenopus Bicaudal-C Is Required for the Differentiation of the Amphibian Pronephros

PubMed Central

Tran, Uyen; Mary Pickney, L.; Duygu Özpolat, B.; Wessely, Oliver

2007-01-01

The RNA-binding molecule Bicaudal-C regulates embryonic development in Drosophila and Xenopus. Interestingly, mouse mutants of Bicaudal-C do not show early patterning defects, but instead develop polycystic kidney disease (PKD). To further investigate the molecular mechanism of Bicaudal-C in kidney development, we analyzed its function in the developing amphibian pronephros. Bicaudal-C mRNA was present in the epithelial structures of the Xenopus pronephros, the tubules and the duct, but not the glomus. Inhibition of the translation of endogenous Bicaudal-C with antisense morpholino oligomers (xBic-C-MO) led to a PKD-like phenotype in Xenopus. Embryos lacking Bicaudal-C developed generalized edemas and dilated pronephric tubules and ducts. This phenotype was caused by impaired differentiation of the pronephros. Molecular markers specifically expressed in the late distal tubule were absent in xBic-C-MO-injected embryos. Furthermore, Bicaudal-C was not required for primary cilia formation, an important organelle affected in PKD. These data support the idea that Bicaudal-C functions downstream or parallel of a cilia-regulated signaling pathway. This pathway is required for terminal differentiation of the late distal tubule of the Xenopus pronephros and regulates renal epithelial cell differentiation, which - when disrupted - results in PKD. PMID:17521625

Effects of tributyltin on early life-stage, reproduction, and gonadal sex differentiation in Japanese medaka (Oryzias latipes).

PubMed

Horie, Yoshifumi; Yamagishi, Takahiro; Shintaku, Yoko; Iguchi, Taisen; Tatarazako, Norihisa

2018-07-01

Tributyltin, an organotin compound, was used worldwide as an antifouling agent in aquatic environments and there has been much concern about the toxicological and ecotoxicological properties of organotin compounds. Even though it has been prohibited worldwide, tributyltin is still detected at low concentrations in aquatic environments. Here we investigated the effects of tributyltin on the early life-stage, reproduction, and gonadal sex differentiation in Japanese medaka (Oryzias latipes). In adults, exposure to tributyltin at 3.82 μg/L suppressed fecundity and fertility and increased mortality. At 10.48 μg/L all medaka died by the sixth day of exposure. Exposure to tributyltin during early life-stages induced no significant differences in mortality or embryonic development, but growth was suppressed in groups exposed to 0.13 and 0.68 μg/L. Furthermore, there was no abnormal gonadal development in Japanese medaka exposed to tributyltin. These results provide evidence of the negative effects of tributyltin on reproduction in a teleost fish. Tributyltin did not affect gonadal sex differentiation in Japanese medaka, but fecundity and fertility were suppressed, although it is not clear whether this suppression resulted from the endocrine-disrupting action of tributyltin or its toxicity. Copyright © 2018 Elsevier Ltd. All rights reserved.

Maize early endosperm growth and development: from fertilization through cell type differentiation.

PubMed

Leroux, Brian M; Goodyke, Austin J; Schumacher, Katelyn I; Abbott, Chelsi P; Clore, Amy M; Yadegari, Ramin; Larkins, Brian A; Dannenhoffer, Joanne M

2014-08-01

• Given the worldwide economic importance of maize endosperm, it is surprising that its development is not the most comprehensively studied of the cereals. We present detailed morphometric and cytological descriptions of endosperm development in the maize inbred line B73, for which the genome has been sequenced, and compare its growth with four diverse Nested Association Mapping (NAM) founder lines.• The first 12 d of B73 endosperm development were described using semithin sections of plastic-embedded kernels and confocal microscopy. Longitudinal sections were used to compare endosperm length, thickness, and area.• Morphometric comparison between Arizona- and Michigan-grown B73 showed a common pattern. Early endosperm development was divided into four stages: coenocytic, cellularization through alveolation, cellularization through partitioning, and differentiation. We observed tightly synchronous nuclear divisions in the coenocyte, elucidated that the onset of cellularization was coincident with endosperm size, and identified a previously undefined cell type (basal intermediate zone, BIZ). NAM founders with small mature kernels had larger endosperms (0-6 d after pollination) than lines with large mature kernels.• Our B73-specific model of early endosperm growth links developmental events to relative endosperm size, while accounting for diverse growing conditions. Maize endosperm cellularizes through alveolation, then random partitioning of the central vacuole. This unique cellularization feature of maize contrasts with the smaller endosperms of Arabidopsis, barley, and rice that strictly cellularize through repeated alveolation. NAM analysis revealed differences in endosperm size during early development, which potentially relates to differences in timing of cellularization across diverse lines of maize. © 2014 Botanical Society of America, Inc.

A Study on the Effects of Ball Defects on the Fatigue Life in Hybrid Bearings

NASA Technical Reports Server (NTRS)

Tang, Ching-Yao; Foerster, Chad E.; O'Brien, Michael J.; Hardy, Brian S.; Goyal, Vinay K.; Nelson, Benjamin A.; Robinson, Ernest Y.; Ward, Peter C.; Hilton, Michael R.

2014-01-01

Hybrid ball bearings using silicon nitride ceramic balls with steel rings are increasingly being used in space mechanism applications due to their high wear resistance and long rolling contact fatigue life. However, qualitative and quantitative reports of the effects of ball defects that cause early fatigue failure are rare. We report on our approach to study these effects. Our strategy includes characterization of defects encountered in use, generation of similar defects in a laboratory setting, execution of full-scale bearing tests to obtain lifetimes, post-test characterization, and related finite-element modeling to understand the stress concentration of these defects. We have confirmed that at least one type of defect of appropriate size can significantly reduce fatigue life. Our method can be used to evaluate other defects as they occur or are encountered.

Histone H3K9 Trimethylase Eggless Controls Germline Stem Cell Maintenance and Differentiation

PubMed Central

Zhou, Jian; McDowell, William; Park, Jungeun; Haug, Jeff; Staehling, Karen; Tang, Hong; Xie, Ting

2011-01-01

Epigenetic regulation plays critical roles in the regulation of cell proliferation, fate determination, and survival. It has been shown to control self-renewal and lineage differentiation of embryonic stem cells. However, epigenetic regulation of adult stem cell function remains poorly defined. Drosophila ovarian germline stem cells (GSCs) are a productive adult stem cell system for revealing regulatory mechanisms controlling self-renewal and differentiation. In this study, we show that Eggless (Egg), a H3K9 methyltransferase in Drosophila, is required in GSCs for controlling self-renewal and in escort cells for regulating germ cell differentiation. egg mutant ovaries primarily exhibit germ cell differentiation defects in young females and gradually lose GSCs with time, indicating that Egg regulates both germ cell maintenance and differentiation. Marked mutant egg GSCs lack expression of trimethylated H3K9 (H3k9me3) and are rapidly lost from the niche, but their mutant progeny can still differentiate into 16-cell cysts, indicating that Egg is required intrinsically to control GSC self-renewal but not differentiation. Interestingly, BMP-mediated transcriptional repression of differentiation factor bam in marked egg mutant GSCs remains normal, indicating that Egg is dispensable for BMP signaling in GSCs. Normally, Bam and Bgcn interact with each other to promote GSC differentiation. Interestingly, marked double mutant egg bgcn GSCs are still lost, but their progeny are able to differentiate into 16-cell cysts though bgcn mutant GSCs normally do not differentiate, indicating that Egg intrinsically controls GSC self-renewal through repressing a Bam/Bgcn-independent pathway. Surprisingly, RNAi-mediated egg knockdown in escort cells leads to their gradual loss and a germ cell differentiation defect. The germ cell differentiation defect is at least in part attributed to an increase in BMP signaling in the germ cell differentiation niche. Therefore, this study has revealed

Identification of factors for physicians to facilitate early differential diagnosis of scrub typhus, murine typhus, and Q fever from dengue fever in Taiwan.

PubMed

Chang, Ko; Lee, Nan-Yao; Ko, Wen-Chien; Tsai, Jih-Jin; Lin, Wei-Ru; Chen, Tun-Chieh; Lu, Po-Liang; Chen, Yen-Hsu

2017-02-01

Dengue fever, rickettsial diseases, and Q fever are acute febrile illnesses with similar manifestations in tropical areas. Early differential diagnosis of scrub typhus, murine typhus, and Q fever from dengue fever may be made by understanding the distinguishing clinical characteristics and the significance of demographic and weather factors. We conducted a retrospective study to identify clinical, demographic, and meteorological characteristics of 454 dengue fever, 178 scrub typhus, 143 Q fever, and 81 murine typhus cases in three Taiwan hospitals. Case numbers of murine typhus and Q fever correlated significantly with temperature and rainfall; the scrub typhus case number was only significantly related with temperature. Neither temperature nor rainfall correlated with the case number of dengue fever. The rarity of dengue fever cases from January to June in Taiwan may be a helpful clue for diagnosis in the area. A male predominance was observed, as the male-to-female rate was 2.1 for murine typhus and 7.4 for Q fever. Multivariate analysis revealed the following six important factors for differentiating the rickettsial diseases and Q fever group from the dengue fever group: fever ≥8 days, alanine aminotransferase > aspartate aminotransferase, platelets >63,000/mL, C-reactive protein >31.9 mg/L, absence of bone pain, and absence of a bleeding syndrome. Understanding the rarity of dengue in the first half of a year in Taiwan and the six differentiating factors may help facilitate the early differential diagnosis of rickettsial diseases and Q fever from dengue fever, permitting early antibiotic treatment. Copyright © 2015. Published by Elsevier B.V.

Effects of differentiation on the geodynamics of the early Earth

NASA Astrophysics Data System (ADS)

Piccolo, Andrea; Kaus, Boris; White, Richard; Johnson, Tim

2016-04-01

Archean geodynamic processes are not well understood, but there is general agreement that the mantle potential temperature was higher than present, and that as a consequence significant amounts of melt were produced both in the mantle and any overlying crust. This has likely resulted in crustal differentiation. An early attempt to model the geodynamic effects of differentiation was made by Johnson et al. (2014), who used numerical modeling to investigate the crust production and recycling in conjunction with representative phase diagrams (based on the inferred chemical composition of the primary melt in accordance with the Archean temperature field). The results of the simulations show that the base of the over-thickened primary basaltic crust becomes gravitational unstable due to the mineral assemblage changes. This instability leads to the dripping of dense material into the mantle, which causes an asthenospheric return flow, local partial melting and new primary crust generation that is rapidly recycled in to mantle. Whereas they gave important insights, the previous simulations were simplified in a number of aspects: 1) the rheology employed was viscous, and both elasticity and pressure-dependent plasticity were not considered; 2) extracted mantle melts were 100% transformed into volcanic rocks, whereas on the present day Earth only about 20-30% are volcanic and the remainder is plutonic; 3) the effect of a free surface was not studied in a systematic manner. In order to better understand how these simplifications affect the geodynamic models, we here present additional simulations to study the effects of each of these parameters. Johnson, T.E., Brown, M., Kaus, B., and VanTongeren, J.A., 2014, Delamination and recycling of Archaean crust caused by gravitational instabilities: Nature Geoscience, v. 7, no. 1, p. 47-52, doi: 10.1038/NGEO2019.

Differential Susceptibility in Early Literacy Instruction through Computer Games: The Role of the Dopamine D4 Receptor Gene (DRD4)

ERIC Educational Resources Information Center

Kegel, Cornelia A. T.; Bus, Adriana G.; van IJzendoorn, Marinus H.

2011-01-01

Not every child seems equally susceptible to the same parental, educational, or environmental influences even if cognitive level is similar. This study is the first randomized controlled trial to apply the differential susceptibility paradigm to education in relation to children's genotype and early literacy skills. A randomized pretest-posttest…

Dielectric Spectroscopic Detection of Early Failures in 3-D Integrated Circuits.

PubMed

Obeng, Yaw; Okoro, C A; Ahn, Jung-Joon; You, Lin; Kopanski, Joseph J

The commercial introduction of three dimensional integrated circuits (3D-ICs) has been hindered by reliability challenges, such as stress related failures, resistivity changes, and unexplained early failures. In this paper, we discuss a new RF-based metrology, based on dielectric spectroscopy, for detecting and characterizing electrically active defects in fully integrated 3D devices. These defects are traceable to the chemistry of the insolation dielectrics used in the through silicon via (TSV) construction. We show that these defects may be responsible for some of the unexplained early reliability failures observed in TSV enabled 3D devices.

Pristine Igneous Rocks and the Early Differentiation of Planetary Materials

NASA Technical Reports Server (NTRS)

Warren, Paul H.

1998-01-01

Our studies are highly interdisciplinary, but are focused on the processes and products of early planetary and asteroidal differentiation, especially the genesis of the ancient lunar crust. Most of the accessible lunar crust consists of materials hybridized by impact-mixing. Rare pristine (unmixed) samples reflect the original genetic diversity of the early crust. We studied the relative importance of internally generated melt (including the putative magma ocean) versus large impact melts in early lunar magmatism, through both sample analysis and physical modeling. Other topics under investigation included: lunar and SNC (martian?) meteorites; igneous meteorites in general; impact breccias, especially metal-rich Apollo samples and polymict eucrites; effects of regolith/megaregolith insulation on thermal evolution and geochronology; and planetary bulk compositions and origins. We investigated the theoretical petrology of impact melts, especially those formed in large masses, such as the unejected parts of the melts of the largest lunar and terrestrial impact basins. We developed constraints on several key effects that variations in melting/displacement ratio (a strong function of both crater size and planetary g) have on impact melt petrology. Modeling results indicate that the impact melt-derived rock in the sampled, megaregolith part of the Moon is probably material that was ejected from deeper average levels than the non-impact-melted material (fragmental breccias and unbrecciated pristine rocks). In the largest lunar impacts, most of the impact melt is of mantle origin and avoids ejection from the crater, while most of the crust, and virtually all of the impact-melted crust, in the area of the crater is ejected. We investigated numerous extraordinary meteorites and Apollo rocks, emphasizing pristine rocks, siderophile and volatile trace elements, and the identification of primary partial melts, as opposed to partial cumulates. Apollo 15 sample 15434,28 is an

Cited2 Gene Controls Pluripotency and Cardiomyocyte Differentiation of Murine Embryonic Stem Cells through Oct4 Gene*

PubMed Central

Li, Qiang; Ramírez-Bergeron, Diana L.; Dunwoodie, Sally L.; Yang, Yu-Chung

2012-01-01

Cited2 (CBP/p300-interacting transactivator with glutamic acid (E)/aspartic acid (D)-rich tail 2) is a transcriptional modulator critical for the development of multiple organs. Although many Cited2-mediated phenotypes and molecular events have been well characterized using in vivo genetic murine models, Cited2-directed cell fate decision in embryonic stem cells (ESCs) remains elusive. In this study, we examined the role of Cited2 in the maintenance of stemness and pluripotency of murine ESCs by a gene-targeting approach. Cited2 knock-out (Cited2Δ/−, KO) ESCs display defective differentiation. Loss of Cited2 in differentiating ESCs results in delayed silencing of the genes involved in the maintenance of pluripotency and self-renewal of stem cells (Oct4, Klf4, Sox2, and c-Myc) and the disturbance in cardiomyocyte, hematopoietic, and neuronal differentiation. In addition, Cited2 KO ESCs experience a delayed induction of cardiomyocyte differentiation-associated proteins, NFAT3 (along with the reduced expression of NFAT3 target genes, Nkx2.5 and β-MHC), N-cadherin, and smooth muscle actin. CITED2 is recruited to the Oct4 promoter to regulate its expression during early ESC differentiation. This is the first demonstration that Cited2 controls ESC pluripotency and differentiation via direct regulation of Oct4 gene expression. PMID:22761414

Primary cellular meningeal defects cause neocortical dysplasia and dyslamination

PubMed Central

Hecht, Jonathan H.; Siegenthaler, Julie A.; Patterson, Katelin P.; Pleasure, Samuel J.

2010-01-01

Objective Cortical malformations are important causes of neurological morbidity, but in many cases their etiology is poorly understood. Mice with Foxc1 mutations have cellular defects in meningeal development. We use hypomorphic and null alleles of Foxc1 to study the effect of meningeal defects on neocortical organization. Methods Embryos with loss of Foxc1 activity were generated using the hypomorphic Foxc1hith allele and the null Foxc1lacZ allele. Immunohistologic analysis was used to assess cerebral basement membrane integrity, marginal zone heterotopia formation, neuronal overmigration, meningeal defects, and changes in basement membrane composition. Dysplasia severity was quantified using two measures. Results Cortical dysplasia resembling cobblestone cortex, with basement membrane breakdown and lamination defects, is seen in Foxc1 mutants. As Foxc1 activity was reduced, abnormalities in basement membrane integrity, heterotopia formation, neuronal overmigration, and meningeal development appeared earlier in gestation and were more severe. Surprisingly, the basement membrane appeared intact at early stages of development in the face of severe deficits in meningeal development. Prominent defects in basement membrane integrity appeared as development proceeded. Molecular analysis of basement membrane laminin subunits demonstrated that loss of the meninges led to changes in basement membrane composition. Interpretation Cortical dysplasia can be caused by cellular defects in the meninges. The meninges are not required for basement membrane establishment but are needed for remodeling as the brain expands. Specific changes in basement membrane composition may contribute to subsequent breakdown. Our study raises the possibility that primary meningeal defects may cortical dysplasia in some cases. PMID:20976766

SIRT1 deficiency compromises mouse embryonic stem cell hematopoietic differentiation, and embryonic and adult hematopoiesis in the mouse

PubMed Central

Ou, Xuan; Chae, Hee-Don; Wang, Rui-Hong; Shelley, William C.; Cooper, Scott; Taylor, Tammi; Kim, Young-June; Deng, Chu-Xia; Yoder, Mervin C.

2011-01-01

SIRT1 is a founding member of a sirtuin family of 7 proteins and histone deacetylases. It is involved in cellular resistance to stress, metabolism, differentiation, aging, and tumor suppression. SIRT1−/− mice demonstrate embryonic and postnatal development defects. We examined hematopoietic and endothelial cell differentiation of SIRT1−/− mouse embryonic stem cells (ESCs) in vitro, and hematopoietic progenitors in SIRT1+/++/−, and −/− mice. SIRT1−/− ESCs formed fewer mature blast cell colonies. Replated SIRT1−/− blast colony-forming cells demonstrated defective hematopoietic potential. Endothelial cell production was unaltered, but there were defects in formation of a primitive vascular network from SIRT1−/−-derived embryoid bodies. Development of primitive and definitive progenitors derived from SIRT1−/− ESCs were also delayed and/or defective. Differentiation delay/defects were associated with delayed capacity to switch off Oct4, Nanog and Fgf5 expression, decreased β-H1 globin, β-major globin, and Scl gene expression, and reduced activation of Erk1/2. Ectopic expression of SIRT1 rescued SIRT1−/− ESC differentiation deficiencies. SIRT1−/− yolk sacs manifested fewer primitive erythroid precursors. SIRT1−/− and SIRT1+/− adult marrow had decreased numbers and cycling of hematopoietic progenitors, effects more apparent at 5%, than at 20%, oxygen tension, and these progenitors survived less well in vitro under conditions of delayed growth factor addition. This suggests a role for SIRT1 in ESC differentiation and mouse hematopoiesis. PMID:20966168

Terminal Differentiation of Adult Hippocampal Progenitor Cells Is a Step Functionally Dissociable from Proliferation and Is Controlled by Tis21, Id3 and NeuroD2

PubMed Central

Micheli, Laura; Ceccarelli, Manuela; Gioia, Roberta; D’Andrea, Giorgio; Farioli-Vecchioli, Stefano; Costanzi, Marco; Saraulli, Daniele; Cestari, Vincenzo; Tirone, Felice

2017-01-01

Cell proliferation and differentiation are interdependent processes. Here, we have asked to what extent the two processes of neural progenitor cell amplification and differentiation are functionally separated. Thus, we analyzed whether it is possible to rescue a defect of terminal differentiation in progenitor cells of the dentate gyrus, where new neurons are generated throughout life, by inducing their proliferation and/or their differentiation with different stimuli appropriately timed. As a model we used the Tis21 knockout mouse, whose dentate gyrus neurons, as demonstrated by us and others, have an intrinsic defect of terminal differentiation. We first tested the effect of two proliferative as well as differentiative neurogenic stimuli, one pharmacological (fluoxetine), the other cognitive (the Morris water maze (MWM) training). Both effectively enhanced the number of new dentate gyrus neurons produced, and fluoxetine also reduced the S-phase length of Tis21 knockout dentate gyrus progenitor cells and increased the rate of differentiation of control cells, but neither factor enhanced the defective rate of differentiation. In contrast, the defect of terminal differentiation was fully rescued by in vivo infection of proliferating dentate gyrus progenitor cells with retroviruses either silencing Id3, an inhibitor of neural differentiation, or expressing NeuroD2, a proneural gene expressed in terminally differentiated dentate gyrus neurons. This is the first demonstration that NeuroD2 or the silencing of Id3 can activate the differentiation of dentate gyrus neurons, complementing a defect of differentiation. It also highlights how the rate of differentiation of dentate gyrus neurons is regulated genetically at several levels and that a neurogenic stimulus for amplification of neural stem/progenitor cells may not be sufficient in itself to modify this rate. PMID:28740463

Blood flow patterns underlie developmental heart defects

PubMed Central

Midgett, Madeline; Thornburg, Kent

2017-01-01

Although cardiac malformations at birth are typically associated with genetic anomalies, blood flow dynamics also play a crucial role in heart formation. However, the relationship between blood flow patterns in the early embryo and later cardiovascular malformation has not been determined. We used the chicken embryo model to quantify the extent to which anomalous blood flow patterns predict cardiac defects that resemble those in humans and found that restricting either the inflow to the heart or the outflow led to reproducible abnormalities with a dose-response type relationship between blood flow stimuli and the expression of cardiac phenotypes. Constricting the outflow tract by 10–35% led predominantly to ventricular septal defects, whereas constricting by 35–60% most often led to double outlet right ventricle. Ligation of the vitelline vein caused mostly pharyngeal arch artery malformations. We show that both cardiac inflow reduction and graded outflow constriction strongly influence the development of specific and persistent abnormal cardiac structure and function. Moreover, the hemodynamic-associated cardiac defects recapitulate those caused by genetic disorders. Thus our data demonstrate the importance of investigating embryonic blood flow conditions to understand the root causes of congenital heart disease as a prerequisite to future prevention and treatment. NEW & NOTEWORTHY Congenital heart defects result from genetic anomalies, teratogen exposure, and altered blood flow during embryonic development. We show here a novel “dose-response” type relationship between the level of blood flow alteration and manifestation of specific cardiac phenotypes. We speculate that abnormal blood flow may frequently underlie congenital heart defects. PMID:28062416

Differential maturation of rhythmic clock gene expression during early development in medaka (Oryzias latipes).

PubMed

Cuesta, Ines H; Lahiri, Kajori; Lopez-Olmeda, Jose Fernando; Loosli, Felix; Foulkes, Nicholas S; Vallone, Daniela

2014-05-01

One key challenge for the field of chronobiology is to identify how circadian clock function emerges during early embryonic development. Teleosts such as the zebrafish are ideal models for studying circadian clock ontogeny since the entire process of development occurs ex utero in an optically transparent chorion. Medaka (Oryzias latipes) represents another powerful fish model for exploring early clock function with, like the zebrafish, many tools available for detailed genetic analysis. However, to date there have been no reports documenting circadian clock gene expression during medaka development. Here we have characterized the expression of key clock genes in various developmental stages and in adult tissues of medaka. As previously reported for other fish, light dark cycles are required for the emergence of clock gene expression rhythms in this species. While rhythmic expression of per and cry genes is detected very early during development and seems to be light driven, rhythmic clock and bmal expression appears much later around hatching time. Furthermore, the maturation of clock function seems to correlate with the appearance of rhythmic expression of these positive elements of the clock feedback loop. By accelerating development through elevated temperatures or by artificially removing the chorion, we show an earlier onset of rhythmicity in clock and bmal expression. Thus, differential maturation of key elements of the medaka clock mechanism depends on the developmental stage and the presence of the chorion.

Shikonin suppresses ERK 1/2 phosphorylation during the early stages of adipocyte differentiation in 3T3-L1 cells

PubMed Central

2013-01-01

Background The naphthoquinone pigment, shikonin, is a major component of Lithospermum erythrorhizon and has been shown to have various biological functions, including antimicrobial, anti-inflammatory, and antitumor effects. In this study, we investigated the effect of shikonin on adipocyte differentiation and its mechanism of action in 3T3-L1 cells. Methods To investigate the effects of shikonin on adipocyte differentiation, 3T3-L1 cells were induced to differentiate using 3-isobutyl-1-methylzanthine, dexamethasone, and insulin (MDI) for 8 days in the presence of 0–2 μM shikonin. Oil Red O staining was performed to determine the lipid accumulation in 3T3-L1 cells. To elucidate the anti-adipogenic mechanism of shikonin, adipogenic transcription factors, the phosphorylation levels of ERK, and adipogenic gene expression were analyzed by Western blotting and quantitative real-time PCR. To further confirm that shikonin inhibits adipogenic differentiation through downregulation of ERK 1/2 activity, 3T3-L1 cells were treated with shikonin in the presence of FGF-2, an activator, or PD98059, an inhibitor, of the ERK1/2 signaling pathway. Results Shikonin effectively suppressed adipogenesis and downregulated the protein levels of 2 major transcription factors, PPARγ and C/EBPα, as well as the adipocyte specific gene aP2 in a dose-dependent manner. qRT-PCR analysis revealed that shikonin inhibited mRNA expression of adipogenesis-related genes, such as PPARγ, C/EBPα, and aP2. Adipocyte differentiation was mediated by ERK 1/2 phosphorylation, which was confirmed by pretreatment with PD98059 (an ERK 1/2 inhibitor) or FGF-2 (an ERK 1/2 activator). The phosphorylation of ERK1/2 during the early stages of adipogenesis in 3T3-L1 cells was inhibited by shikonin. We also confirmed that FGF-2-stimulated ERK 1/2 activity was attenuated by shikonin. Conclusions These results demonstrate that shikonin inhibits adipogenic differentiation via suppression of the ERK signaling pathway

Shikonin suppresses ERK 1/2 phosphorylation during the early stages of adipocyte differentiation in 3T3-L1 cells.

PubMed

Gwon, So Young; Ahn, Ji Yun; Jung, Chang Hwa; Moon, Bo Kyung; Ha, Tae Youl

2013-08-06

The naphthoquinone pigment, shikonin, is a major component of Lithospermum erythrorhizon and has been shown to have various biological functions, including antimicrobial, anti-inflammatory, and antitumor effects. In this study, we investigated the effect of shikonin on adipocyte differentiation and its mechanism of action in 3T3-L1 cells. To investigate the effects of shikonin on adipocyte differentiation, 3T3-L1 cells were induced to differentiate using 3-isobutyl-1-methylzanthine, dexamethasone, and insulin (MDI) for 8 days in the presence of 0-2 μM shikonin. Oil Red O staining was performed to determine the lipid accumulation in 3T3-L1 cells. To elucidate the anti-adipogenic mechanism of shikonin, adipogenic transcription factors, the phosphorylation levels of ERK, and adipogenic gene expression were analyzed by Western blotting and quantitative real-time PCR. To further confirm that shikonin inhibits adipogenic differentiation through downregulation of ERK 1/2 activity, 3T3-L1 cells were treated with shikonin in the presence of FGF-2, an activator, or PD98059, an inhibitor, of the ERK1/2 signaling pathway. Shikonin effectively suppressed adipogenesis and downregulated the protein levels of 2 major transcription factors, PPARγ and C/EBPα, as well as the adipocyte specific gene aP2 in a dose-dependent manner. qRT-PCR analysis revealed that shikonin inhibited mRNA expression of adipogenesis-related genes, such as PPARγ, C/EBPα, and aP2. Adipocyte differentiation was mediated by ERK 1/2 phosphorylation, which was confirmed by pretreatment with PD98059 (an ERK 1/2 inhibitor) or FGF-2 (an ERK 1/2 activator). The phosphorylation of ERK1/2 during the early stages of adipogenesis in 3T3-L1 cells was inhibited by shikonin. We also confirmed that FGF-2-stimulated ERK 1/2 activity was attenuated by shikonin. These results demonstrate that shikonin inhibits adipogenic differentiation via suppression of the ERK signaling pathway during the early stages of adipogenesis.

Active magnetic bearings used as exciters for rolling element bearing outer race defect diagnosis.

PubMed

Xu, Yuanping; Di, Long; Zhou, Jin; Jin, Chaowu; Guo, Qintao

2016-03-01

The active health monitoring of rotordynamic systems in the presence of bearing outer race defect is considered in this paper. The shaft is assumed to be supported by conventional mechanical bearings and an active magnetic bearing (AMB) is used in the mid of the shaft location as an exciter to apply electromagnetic force to the system. We investigate a nonlinear bearing-pedestal system model with the outer race defect under the electromagnetic force. The nonlinear differential equations are integrated using the fourth-order Runge-Kutta algorithm. The simulation and experimental results show that the characteristic signal of outer race incipient defect is significantly amplified under the electromagnetic force through the AMBs, which is helpful to improve the diagnosis accuracy of rolling element bearing׳s incipient outer race defect. Copyright © 2016 ISA. Published by Elsevier Ltd. All rights reserved.

Early local differentiation of the cell wall matrix defines the contact sites in lobed mesophyll cells of Zea mays.

PubMed

Giannoutsou, E; Sotiriou, P; Apostolakos, P; Galatis, B

2013-10-01

The morphogenesis of lobed mesophyll cells (MCs) is highly controlled and coupled with intercellular space formation. Cortical microtubule rings define the number and the position of MC isthmi. This work investigated early events of MC morphogenesis, especially the mechanism defining the position of contacts between MCs. The distributions of plasmodesmata, the hemicelluloses callose and (1 → 3,1 → 4)-β-d-glucans (MLGs) and the pectin epitopes recognized by the 2F4, JIM5, JIM7 and LM6 antibodies were studied in the cell walls of Zea mays MCs. Matrix cell wall polysaccharides were immunolocalized in hand-made sections and in sections of material embedded in LR White resin. Callose was also localized using aniline blue in hand-made sections. Plasmodesmata distribution was examined by transmission electron microscopy. Before reorganization of the dispersed cortical microtubules into microtubule rings, particular bands of the longitudinal MC walls, where the MC contacts will form, locally differentiate by selective (1) deposition of callose and the pectin epitopes recognized by the 2F4, LM6, JIM5 and JIM7 antibodies, (2) degradation of MLGs and (3) formation of secondary plasmodesmata clusterings. This cell wall matrix differentiation persists in cell contacts of mature MCs. Simultaneously, the wall bands between those of future cell contacts differentiate with (1) deposition of local cell wall thickenings including cellulose microfibrils, (2) preferential presence of MLGs, (3) absence of callose and (4) transient presence of the pectins identified by the JIM5 and JIM7 antibodies. The wall areas between cell contacts expand determinately to form the cell isthmi and the cell lobes. The morphogenesis of lobed MCs is characterized by the early patterned differentiation of two distinct cell wall subdomains, defining the sites of the future MC contacts and of the future MC isthmi respectively. This patterned cell wall differentiation precedes cortical microtubule

Reconstruction of cartilage with clonal mesenchymal stem cell-acellular dermal matrix in cartilage defect model in nonhuman primates.

PubMed

Ma, Anlun; Jiang, Li; Song, Lijun; Hu, Yanxin; Dun, Hao; Daloze, Pierre; Yu, Yonglin; Jiang, Jianyuan; Zafarullah, Muhammad; Chen, Huifang

2013-07-01

Articular cartilage defects are commonly associated with trauma, inflammation and osteoarthritis. Mesenchymal stem cell (MSC)-based therapy is a promising novel approach for repairing articular cartilage. Direct intra-articular injection of uncommitted MSCs does not regenerate high-quality cartilage. This study explored utilization of a new three-dimensional, selected chondrogenic clonal MSC-loaded monkey acellular dermal matrix (MSC-ADM) scaffold to repair damaged cartilage in an experimental model of knee joint cartilage defect in Cynomolgus monkeys. MSCs were characterized for cell size, cell yield, phenotypes, proliferation and chondrogenic differentiation capacity. Chondrogenic differentiation assays were performed at different MSC passages by sulfated glycosaminoglycans (sGAG), collagen, and fluorescence activated cell sorter (FACS) analysis. Selected chondrogenic clonal MSCs were seeded onto ADM scaffold with the sandwich model and MSC-loaded ADM grafts were analyzed by confocal microscopy and scanning electron microscopy. Cartilage defects were treated with normal saline, clonal MSCs and clonal MSC-ADM grafts, respectively. The clinical parameters, and histological and immunohistochemical examinations were evaluated at weeks 8, 16, 24 post-treatment, respectively. Polyclonal and clonal MSCs could differentiate into the chondrogenic lineage after stimulation with suitable chondrogenic factors. They expressed mesenchymal markers and were negative for hematopoietic markers. Articular cartilage defects were considerably improved and repaired by selected chondrogenic clonal MSC-based treatment, particularly, in MSC-ADM-treated group. The histological scores in MSC-ADM-treated group were consistently higher than those of other groups. Our results suggest that selected chondrogenic clonal MSC-loaded ADM grafts could improve the cartilage lesions in Cynomolgus monkey model, which may be applicable for repairing similar human cartilage defects. Copyright © 2013

Immobile defects in ferroelastic walls: Wall nucleation at defect sites

NASA Astrophysics Data System (ADS)

He, X.; Salje, E. K. H.; Ding, X.; Sun, J.

2018-02-01

Randomly distributed, static defects are enriched in ferroelastic domain walls. The relative concentration of defects in walls, Nd, follows a power law distribution as a function of the total defect concentration C: N d ˜ C α with α = 0.4 . The enrichment Nd/C ranges from ˜50 times when C = 10 ppm to ˜3 times when C = 1000 ppm. The resulting enrichment is due to nucleation at defect sites as observed in large scale MD simulations. The dynamics of domain nucleation and switching is dependent on the defect concentration. Their energy distribution follows the power law with exponents during yield between ɛ ˜ 1.82 and 2.0 when the defect concentration increases. The power law exponent is ɛ ≈ 2.7 in the plastic regime, independent of the defect concentration.

Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8/S100A9

PubMed Central

Schneider, Rebekka K.; Schenone, Monica; Ferreira, Monica Ventura; Kramann, Rafael; Joyce, Cailin E.; Hartigan, Christina; Beier, Fabian; Brümmendorf, Tim H.; Gehrming, Ulrich; Platzbecker, Uwe; Büsche, Guntram; Knüchel, Ruth; Chen, Michelle C.; Waters, Christopher S.; Chen, Edwin; Chu, Lisa P.; Novina, Carl D.; Lindsley, R. Coleman; Carr, Steven A.; Ebert, Benjamin L.

2016-01-01

Heterozygous deletion of RPS14 occurs in del(5q) MDS and has been linked to impaired erythropoiesis, characteristic of this disease subtype. We generated a murine model with conditional inactivation of Rps14 and demonstrated a p53-dependent erythroid differentiation defect with apoptosis at the transition from polychromatic to orthochromatic erythroblasts resulting in age-dependent progressive anemia, megakaryocyte dysplasia, and loss of hematopoietic stem cell (HSC) quiescence. Using quantitative proteomics, we identified significantly increased expression of proteins involved in innate immune signaling, particularly the heterodimeric S100a8/S100a9 proteins in purified erythroblasts. S100a8 expression was significantly increased in erythroblasts, monocytes and macrophages and recombinant S100a8 was sufficient to induce an erythroid differentiation defect in wild-type cells. We rescued the erythroid differentiation defect in Rps14 haploinsufficient HSCs by genetic inactivation of S100a8 expression. Our data link Rps14 haploinsufficiency to activation of the innate immune system via induction of S100A8/A9 and the p53-dependant erythroid differentiation defect in del(5q) MDS. PMID:26878232

Differential risk for late adolescent conduct problems and mood dysregulation among children with early externalizing behavior problems.

PubMed

Okado, Yuko; Bierman, Karen L

2015-05-01

To investigate the differential emergence of antisocial behaviors and mood dysregulation among children with externalizing problems, the present study prospectively followed 317 high-risk children with early externalizing problems from school entry (ages 5-7) to late adolescence (ages 17-19). Latent class analysis conducted on their conduct and mood symptoms in late adolescence revealed three distinct patterns of symptoms, characterized by: 1) criminal offenses, conduct disorder symptoms, and elevated anger ("conduct problems"), 2) elevated anger, dysphoric mood, and suicidal ideation ("mood dysregulation"), and 3) low levels of severe conduct and mood symptoms. A diathesis-stress model predicting the first two outcomes was tested. Elevated overt aggression at school entry uniquely predicted conduct problems in late adolescence, whereas elevated emotion dysregulation at school entry uniquely predicted mood dysregulation in late adolescence. Experiences of low parental warmth and peer rejection in middle childhood moderated the link between early emotion dysregulation and later mood dysregulation but did not moderate the link between early overt aggression and later conduct problems. Thus, among children with early externalizing behavior problems, increased risk for later antisocial behavior or mood dysfunction may be identifiable in early childhood based on levels of overt aggression and emotion dysregulation. For children with early emotion dysregulation, however, increased risk for mood dysregulation characterized by anger, dysphoric mood, and suicidality--possibly indicative of disruptive mood dysregulation disorder--emerges only in the presence of low parental warmth and/or peer rejection during middle childhood.

[Perinatal management of twins with discordant congenital defects].

PubMed

Yu, Hai-yan; Xing, Ai-yun; You, Yong; Liu, Xing-hui; Wang, Xiao-dong

2014-11-01

To review the outcomes of perinatal management of twins with discordant congenital defects. We retrospectively examined the cases of twins with discordant congenital defects treated in the West China Second University Hospital from December 2011 to December 2013. There were 26 cases of twins (14 dichorionic and 12 monochorionic) with one anomalous fetus. Of those twins, 16 were conceived by nature and 10 by in vitro fertilization and embryo tansfer (IVF-ET). Counselling services were offered to the parents by a multidisciplinary team about options of pregnancy. Termination of pregnancy was chosen on three monochorionic twins. Twelve pairs of twin were delivered at 26(+3)-37(+6) weeks gestation. One pair ended with neonatal death, and another one with gastroschisis was given intrapartum fetal operation. Selective termination was chosen on 11 cases using intracardiac injection of potassium chloride under ultrasonographic guidance (9 cases) or bipolar cord coagulation (2 cases). This resulted in ten live births delivered at 25(+5)-38(+4) gustation and one neonatal death. Early diagnosis of twins with discordant congenital defects is important. Multidisciplinary counselling services to parents are recommended for determination of options. Intensive prenatal care is essential in management of twins with discordant congenital defects.

Prevention of congenital defects induced by prenatal alcohol exposure (Conference Presentation)

NASA Astrophysics Data System (ADS)

Sheehan, Megan M.; Karunamuni, Ganga; Pedersen, Cameron J.; Gu, Shi; Doughman, Yong Qiu; Jenkins, Michael W.; Watanabe, Michiko; Rollins, Andrew M.

2017-02-01

Nearly 2 million women in the United States alone are at risk for an alcohol-exposed pregnancy, including more than 600,000 who binge drink. Even low levels of prenatal alcohol exposure (PAE) can lead to a variety of birth defects, including craniofacial and neurodevelopmental defects, as well as increased risk of miscarriages and stillbirths. Studies have also shown an interaction between drinking while pregnant and an increase in congenital heart defects (CHD), including atrioventricular septal defects and other malformations. We have previously established a quail model of PAE, modeling a single binge drinking episode in the third week of a woman's pregnancy. Using optical coherence tomography (OCT), we quantified intraventricular septum thickness, great vessel diameters, and atrioventricular valve volumes. Early-stage ethanol-exposed embryos had smaller cardiac cushions (valve precursors) and increased retrograde flow, while late-stage embryos presented with gross head/body defects, and exhibited smaller atrio-ventricular (AV) valves, interventricular septum, and aortic vessels. We previously showed that supplementation with the methyl donor betaine reduced gross defects, improved survival rates, and prevented cardiac defects. Here we show that these preventative effects are also observed with folate (another methyl donor) supplementation. Folate also appears to normalize retrograde flow levels which are elevated by ethanol exposure. Finally, preliminary findings have shown that glutathione, a crucial antioxidant, is noticeably effective at improving survival rates and minimizing gross defects in ethanol-exposed embryos. Current investigations will examine the impact of glutathione supplementation on PAE-related CHDs.

HNF1α defect influences post-prandial lipid regulation

PubMed Central

St-Jean, Matthieu; Boudreau, François; Carpentier, André C.

2017-01-01

Purpose Hepatocyte nuclear factor 1 alpha (HNF1α) defects cause Mature Onset Diabetes of the Young type 3 (MODY3), characterized by defects in beta-cell insulin secretion. However, HNF1α is involved in many other metabolic pathways with relevance for monogenic or polygenic type 2 diabetes. We aimed to investigate gut hormones, lipids, and insulin regulation in response to a meal test in HNF1α defect carriers (MODY3) compared to non-diabetic subjects (controls) and type 2 diabetes (T2D). Methods We administered a standardized liquid meal to each participant. Over 6 hours, we measured post-meal responses of insulin regulation (blood glucose, c-peptide, insulin), gut hormones (ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1) and lipids (non-esterified fatty acids [NEFA] and triglycerides). Results We found that MODY3 participants had lower insulin secretion indices than controls and T2D participants, showing the expected β-cell defect. MODY3 had similar glycated hemoglobin levels (HbA1c median [IQR]: 6.5 [5.6–7.6]%) compared to T2D (median: 6.6 [6.2–6.9]%; P<0.05). MODY3 had greater insulin sensitivity (Matsuda index: 71.9 [29.6; 125.5]) than T2D (3.2 [4.0; 6.0]; P<0.05). MODY3 experienced a larger decrease in the ratio of NEFA to insulin (NEFA 30–0 / insulin 30–0: -39 [-78; -30] x104) in the early post-prandial period (0–30 minutes) compared to controls and to T2D (-2.0 [-0.6; -6.4] x104; P<0.05). MODY3 had lower fasting (0.66 [0.46; 1.2] mM) and post-meal triglycerides levels compared to T2D (fasting: 2.3 [1.7; 2.7] mM; P<0.05). We did not detect significant post-meal differences in ghrelin and incretins between MODY3 and other groups. Conclusion In response to a standard meal test, MODY3 showed greater early post-prandial NEFA diminution in response to relatively low early insulin secretion, and they maintained very low post-prandial triglycerides levels. PMID:28493909

Command of active matter by topological defects and patterns

NASA Astrophysics Data System (ADS)

Peng, Chenhui; Turiv, Taras; Guo, Yubing; Wei, Qi-Huo; Lavrentovich, Oleg D.

2016-11-01

Self-propelled bacteria are marvels of nature with a potential to power dynamic materials and microsystems of the future. The challenge lies in commanding their chaotic behavior. By dispersing swimming Bacillus subtilis in a liquid crystalline environment with spatially varying orientation of the anisotropy axis, we demonstrate control over the distribution of bacterial concentration, as well as the geometry and polarity of their trajectories. Bacteria recognize subtle differences in liquid crystal deformations, engaging in bipolar swimming in regions of pure splay and bend but switching to unipolar swimming in mixed splay-bend regions. They differentiate topological defects, heading toward defects of positive topological charge and avoiding negative charges. Sensitivity of bacteria to preimposed orientational patterns represents a previously unknown facet of the interplay between hydrodynamics and topology of active matter.

Studies of Point Defects and Defect Interactions in Metals Using Perturbed Gamma Gamma Angular Correlations

NASA Astrophysics Data System (ADS)

Shropshire, Steven Leslie

Point defects in plastically deformed Au, Pt, and Ni were studied with atomic-scale sensitivity using the perturbed gamma-gamma angular correlations (PAC) technique by monitoring formation and transformation of complexes of vacancy defects with very dilute ^{111}In/ ^{111}Cd solute probes. Three topics were investigated: (1) Production of vacancy defects during plastic deformation of Au was investigated to differentiate models of defect production. Concentrations of mono-, di-, and tri-vacancy species were measured in Au, and the ratio of mono- to di-vacancies was found to be independent of the amount of deformation. Results indicate that point defects are produced in correlated lattice locations, such as in "strings", as a consequence of dislocation interactions and not at random locations. (2) Hydrogen interactions with vacancy-solute complexes were studied in Pt. From thermal detrapping experiments, binding of hydrogen in complexes with mono-, di- and tri-vacancies was determined using a model for hydrogen diffusing in a medium with traps, with enthalpies all measured in the narrow range 0.23-0.28 eV, proving that the binding is insensitive to the precise structure of small vacancy clusters. Nuclear relaxation of the probe in a trivacancy complex in Pt was studied as a function of temperature, from which an activation energy of 0.34 eV was measured. This value is inconsistent with relaxation caused by diffusion or trapping of hydrogen, but explainable by dynamical hopping of the PAC probe atom in a cage of vacancies. (3) By observing transformations between vacancy-solute complexes induced by annihilation reactions, it was demonstrated that interstitials are produced during plastic deformation. The evolution of concentrations of the different vacancy complexes under an interstitial flux was measured and analyzed using a kinetic-rate model, from which interstitial capture cross-sections for the different vacancy complexes and the relative quantities of

Entorhinal cortical defects in Tg2576 mice are present as early as 2–4 months of age

PubMed Central

Duffy, Áine M.; Morales-Corraliza, Jose; Bermudez-Hernandez, Keria M.; Schaner, Michael J.; Magagna-Poveda, Alejandra; Mathews, Paul M.; Scharfman, Helen E.

2014-01-01

The entorhinal cortex (EC) is one of the first brain areas to display neuropathology in Alzheimer’s disease (AD). A mouse model which simulates amyloid-β (Aβ) neuropathology, the Tg2576 mouse, was used to address these early changes. Here we show EC abnormalities occur in 2–4 month-old Tg2576 mice, an age prior to β-amyloid deposition and where previous studies suggest that there are few behavioral impairments. First we show, using sandwich ELISA, that soluble human Aβ40 and Aβ42 are detectable in the EC of 2-month-old Tg2576 mice prior to β-amyloid deposition. We then demonstrate that 2–4 month-old Tg2576 mice are impaired at object placement, an EC-dependent cognitive task. Next we show that defects in NeuN expression and myelin uptake occur in the superficial layers of the EC in 2–4-month-old Tg2576 mice. In slices from Tg2576 mice that contained the EC, there were repetitive field potentials evoked by a single stimulus to the underlying white matter, and a greater response to reduced extracellular magnesium ([Mg2+]o), suggesting increased excitability. However, deep layer neurons in Tg2576 mice had longer latencies to antidromic activation than wild type mice. The results show changes in the EC at early ages, and suggest that altered excitability occurs before extensive plaque pathology. PMID:25109765

Convergent Validity of the Mullen Scales of Early Learning and the Differential Ability Scales in Children with Autism Spectrum Disorders

ERIC Educational Resources Information Center

Bishop, Somer L.; Guthrie, Whitney; Coffing, Mia; Lord, Catherine

2011-01-01

Despite widespread use of the Mullen Scales of Early Learning (MSEL; E. M. Mullen, 1995) as a cognitive test for children with autism spectrum disorders and other developmental disabilities, the instrument has not been independently validated for use in these populations. Convergent validity of the MSEL and the Differential Ability Scales (DAS; C.…

Predicting Defects Using Information Intelligence Process Models in the Software Technology Project

PubMed Central

Selvaraj, Manjula Gandhi; Jayabal, Devi Shree; Srinivasan, Thenmozhi; Balasubramanie, Palanisamy

2015-01-01

A key differentiator in a competitive market place is customer satisfaction. As per Gartner 2012 report, only 75%–80% of IT projects are successful. Customer satisfaction should be considered as a part of business strategy. The associated project parameters should be proactively managed and the project outcome needs to be predicted by a technical manager. There is lot of focus on the end state and on minimizing defect leakage as much as possible. Focus should be on proactively managing and shifting left in the software life cycle engineering model. Identify the problem upfront in the project cycle and do not wait for lessons to be learnt and take reactive steps. This paper gives the practical applicability of using predictive models and illustrates use of these models in a project to predict system testing defects thus helping to reduce residual defects. PMID:26495427

Predicting Defects Using Information Intelligence Process Models in the Software Technology Project.

PubMed

Selvaraj, Manjula Gandhi; Jayabal, Devi Shree; Srinivasan, Thenmozhi; Balasubramanie, Palanisamy

2015-01-01

A key differentiator in a competitive market place is customer satisfaction. As per Gartner 2012 report, only 75%-80% of IT projects are successful. Customer satisfaction should be considered as a part of business strategy. The associated project parameters should be proactively managed and the project outcome needs to be predicted by a technical manager. There is lot of focus on the end state and on minimizing defect leakage as much as possible. Focus should be on proactively managing and shifting left in the software life cycle engineering model. Identify the problem upfront in the project cycle and do not wait for lessons to be learnt and take reactive steps. This paper gives the practical applicability of using predictive models and illustrates use of these models in a project to predict system testing defects thus helping to reduce residual defects.

Small RNA Sequencing Reveals Differential miRNA Expression in the Early Development of Broccoli (Brassica oleracea var. italica) Pollen

PubMed Central

Li, Hui; Wang, Yu; Wu, Mei; Li, Lihong; Jin, Chuan; Zhang, Qingli; Chen, Chengbin; Song, Wenqin; Wang, Chunguo

2017-01-01

Pollen development is an important and complex biological process in the sexual reproduction of flowering plants. Although the cytological characteristics of pollen development are well defined, the regulation of its early stages remains largely unknown. In the present study, miRNAs were explored in the early development of broccoli (Brassica oleracea var. italica) pollen. A total of 333 known miRNAs that originated from 235 miRNA families were detected. Fifty-five novel miRNA candidates were identified. Sixty of the 333 known miRNAs and 49 of the 55 predicted novel miRNAs exhibited significantly differential expression profiling in the three distinct developmental stages of broccoli pollen. Among these differentially expressed miRNAs, miRNAs that would be involved in the developmental phase transition from uninucleate microspores to binucleate pollen grains or from binucleate to trinucleate pollen grains were identified. miRNAs that showed significantly enriched expression in a specific early stage of broccoli pollen development were also observed. In addition, 552 targets for 127 known miRNAs and 69 targets for 40 predicted novel miRNAs were bioinformatically identified. Functional annotation and GO (Gene Ontology) analysis indicated that the putative miRNA targets showed significant enrichment in GO terms that were related to plant organ formation and morphogenesis. Some of enriched GO terms were detected for the targets directly involved in plant male reproduction development. These findings provided new insights into the functions of miRNA-mediated regulatory networks in broccoli pollen development. PMID:28392797

Small RNA Sequencing Reveals Differential miRNA Expression in the Early Development of Broccoli (Brassica oleracea var. italica) Pollen.

PubMed

Li, Hui; Wang, Yu; Wu, Mei; Li, Lihong; Jin, Chuan; Zhang, Qingli; Chen, Chengbin; Song, Wenqin; Wang, Chunguo

2017-01-01

Pollen development is an important and complex biological process in the sexual reproduction of flowering plants. Although the cytological characteristics of pollen development are well defined, the regulation of its early stages remains largely unknown. In the present study, miRNAs were explored in the early development of broccoli ( Brassica oleracea var. italica ) pollen. A total of 333 known miRNAs that originated from 235 miRNA families were detected. Fifty-five novel miRNA candidates were identified. Sixty of the 333 known miRNAs and 49 of the 55 predicted novel miRNAs exhibited significantly differential expression profiling in the three distinct developmental stages of broccoli pollen. Among these differentially expressed miRNAs, miRNAs that would be involved in the developmental phase transition from uninucleate microspores to binucleate pollen grains or from binucleate to trinucleate pollen grains were identified. miRNAs that showed significantly enriched expression in a specific early stage of broccoli pollen development were also observed. In addition, 552 targets for 127 known miRNAs and 69 targets for 40 predicted novel miRNAs were bioinformatically identified. Functional annotation and GO (Gene Ontology) analysis indicated that the putative miRNA targets showed significant enrichment in GO terms that were related to plant organ formation and morphogenesis. Some of enriched GO terms were detected for the targets directly involved in plant male reproduction development. These findings provided new insights into the functions of miRNA-mediated regulatory networks in broccoli pollen development.

Brain cytoplasmic RNA 1 suppresses smooth muscle differentiation and vascular development in mice.

PubMed

Wang, Yung-Chun; Chuang, Ya-Hui; Shao, Qiang; Chen, Jian-Fu; Chen, Shi-You

2018-04-13

The cardiovascular system develops during the early stages of embryogenesis, and differentiation of smooth muscle cells (SMCs) is essential for that process. SMC differentiation is critically regulated by transforming growth factor (TGF)-β/SMAD family member 3 (SMAD3) signaling, but other regulators may also play a role. For example, long noncoding RNAs (lncRNAs) regulate various cellular activities and events, such as proliferation, differentiation, and apoptosis. However, whether long noncoding RNAs also regulate SMC differentiation remains largely unknown. Here, using the murine cell line C3H10T1/2, we found that brain cytoplasmic RNA 1 (BC1) is an important regulator of SMC differentiation. BC1 overexpression suppressed, whereas BC1 knockdown promoted, TGF-β-induced SMC differentiation, as indicated by altered cell morphology and expression of multiple SMC markers, including smooth muscle α-actin (αSMA), calponin, and smooth muscle 22α (SM22α). BC1 appeared to block SMAD3 activity and inhibit SMC marker gene transcription. Mechanistically, BC1 bound to SMAD3 via RNA SMAD-binding elements (rSBEs) and thus impeded TGF-β-induced SMAD3 translocation to the nucleus. This prevented SMAD3 from binding to SBEs in SMC marker gene promoters, an essential event in SMC marker transcription. In vivo , BC1 overexpression in mouse embryos impaired vascular SMC differentiation, leading to structural defects in the artery wall, such as random breaks in the elastic lamina, abnormal collagen deposition on SM fibers, and disorganized extracellular matrix proteins in the media of the neonatal aorta. Our results suggest that BC1 is a suppressor of SMC differentiation during vascular development. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Hypoplasia-associated Severe Early Childhood Caries – A Proposed Definition

PubMed Central

Caufield, P.W.; Li, Y.; Bromage, T.G.

2012-01-01

We propose a new classification of severe early childhood caries (S-ECC): hypoplasia-associated severe early childhood caries (HAS-ECC). This form of caries affects mostly young children living at or below poverty, characterized by structurally damaged primary teeth that are particularly vulnerable to dental caries. These predisposing developmental dental defects are mainly permutations of enamel hypoplasia (EHP). Anthropologists and dental researchers consider EHP an indicator for infant and maternal stresses including malnutrition, a variety of illnesses, and adverse birthing conditions. Differentiation of HAS-ECC from other forms of early childhood caries is warranted because of its distinct etiology, clinical presentation, and eventual management. Defining HAS-ECC has important clinical implications: Therapies that control or prevent other types of caries are likely to be less effective with HAS-ECC because the structural integrity of the teeth is compromised prior to their emergence into the oral cavity. By the time these children present to the dentist, the treatment options often become limited to surgical management under general anesthesia. To prevent HAS-ECC, dentists must partner with other health providers to develop interventions that begin with pregnant mothers, with the aim of eliminating or ameliorating the covariates accompanying poverty, including better pre- and post-natal care and nutrition. PMID:22529242

Discovery of novel differentiation markers in the early stage of chondrogenesis by glycoform-focused reverse proteomics and genomics.

PubMed

Ishihara, Takeshi; Kakiya, Kiyoshi; Takahashi, Koji; Miwa, Hiroto; Rokushima, Masatomo; Yoshinaga, Tomoyo; Tanaka, Yoshikazu; Ito, Takaomi; Togame, Hiroko; Takemoto, Hiroshi; Amano, Maho; Iwasaki, Norimasa; Minami, Akio; Nishimura, Shin-Ichiro

2014-01-01

Osteoarthritis (OA) is one of the most common chronic diseases among adults, especially the elderly, which is characterized by destruction of the articular cartilage. Despite affecting more than 100 million individuals all over the world, therapy is currently limited to treating pain, which is a principal symptom of OA. New approaches to the treatment of OA that induce regeneration and repair of cartilage are strongly needed. To discover potent markers for chondrogenic differentiation, glycoform-focused reverse proteomics and genomics were performed on the basis of glycoblotting-based comprehensive approach. Expression levels of high-mannose type N-glycans were up-regulated significantly at the late stage of differentiation of the mouse chondroprogenitor cells. Among 246 glycoproteins carrying this glycotype identified by ConA affinity chromatography and LC/MS, it was demonstrated that 52% are classified as cell surface glycoproteins. Gene expression levels indicated that mRNAs for 15 glycoproteins increased distinctly in the earlier stages during differentiation compared with Type II collagen. The feasibility of mouse chondrocyte markers in human chondrogenesis model was demonstrated by testing gene expression levels of these 15 glycoproteins during differentiation in human mesenchymal stem cells. The results showed clearly an evidence of up-regulation of 5 genes, ectonucleotide pyrophosphatase/phosphodiesterase family member 1, collagen alpha-1(III) chain, collagen alpha-1(XI) chain, aquaporin-1, and netrin receptor UNC5B, in the early stages of differentiation. These cell surface 5 glycoproteins become highly sensitive differentiation markers of human chondrocytes that contribute to regenerative therapies, and development of novel therapeutic reagents. © 2013.

[The repair of bulky tissue defect of forearm with skin flaps].

PubMed

Huang, Xiaoyuan; Long, Jianhong; Xie, Tinghong; Zhang, Minghua; Zhang, Pihong; Yang, Xinghua; Zhong, Keqin

2002-12-01

To evaluate the repairing methods of bulky tissue defect of forearm with flaps. Twenty-one burned patients with wounds in the forearm were enrolled in this study. The injury causes were high-voltage electricity, hot press or crush injury. After local debridement, the forearm defects were repaired with pedicled complex flaps, latissimus dorsi musculocutaneous island flaps or large thoraco-abdominal flaps immediately. All the flaps survived very well with satisfactory results except for 1 patient in whom local ischemic necrosis and sub-flap infection at the distal end of the flap occurred. Early debridement followed by skin flaps with pedicles or musculocutaneous flaps transfer could be simple, safe and reliable treatment strategies in the management of bulky tissue defects of the forearm due to burn, electric injury, or other devastating injuries.

Early expression of triggering receptors and regulatory role of 2B4 in human natural killer cell precursors undergoing in vitro differentiation

PubMed Central

Sivori, Simona; Falco, Michela; Marcenaro, Emanuela; Parolini, Silvia; Biassoni, Roberto; Bottino, Cristina; Moretta, Lorenzo; Moretta, Alessandro

2002-01-01

In this study we analyzed the progression of cell surface receptor expression during the in vitro-induced human natural killer (NK) cell maturation from CD34+ Lin− cell precursors. NKp46 and NKp30, two major triggering receptors that play a central role in natural cytotoxicity, were expressed before the HLA class I-specific inhibitory receptors. Moreover, their appearance at the cell surface correlated with the acquisition of cytolytic activity by developing NK cells. Although the early expression of triggering receptors may provide activating signals required for inducing further cell differentiation, it may also affect the self-tolerance of developing NK cells. Our data show that a fail-safe mechanism preventing killing of normal autologous cells may be provided by the 2B4 surface molecule, which, at early stages of NK cell differentiation, functions as an inhibitory rather than as an activating receptor. PMID:11917118

Early Psoriatic Arthritis Versus Early Seronegative Rheumatoid Arthritis: Role of Dermoscopy Combined with Ultrasonography for Differential Diagnosis.

PubMed

Zabotti, Alen; Errichetti, Enzo; Zuliani, Francesca; Quartuccio, Luca; Sacco, Stefania; Stinco, Giuseppe; De Vita, Salvatore

2018-05-01

Exclusion of psoriatic skin/nail lesions is important in differentiating early seronegative rheumatoid arthritis (ERA) from early polyarticular psoriatic arthritis (EPsA) and such manifestations may go unnoticed in atypical or minimally expressed cases. The aim of this study is to assess the usefulness of integrated rheumatological-dermatological evaluation in highlighting dermatological lesions missed on rheumatological examination and to investigate the role of ultrasonography (US) and dermoscopy in improving the recognition of subclinical psoriatic findings. Patients with a new diagnosis of seropositive or seronegative ERA and EPsA with prevalent hands involvement were recruited. All were reassessed for the presence of psoriatic lesions during an integrated rheumatological-dermatological clinical evaluation and underwent hands US and proximal nailfold dermoscopy. Seventy-three consecutive subjects were included in the study: 25 with seropositive ERA, 23 with seronegative ERA, and 25 with EPsA. One-fourth of the subjects initially diagnosed as seronegative ERA presented cutaneous or nail psoriasis on integrated rheumatological-dermatological evaluation, thereby being reclassified as EPsA. The presence of at least 1 extrasynovial feature on hand US and dotted vessels on proximal nailfold dermoscopy was significantly associated with EPsA, with a sensitivity of 68.0% and 96.0% and a specificity of 88.1% and 83.3% for US and dermoscopy, respectively. When used together, specificity for PsA diagnosis raised to 90.5%. Integrated rheumatological-dermatological clinical evaluation may be helpful in identifying patients with EPsA misclassified as seronegative ERA. Additionally, US and dermoscopy may be used as supportive tools in identifying subclinical psoriatic features, which may come in handy in distinguishing EPsA from ERA.

Early differential sensitivity of evoked-potentials to local and global shape during the perception of three-dimensional objects.

PubMed

Leek, E Charles; Roberts, Mark; Oliver, Zoe J; Cristino, Filipe; Pegna, Alan J

2016-08-01

Here we investigated the time course underlying differential processing of local and global shape information during the perception of complex three-dimensional (3D) objects. Observers made shape matching judgments about pairs of sequentially presented multi-part novel objects. Event-related potentials (ERPs) were used to measure perceptual sensitivity to 3D shape differences in terms of local part structure and global shape configuration - based on predictions derived from hierarchical structural description models of object recognition. There were three types of different object trials in which stimulus pairs (1) shared local parts but differed in global shape configuration; (2) contained different local parts but shared global configuration or (3) shared neither local parts nor global configuration. Analyses of the ERP data showed differential amplitude modulation as a function of shape similarity as early as the N1 component between 146-215ms post-stimulus onset. These negative amplitude deflections were more similar between objects sharing global shape configuration than local part structure. Differentiation among all stimulus types was reflected in N2 amplitude modulations between 276-330ms. sLORETA inverse solutions showed stronger involvement of left occipitotemporal areas during the N1 for object discrimination weighted towards local part structure. The results suggest that the perception of 3D object shape involves parallel processing of information at local and global scales. This processing is characterised by relatively slow derivation of 'fine-grained' local shape structure, and fast derivation of 'coarse-grained' global shape configuration. We propose that the rapid early derivation of global shape attributes underlies the observed patterns of N1 amplitude modulations. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Nucleic acid-based approaches to investigate microbial-related cheese quality defects

PubMed Central

O'Sullivan, Daniel J.; Giblin, Linda; McSweeney, Paul L. H.; Sheehan, Jeremiah J.; Cotter, Paul D.

2012-01-01

The microbial profile of cheese is a primary determinant of cheese quality. Microorganisms can contribute to aroma and taste defects, form biogenic amines, cause gas and secondary fermentation defects, and can contribute to cheese pinking and mineral deposition issues. These defects may be as a result of seasonality and the variability in the composition of the milk supplied, variations in cheese processing parameters, as well as the nature and number of the non-starter microorganisms which come from the milk or other environmental sources. Such defects can be responsible for production and product recall costs and thus represent a significant economic burden for the dairy industry worldwide. Traditional non-molecular approaches are often considered biased and have inherently slow turnaround times. Molecular techniques can provide early and rapid detection of defects that result from the presence of specific spoilage microbes and, ultimately, assist in enhancing cheese quality and reducing costs. Here we review the DNA-based methods that are available to detect/quantify spoilage bacteria, and relevant metabolic pathways in cheeses and, in the process, highlight how these strategies can be employed to improve cheese quality and reduce the associated economic burden on cheese processors. PMID:23346082

Two Pore Channel 2 Differentially Modulates Neural Differentiation of Mouse Embryonic Stem Cells

PubMed Central

Zhang, Zhe-Hao; Lu, Ying-Ying; Yue, Jianbo

2013-01-01

Nicotinic acid adenine dinucleotide phosphate (NAADP) is an endogenous Ca2+ mobilizing nucleotide presented in various species. NAADP mobilizes Ca2+ from acidic organelles through two pore channel 2 (TPC2) in many cell types and it has been previously shown that NAADP can potently induce neuronal differentiation in PC12 cells. Here we examined the role of TPC2 signaling in the neural differentiation of mouse embryonic stem (ES) cells. We found that the expression of TPC2 was markedly decreased during the initial ES cell entry into neural progenitors, and the levels of TPC2 gradually rebounded during the late stages of neurogenesis. Correspondingly, TPC2 knockdown accelerated mouse ES cell differentiation into neural progenitors but inhibited these neural progenitors from committing to neurons. Overexpression of TPC2, on the other hand, inhibited mouse ES cell from entering the early neural lineage. Interestingly, TPC2 knockdown had no effect on the differentiation of astrocytes and oligodendrocytes of mouse ES cells. Taken together, our data indicate that TPC2 signaling plays a temporal and differential role in modulating the neural lineage entry of mouse ES cells, in that TPC2 signaling inhibits ES cell entry to early neural progenitors, but is required for late neuronal differentiation. PMID:23776607

Optimizing image-based patterned defect inspection through FDTD simulations at multiple ultraviolet wavelengths

NASA Astrophysics Data System (ADS)

Barnes, Bryan M.; Zhou, Hui; Henn, Mark-Alexander; Sohn, Martin Y.; Silver, Richard M.

2017-06-01

The sizes of non-negligible defects in the patterning of a semiconductor device continue to decrease as the dimensions for these devices are reduced. These "killer defects" disrupt the performance of the device and must be adequately controlled during manufacturing, and new solutions are required to improve optics-based defect inspection. To this end, our group has reported [Barnes et al., Proc. SPIE 1014516 (2017)] our initial five-wavelength simulation study, evaluating the extensibility of defect inspection by reducing the inspection wavelength from a deep-ultraviolet wavelength to wavelengths in the vacuum ultraviolet and the extreme ultraviolet. In that study, a 47 nm wavelength yielded enhancements in the signal to noise (SNR) by a factor of five compared to longer wavelengths and in the differential intensities by as much as three orders-of-magnitude compared to 13 nm. This paper briefly reviews these recent findings and investigates the possible sources for these disparities between results at 13 nm and 47 nm wavelengths. Our in-house finite-difference time-domain code (FDTD) is tested in both two and three dimensions to determine how computational conditions contributed to the results. A modified geometry and materials stack is presented that offers a second viewpoint of defect detectability as functions of wavelength, polarization, and defect type. Reapplication of the initial SNR-based defect metric again yields no detection of a defect at λ = 13 nm, but additional image preprocessing now enables the computation of the SNR for λ = 13 nm simulated images and has led to a revised defect metric that allows comparisons at all five wavelengths.

Correlation between ubiquitination and defects of bull spermatozoa and removal of defective spermatozoa using anti-ubiquitin antibody-coated magnetized beads.

PubMed

Zhang, Jian; Su, Jie; Hu, Shuxiang; Zhang, Jindun; Ding, Rui; Guo, Jitong; Cao, Guifang; Li, Rongfeng; Sun, Qing-Yuan; Li, Xihe

2018-05-01

Ubiquitination is an important cellular process in spermatogenesis and involves the regulation of spermatid differentiation and spermiogenesis. In the current study, the correlation between bull sperm ubiquitination and sperm defects was analyzed, and the feasibility using anti-ubiquitin specific antibody immobilized magnetic beads to remove the spermatozoa with defects was assessed. A total of nine bulls were examined, and the amount of sperm ubiquitination ranged from 55 to 151. Correspondingly, the percentage of sperm deformity ranged from 9.3% to 28.1%. The coefficient of correlation was r = 0.92, indicating a significant correlation between the percentage of sperm deformity and the amount of ubiquitination (P < 0.05). The results from use of fluorescence staining and single-channel flow cytometry indicated there was a significant correlation between the sperm deformity and amount of ubiquitination (r = 0.86, P < 0.05). Results gained by use of the TUNEL and ubiquitination assays by double-channel flow cytometry indicated that the proportion of genetically defective spermatozoa with ubiquitination in Q3 and Q2 quartiles was markedly greater than that of spermatozoa with ubiquitination in Q1 and Q4 quartiles (82.1% compared with 17.9%). All these results confirmed that sperm ubiquitination is associated with genetic DNA defects (P < 0.01). Furthermore, nine semen samples with sperm motility of less than 50% (minimal motility), 50% to 70% (moderate motility) and greater than 70% (greatest motility) were selected for sorting defective spermatozoa using anti-ubiquitin specific antibody-coated magnetic beads. Strikingly, the percentage of sperm deformity significantly decreased from 18.8%, 19.0% and 17.1% to 11.7%, 11.0% and 11.0%, respectively (P < 0.05), suggesting that this method might be a feasible technology to improve the productivity via removal of the defective spermatozoa from bull semen. Copyright © 2018 Elsevier B.V. All rights

Insights into Metabolic Mechanisms Underlying Folate-Responsive Neural Tube Defects: A Minireview

PubMed Central

Beaudin, Anna E.; Stover, Patrick J.

2015-01-01

Neural tube defects (NTDs), including anencephaly and spina bifida, arise from the failure of neurulation during early embryonic development. Neural tube defects are common birth defects with a heterogenous and multifactorial etiology with interacting genetic and environmental risk factors. Although the mechanisms resulting in failure of neural tube closure are unknown, up to 70% of NTDs can be prevented by maternal folic acid supplementation. However, the metabolic mechanisms underlying the association between folic acid and NTD pathogenesis have not been identified. This review summarizes our current understanding of the mechanisms by which impairments in folate metabolism might ultimately lead to failure of neural tube closure, with an emphasis on untangling the relative contributions of nutritional deficiency and genetic risk factors to NTD pathogenesis. PMID:19180567

Are infants differentially sensitive to parenting? Early maternal care, DRD4 genotype and externalizing behavior during adolescence.

PubMed

Nikitopoulos, Jörg; Zohsel, Katrin; Blomeyer, Dorothea; Buchmann, Arlette F; Schmid, Brigitte; Jennen-Steinmetz, Christine; Becker, Katja; Schmidt, Martin H; Esser, Günter; Brandeis, Daniel; Banaschewski, Tobias; Laucht, Manfred

2014-12-01

Insensitive and unresponsive caregiving during infancy has been linked to externalizing behavior problems during childhood and adolescence. The 7-repeat (7r) allele of the dopamine D4 receptor (DRD4) gene has meta-analytically been associated with a heightened susceptibility to adverse as well as supportive environments. In the present study, we examined long-term effects of early maternal care, DRD4 genotype and the interaction thereof on externalizing and internalizing psychopathology during adolescence. As part of an ongoing epidemiological cohort study, early maternal care was assessed at child's age 3 months during a nursing and playing situation. In a sample of 296 offspring, externalizing and internalizing symptoms were assessed using a psychiatric interview conducted at age 15 years. Parents additionally filled out a questionnaire on their children's psychopathic behaviors. Results indicated that adolescents with the DRD4 7r allele who experienced less responsive and stimulating early maternal care exhibited more symptoms of ADHD and CD/ODD as well as higher levels of psychopathic behavior. In accordance with the hypothesis of differential susceptibility, 7r allele carriers showed fewer ADHD symptoms and lower levels of psychopathic behavior when exposed to especially beneficial early caregiving. In contrast, individuals without the DRD4 7r allele proved to be insensitive to the effects of early maternal care. This study replicates earlier findings with regard to an interaction between DRD4 genotype and early caregiving on externalizing behavior problems in preschoolers. It is the first one to imply continuity of this effect until adolescence. Copyright © 2014 Elsevier Ltd. All rights reserved.

Differential Risk for Late Adolescent Conduct Problems and Mood Dysregulation Among Children with Early Externalizing Behavior Problems

PubMed Central

Bierman, Karen L.

2016-01-01

To investigate the differential emergence of antisocial behaviors and mood dysregulation among children with externalizing problems, the present study prospectively followed 317 high-risk children with early externalizing problems from school entry (ages 5–7) to late adolescence (ages 17–19). Latent class analysis conducted on their conduct and mood symptoms in late adolescence revealed three distinct patterns of symptoms, characterized by: 1) criminal offenses, conduct disorder symptoms, and elevated anger (“conduct problems”), 2) elevated anger, dysphoric mood, and suicidal ideation (“mood dysregulation”), and 3) low levels of severe conduct and mood symptoms. A diathesis-stress model predicting the first two outcomes was tested. Elevated overt aggression at school entry uniquely predicted conduct problems in late adolescence, whereas elevated emotion dysregulation at school entry uniquely predicted mood dysregulation in late adolescence. Experiences of low parental warmth and peer rejection in middle childhood moderated the link between early emotion dysregulation and later mood dysregulation but did not moderate the link between early overt aggression and later conduct problems. Thus, among children with early externalizing behavior problems, increased risk for later antisocial behavior or mood dysfunction may be identifiable in early childhood based on levels of overt aggression and emotion dysregulation. For children with early emotion dysregulation, however, increased risk for mood dysregulation characterized by anger, dysphoric mood, and suicidality – possibly indicative of disruptive mood dysregulation disorder – emerges only in the presence of low parental warmth and/or peer rejection during middle childhood. PMID:25183553

Analysis of cell cycle-related proteins in gastric intramucosal differentiated-type cancers based on mucin phenotypes: a novel hypothesis of early gastric carcinogenesis based on mucin phenotype

PubMed Central

2010-01-01

Background Abnormalities of cell cycle regulators are common features in human cancers, and several of these factors are associated with the early development of gastric cancers. However, recent studies have shown that gastric cancer tumorigenesis was characterized by mucin expression. Thus, expression patterns of cell cycle-related proteins were investigated in the early phase of differentiated-type gastric cancers to ascertain any mechanistic relationships with mucin phenotypes. Methods Immunostaining for Cyclins D1, A, E, and p21, p27, p53 and β-catenin was used to examine impairments of the cell cycle in 190 gastric intramucosal differentiated-type cancers. Mucin phenotypes were determined by the expressions of MUC5AC, MUC6, MUC2 and CD10. A Ki-67 positive rate (PR) was also examined. Results Overexpressions of p53, cyclin D1 and cyclin A were significantly more frequent in a gastric phenotype than an intestinal phenotype. Cyclin A was overexpressed in a mixed phenotype compared with an intestinal phenotype, while p27 overexpression was more frequent in an intestinal phenotype than in a mixed phenotype. Reduction of p21 was a common feature of the gastric intramucosal differentiated-type cancers examined. Conclusions Our results suggest that the levels of some cell cycle regulators appear to be associated with mucin phenotypes of early gastric differentiated-type cancers. PMID:20525401

Effects of Hypogravity on Osteoblast Differentiation

NASA Technical Reports Server (NTRS)

Globus, Ruth; Doty, Steven

1997-01-01

Weightbearing is essential for normal skeletal function. Without weightbearing, the rate of bone formation by osteoblasts decreases in the growing rat. Defective formation may account for the decrease in the maturation, strength and mass of bone that is caused by spaceflight. These skeletal defects may be mediated by a combination of physiologic changes triggered by spaceflight, including skeletal unloading, fluid shifts, and stress-induced endocrine factors. The fundamental question of whether the defects in osteoblast function due to weightlessness are mediated by localized skeletal unloading or by systemic physiologic adaptations such as fluid shifts has not been answered. Furthermore, bone-forming activity of osteoblasts during unloading may be affected by paracrine signals from vascular, monocytic, and neural cells that also reside in skeletal tissue. Therefore we proposed to examine whether exposure of cultured rat osteoblasts to spaceflight inhibits cellular differentiation and impairs mineralization when isolated from the influence of both systemic factors and other skeletal cells.

Multifocal visual evoked potentials for early glaucoma detection.

PubMed

Weizer, Jennifer S; Musch, David C; Niziol, Leslie M; Khan, Naheed W

2012-07-01

To compare multifocal visual evoked potentials (mfVEP) with other detection methods in early open-angle glaucoma. Ten patients with suspected glaucoma and 5 with early open-angle glaucoma underwent mfVEP, standard automated perimetry (SAP), short-wave automated perimetry, frequency-doubling technology perimetry, and nerve fiber layer optical coherence tomography. Nineteen healthy control subjects underwent mfVEP and SAP for comparison. Comparisons between groups involving continuous variables were made using independent t tests; for categorical variables, Fisher's exact test was used. Monocular mfVEP cluster defects were associated with an increased SAP pattern standard deviation (P = .0195). Visual fields that showed interocular mfVEP cluster defects were more likely to also show superior quadrant nerve fiber layer thinning by OCT (P = .0152). Multifocal visual evoked potential cluster defects are associated with a functional and an anatomic measure that both relate to glaucomatous optic neuropathy. Copyright 2012, SLACK Incorporated.

Magnetic resonance imaging for diagnosis and assessment of cartilage defect repairs.

PubMed

Marlovits, Stefan; Mamisch, Tallal Charles; Vekszler, György; Resinger, Christoph; Trattnig, Siegfried

2008-04-01

Clinical magnetic resonance imaging (MRI) is the method of choice for the non-invasive evaluation of articular cartilage defects and the follow-up of cartilage repair procedures. The use of cartilage-sensitive sequences and a high spatial-resolution technique enables the evaluation of cartilage morphology even in the early stages of disease, as well as assessment of cartilage repair. Sequences that offer high contrast between articular cartilage and adjacent structures, such as the fat-suppressed, 3-dimensional, spoiled gradient-echo sequence and the fast spin-echo sequence, are accurate and reliable for evaluating intrachondral lesions and surface defects of articular cartilage. These sequences can also be performed together in reasonable examination times. In addition to morphology, new MRI techniques provide insight into the biochemical composition of articular cartilage and cartilage repair tissue. These techniques enable the diagnosis of early cartilage degeneration and help to monitor the effect and outcome of various surgical and non-surgical cartilage repair therapies.

Command of active matter by topological defects and patterns.

PubMed

Peng, Chenhui; Turiv, Taras; Guo, Yubing; Wei, Qi-Huo; Lavrentovich, Oleg D

2016-11-18

Self-propelled bacteria are marvels of nature with a potential to power dynamic materials and microsystems of the future. The challenge lies in commanding their chaotic behavior. By dispersing swimming Bacillus subtilis in a liquid crystalline environment with spatially varying orientation of the anisotropy axis, we demonstrate control over the distribution of bacterial concentration, as well as the geometry and polarity of their trajectories. Bacteria recognize subtle differences in liquid crystal deformations, engaging in bipolar swimming in regions of pure splay and bend but switching to unipolar swimming in mixed splay-bend regions. They differentiate topological defects, heading toward defects of positive topological charge and avoiding negative charges. Sensitivity of bacteria to preimposed orientational patterns represents a previously unknown facet of the interplay between hydrodynamics and topology of active matter. Copyright © 2016, American Association for the Advancement of Science.

Biochemical defects of mutant nudel alleles causing early developmental arrest or dorsalization of the Drosophila embryo.

PubMed Central

LeMosy, E K; Leclerc, C L; Hashimoto, C

2000-01-01

The nudel gene of Drosophila is maternally required both for structural integrity of the egg and for dorsoventral patterning of the embryo. It encodes a structurally modular protein that is secreted by ovarian follicle cells. Genetic and molecular studies have suggested that the Nudel protein is also functionally modular, with a serine protease domain that is specifically required for ventral development. Here we describe biochemical and immunolocalization studies that provide insight into the molecular basis for the distinct phenotypes produced by nudel mutations and for the interactions between these alleles. Mutations causing loss of embryonic dorsoventral polarity result in a failure to activate the protease domain of Nudel. Our analyses support previous findings that catalytic activity of the protease domain is required for dorsoventral patterning and that the Nudel protease is auto-activated and reveal an important role for a region adjacent to the protease domain in Nudel protease function. Mutations causing egg fragility and early embryonic arrest result in a significant decrease in extracellular Nudel protein, due to defects in post-translational processing, stability, or secretion. On the basis of these and other studies of serine proteases, we suggest potential mechanisms for the complementary and antagonistic interactions between the nudel alleles. PMID:10628985

Reactive impinging-flow technique for polymer-electrolyte-fuel-cell electrode-defect detection

NASA Astrophysics Data System (ADS)

Zenyuk, Iryna V.; Englund, Nicholas; Bender, Guido; Weber, Adam Z.; Ulsh, Michael

2016-11-01

Reactive impinging flow (RIF) is a novel quality-control method for defect detection (i.e., reduction in Pt catalyst loading) in gas-diffusion electrodes (GDEs) on weblines. The technique uses infrared thermography to detect temperature of a nonflammable (<4% H2) reactive mixture of H2/O2 in N2 impinging and reacting on a Pt catalytic surface. In this paper, different GDE size defects (with catalyst-loading reductions of 25, 50, and 100%) are detected at various webline speeds (3.048 and 9.144 m min-1) and gas flowrates (32.5 or 50 standard L min-1). Furthermore, a model is developed and validated for the technique, and it is subsequently used to optimize operating conditions and explore the applicability of the technique to a range of defects. The model suggests that increased detection can be achieved by recting more of the impinging H2, which can be accomplished by placing blocking substrates on the top, bottom, or both of the GDE; placing a substrate on both results in a factor of four increase in the temperature differential, which is needed for smaller defect detection. Overall, the RIF technique is shown to be a promising route for in-line, high-speed, large-area detection of GDE defects on moving weblines.

Heterogeneous rates for birth defects in Latin America: hints on causality.

PubMed

Lopez-Camelo, J S; Orioli, I M

1996-01-01

The aim of this work was to disclose risk factors associated with birth defects which were heterogeneously distributed in the different geographic regions sampled by the Latin American Collaborative Study of Congenital Malformations (ECLAMC). The material included 2,159,065 hospital births, delivered in the 1967-1989 period in 24 geographic regions of Latin America. Birth defect types with 50 case-control pairs or more were analyzed. A risk factor was defined as that available variable with differential geographic rates, correlated with those of a given birth defect type. Identified factors were tested by case-control multivariate logistic regression to confirm their role in the occurrence of the defect. Altitude and maternal acute illness during first trimester of pregnancy, named influenza, were risk factors for microtia. Prenatal drug exposure, mainly sex hormones, were connected with the occurrence of hypospadias in low frequency areas, while Native ancestry was a "protective" factor in the same regions. Acute (influenza), and chronic (epilepsy and syphilis) maternal illness during first trimester of pregnancy and gravidity higher than four were risk factors for cleft lip. The independence of these variables from maternal age suggested that low maternal socioeconomic level could explain the high birth defect order and, perhaps, syphilis in mothers. Postaxial polydactyly was associated with parental consanguinity, as well as Afro-American ancestry, suggesting genetic heterogeneity.

Alkaline biodegradable implants for osteoporotic bone defects--importance of microenvironment pH.

PubMed

Liu, W; Wang, T; Yang, C; Darvell, B W; Wu, J; Lin, K; Chang, J; Pan, H; Lu, W W

2016-01-01

Change of microenvironment pH by biodegradable implants may ameliorate unbalanced osteoporotic bone remodeling. The present work demonstrated that a weak alkaline condition stimulated osteoblasts differentiation while suppressed osteoclast generation. In vivo, implants with an alkaline microenvironment pH (monitored by a pH microelectrode) exhibited a promising healing effect for the repair of osteoporotic bone defects. Under osteoporotic conditions, the response of the bone microenvironment to an endosseous implant is significantly impaired, and this substantially increases the risk of fracture, non-union and aseptic implant loosening. Acid-base equilibrium is an important factor influencing bone cell behaviour. The present purpose was to study the effect of a series of alkaline biodegradable implant materials on regeneration of osteoporotic bone defect, monitoring the microenvironment pH (μe-pH) over time. The proliferation and differentiation potential of osteoporotic rat bone marrow stromal cells and RAW 264.7 cells were examined under various pH conditions. Ovariectomized rat bone defects were filled with specific biodegradable materials, and μe-pH was measured by pH microelectrode. New osteoid and tartrate-resistant acid phosphatase-positive osteoclast-like cells were examined by Goldner's trichrome and TRAP staining, respectively. The intermediate layer between implants and new bone were studied using energy-dispersive X-ray spectroscopy (EDX) linear scanning. In vitro, weak alkaline conditions stimulated osteoporotic rat bone marrow stromal cells (oBMSC) differentiation, while inhibiting the formation of osteoclasts. In vivo, μe-pH differs from that of the homogeneous peripheral blood and exhibits variations over time particular to each material. Higher initial μe-pH was associated with more new bone formation, late response of TRAP-positive osteoclast-like cells and the development of an intermediate 'apatitic' layer in vivo. EDX suggested that

Telomere length and early trauma in schizophrenia.

PubMed

Riley, Gabriella; Perrin, Mary; Vaez-Azizi, Leila M; Ruby, Eugene; Goetz, Raymond R; Dracxler, Roberta; Walsh-Messinger, Julie; Keefe, David L; Buckley, Peter F; Szeszko, Philip R; Malaspina, Dolores

2018-04-02

Childhood trauma is emerging as a risk factor for schizophrenia, but its mechanism with respect to etiology is unknown. One possible pathway is through leucocyte telomere length (LTL) shortening, a measure of cellular aging associated with trauma. This study examined early trauma and LTL shortening in schizophrenia and considered sex effects. The early trauma inventory (ETI) was administered to 48 adults with DSM-5 schizophrenia and 18 comparison participants. LTL was measured using qPCR. Cases had significantly more global trauma (F=4.10, p<0.01) and traumatic events (F=11.23, p<0.001), but case and control groups had similar LTL (1.91±0.74 and 1.83±0.62: p=0.68). The association of early trauma and LTL differed by sex in cases and controls (Fisher's R: Z<0.05). Significant negative associations were shown in male cases and, conversely, in female controls. For example, physical punishment was associated LTL shortening in males' cases (r=-0.429, p<01). Only female controls showed significant telomere shortening in association with early trauma. This data confirms the substantial excess of early trauma among schizophrenia cases. There were significant sex-differences in the relationship of the trauma to LTL, with only male cases showing the expected shortening. There were converse sex effects in the control group. Mean LTL was notably similar in cases and controls, despite the trauma-related shortening in male cases, cigarette smoking, older age and chronic illness of the cases. Factors may lengthen LTL in some schizophrenia cases. The converse sex differences in the cases are consistent with findings defective sexual differentiation in schizophrenia, consistent with other findings in the field. Copyright © 2018 Elsevier B.V. All rights reserved.

Detection of critical congenital heart defects: Review of contributions from prenatal and newborn screening

PubMed Central

Olney, Richard S.; Ailes, Elizabeth C.; Sontag, Marci K.

2015-01-01

In 2011, statewide newborn screening programs for critical congenital heart defects began in the United States, and subsequently screening has been implemented widely. In this review, we focus on data reports and collection efforts related to both prenatal diagnosis and newborn screening. Defect-specific, maternal, and geographic factors are associated with variations in prenatal detection, so newborn screening provides a population-wide safety net for early diagnosis. A new web-based repository is collecting information on newborn screening program policies, quality indicators related to screening programs, and specific case-level data on infants with these defects. Birth defects surveillance programs also collect data about critical congenital heart defects, particularly related to diagnostic timing, mortality, and services. Individuals from state programs, federal agencies, and national organizations will be interested in these data to further refine algorithms for screening in normal newborn nurseries, neonatal intensive care settings, and other special populations; and ultimately to evaluate the impact of screening on outcomes. PMID:25979782

Detection of critical congenital heart defects: Review of contributions from prenatal and newborn screening.

PubMed

Olney, Richard S; Ailes, Elizabeth C; Sontag, Marci K

2015-04-01

In 2011, statewide newborn screening programs for critical congenital heart defects began in the United States, and subsequently screening has been implemented widely. In this review, we focus on data reports and collection efforts related to both prenatal diagnosis and newborn screening. Defect-specific, maternal, and geographic factors are associated with variations in prenatal detection, so newborn screening provides a population-wide safety net for early diagnosis. A new web-based repository is collecting information on newborn screening program policies, quality indicators related to screening programs, and specific case-level data on infants with these defects. Birth defects surveillance programs also collect data about critical congenital heart defects, particularly related to diagnostic timing, mortality, and services. Individuals from state programs, federal agencies, and national organizations will be interested in these data to further refine algorithms for screening in normal newborn nurseries, neonatal intensive care settings, and other special populations; and ultimately to evaluate the impact of screening on outcomes. Published by Elsevier Inc.

Evaluation of Soft Tissue Coverage over Porous Polymethylmethacrylate Space Maintainers Within Nonhealing Alveolar Bone Defects

PubMed Central

Kretlow, James D.; Shi, Meng; Young, Simon; Spicer, Patrick P.; Demian, Nagi; Jansen, John A.; Wong, Mark E.; Kasper, F. Kurtis

2010-01-01

Current treatment of traumatic craniofacial injuries often involves early free tissue transfer, even if the recipient site is contaminated or lacks soft tissue coverage. There are no current tissue engineering strategies to definitively regenerate tissues in such an environment at an early time point. For a tissue engineering approach to be employed in the treatment of such injuries, a two-stage approach could potentially be used. The present study describes methods for fabrication, characterization, and processing of porous polymethylmethacrylate (PMMA) space maintainers for temporary retention of space in bony craniofacial defects. Carboxymethylcellulose hydrogels were used as a porogen. Implants with controlled porosity and pore interconnectivity were fabricated by varying the ratio of hydrogel:polymer and the amount of carboxymethylcellulose within the hydrogel. The in vivo tissue response to the implants was observed by implanting solid, low-porosity, and high-porosity implants (n = 6) within a nonhealing rabbit mandibular defect that included an oral mucosal defect to allow open communication between the oral cavity and the mandibular defect. Oral mucosal wound healing was observed after 12 weeks and was complete in 3/6 defects filled with solid PMMA implants and 5/6 defects filled with either a low- or high-porosity PMMA implant. The tissue response around and within the pores of the two formulations of porous implants tested in vivo was characterized, with the low-porosity implants surrounded by a minimal but well-formed fibrous capsule in contrast to the high-porosity implants, which were surrounded and invaded by almost exclusively inflammatory tissue. On the basis of these results, PMMA implants with limited porosity hold promise for temporary implantation and space maintenance within clean/contaminated bone defects. PMID:20524844

Computer simulation of electrical characteristics of singlewalled carbon nanotube (9,0) with Stone-Wales defect

NASA Astrophysics Data System (ADS)

Sergeyev, D.; Zhanturina, N.

2018-05-01

In the framework of the density functional theory, using the method of nonequilibrium Green's functions and in the local density approximation, the electrical characteristics of different configurations of a single-walled carbon nanotube with Stone-Wales defects are investigated. The calculation is implemented in the Atomistix ToolKit with Virtual NanoLab program. The current-voltage, dI/dV-characteristics and the density of states of the nanostructures under consideration were calculated. It is shown that the nature of the current flowing through defective carbon nanotubes depends on the extent of the Stone-Wales defects. It was found that a carbon nanotube with two consecutively connected Stone-Wales defects at a bias voltage of ± 2.6 V has a negative differential conductivity of -170 μS. The obtained results can be useful for calculations of new promising electronic devices of nanoelectronics based on a carbon nanotube.

Human immunodeficiency virus infection of helper T cell clones. Early proliferative defects despite intact antigen-specific recognition and interleukin 4 secretion.

PubMed Central

Laurence, J; Friedman, S M; Chartash, E K; Crow, M K; Posnett, D N

1989-01-01

HIV selectively inhibited the proliferative response of clonal CD4+ T lymphocytes to alloantigen while other alloantigen-dependent responses were unperturbed. Specifically, impaired blastogenesis could be dissociated from alloantigen-specific induction of the B cell activation molecule CD23, IL-4 release, and inositol lipid hydrolysis. In addition, membrane expression of pertinent T cell receptor molecules, including CD2, CD3, and T cell antigen receptor (Ti), remained intact. Using two MHC class II-specific human CD4+ helper T cell clones, the proliferative defect was shown to be an early consequence of HIV infection, occurring within 4 d of viral inoculation and preceding increases in mature virion production. It was generalizable to three distinct methods of T cell activation, all independent of antigen-presenting cells: anti-CD3 mediated cross-linking of the CD3/Ti complex; anti-CD2 and phorbol 12-myristic 13-acetate (PMA); and anti-CD28 plus PMA. These abnormalities were not mitigated by addition of exogenous IL-2, even though expression of the IL-2 receptor (CD25) was unaltered. These studies define a selective blockade in T cell function early after HIV exposure that could serve as a model for certain in vivo manifestations of AIDS. PMID:2470786

Differential tissue growth and cell adhesion alone drive early tooth morphogenesis: An ex vivo and in silico study

PubMed Central

Savriama, Yoland; Jernvall, Jukka

2018-01-01

From gastrulation to late organogenesis animal development involves many genetic and bio-mechanical interactions between epithelial and mesenchymal tissues. Ectodermal organs, such as hairs, feathers and teeth are well studied examples of organs whose development is based on epithelial-mesenchymal interactions. These develop from a similar primordium through an epithelial folding and its interaction with the mesenchyme. Despite extensive knowledge on the molecular pathways involved, little is known about the role of bio-mechanical processes in the morphogenesis of these organs. We propose a simple computational model for the biomechanics of one such organ, the tooth, and contrast its predictions against cell-tracking experiments, mechanical relaxation experiments and the observed tooth shape changes over developmental time. We found that two biomechanical processes, differential tissue growth and differential cell adhesion, were enough, in the model, for the development of the 3D morphology of the early tooth germ. This was largely determined by the length and direction of growth of the cervical loops, lateral folds of the enamel epithelium. The formation of these cervical loops was found to require accelerated epithelial growth relative to other tissues and their direction of growth depended on specific differential adhesion between the three tooth tissues. These two processes and geometrical constraints in early tooth bud also explained the shape asymmetry between the lateral cervical loops and those forming in the anterior and posterior of the tooth. By performing mechanical perturbations ex vivo and in silico we inferred the distribution and direction of tensile stresses in the mesenchyme that restricted cervical loop lateral growth and forced them to grow downwards. Overall our study suggests detailed quantitative explanations for how bio-mechanical processes lead to specific morphological 3D changes over developmental time. PMID:29481561

Neural Tube Defects

MedlinePlus

Neural tube defects are birth defects of the brain, spine, or spinal cord. They happen in the ... that she is pregnant. The two most common neural tube defects are spina bifida and anencephaly. In ...

[Forensic medical evaluation of stab-incised wounds caused by knives with point defects].

PubMed

Krupin, K N; Leonov, S V

2011-01-01

The present experimental study allowed to characterize specific signs of stab-incised wounds caused by knives with operational point defects. Diagnostic coefficients calculated for these macro- and microscopic features facilitate differential diagnostics of the injuries and make it possible to identify a concrete stabbing/cutting weapon with which the wound was inflicted..

Characterization of iron metabolism and erythropoiesis in erythrocyte membrane defects and thalassemia traits.

PubMed

Sulovska, Lucie; Holub, Dusan; Zidova, Zuzana; Divoka, Martina; Hajduch, Marian; Mihal, Vladimir; Vrbkova, Jana; Horvathova, Monika; Pospisilova, Dagmar

2016-06-01

Erythropoiesis is closely related to iron metabolism in a balanced homeostasis. Analyses of diverse erythroid and iron metabolism disorders have shown that disrupted erythropoiesis negatively affects iron homeostasis and vice versa. The aim of this study was to characterize the relationship between erythropoietic activity and iron homeostasis in pediatric patients with erythrocyte membrane defects and thalassemia traits. Selected markers of erythropoietic activity (erythropoietin, soluble transferrin receptor - sTfR and growth differentiation factor 15) and iron status parameters (serum iron, ferritin and hepcidin) were evaluated in pediatric patients with erythrocyte membrane defects and thalassemia traits. The patients with erythrocyte membrane defects and thalassemia traits had altered iron homeostasis due to disturbed erythropoiesis. In comparison with healthy controls, they had a normal to low hepcidin/ferritin ratio and concomitantly elevated sTfR. The findings suggest that pediatric patients with erythrocyte membrane defects and thalassemia traits are more susceptible to iron overload than the general population and that the (hepcidin/ferritin)/sTfR ratio can be used to monitor any worsening of the disease.

Chitosan-Graphene Oxide 3D scaffolds as Promising Tools for Bone Regeneration in Critical-Size Mouse Calvarial Defects.

PubMed

Hermenean, Anca; Codreanu, Ada; Herman, Hildegard; Balta, Cornel; Rosu, Marcel; Mihali, Ciprian Valentin; Ivan, Alexandra; Dinescu, Sorina; Ionita, Mariana; Costache, Marieta

2017-11-30

Limited self-regenerating capacity of human skeleton makes the reconstruction of critical size bone defect a significant challenge for clinical practice. Aimed for regenerating bone tissues, this study was designed to investigate osteogenic differentiation, along with bone repair capacity of 3D chitosan (CHT) scaffolds enriched with graphene oxide (GO) in critical-sized mouse calvarial defect. Histopathological/histomorphometry and scanning electron microscopy(SEM) analysis of the implants revealed larger amount of new bone in the CHT/GO-filled defects compared with CHT alone (p < 0.001). When combined with GO, CHT scaffolds synergistically promoted the increase of alkaline phosphatase activity both in vitro and in vivo experiments. This enhanced osteogenesis was corroborated with increased expression of bone morphogenetic protein (BMP) and Runx-2 up to week 4 post-implantation, which showed that GO facilitates the differentiation of osteoprogenitor cells. Meanwhile, osteogenesis was promoted by GO at the late stage as well, as indicated by the up-regulation of osteopontin and osteocalcin at week 8 and overexpressed at week 18, for both markers. Our data suggest that CHT/GO biomaterial could represent a promising tool for the reconstruction of large bone defects, without using exogenous living cells or growth factors.

Do guilt- and shame-proneness differentially predict prosocial, aggressive, and withdrawn behaviors during early adolescence?

PubMed

Roos, Sanna; Hodges, Ernest V E; Salmivalli, Christina

2014-03-01

In this short-term longitudinal study, we systematically examined the distinctiveness of guilt- and shame-proneness in early adolescents (N = 395, mean age = 11.8 years) in terms of differential relations with peer reported prosocial behavior, withdrawal, and aggression. Results from structural equation modeling indicated that guilt-proneness concurrently predicted more aggressive and less prosocial behavior as well as subsequent increases in prosocial behavior. Shame-proneness predicted subsequent decreases in prosocial behavior. Although girls reported a greater proneness to experience guilt and shame than boys, the associations between the two dispositional emotions and social behaviors were found to be similar across time and gender. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Maternal Sensitivity Predicts Fewer Sleep Problems at Early Adolescence for Toddlers with Negative Emotionality: A Case of Differential Susceptibility.

PubMed

Conway, Anne; Modrek, Anahid; Gorroochurn, Prakash

2018-02-01

Theory underscores the importance of parenting in sleep development, but few studies have examined whether links vary by temperament. To address this gap, we tested whether potential links between early maternal sensitivity and early adolescent sleep problems varied by child negative emotionality and delay of gratification. Using data from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (N = 820), we found that high maternal sensitivity predicted fewer bedtime problems and longer sleep duration at 6th grade for toddlers with high negative emotionality, whereas low maternal sensitivity predicted the reverse. No differences were observed for low negative emotionality. Moreover, delay of gratification predicted fewer bedtime problems at 6th grade, but did not moderate associations between maternal sensitivity, negative emotionality, and sleep. Findings demonstrate that high, but not low, negative emotionality renders toddlers differentially susceptible and receptive to maternal sensitivity in relation to sleep.

A one-dimensional peridynamic model of defect propagation and its relation to certain other continuum models

NASA Astrophysics Data System (ADS)

Wang, Linjuan; Abeyaratne, Rohan

2018-07-01

The peridynamic model of a solid does not involve spatial gradients of the displacement field and is therefore well suited for studying defect propagation. Here, bond-based peridynamic theory is used to study the equilibrium and steady propagation of a lattice defect - a kink - in one dimension. The material transforms locally, from one state to another, as the kink passes through. The kink is in equilibrium if the applied force is less than a certain critical value that is calculated, and propagates if it exceeds that value. The kinetic relation giving the propagation speed as a function of the applied force is also derived. In addition, it is shown that the dynamical solutions of certain differential-equation-based models of a continuum are the same as those of the peridynamic model provided the micromodulus function is chosen suitably. A formula for calculating the micromodulus function of the equivalent peridynamic model is derived and illustrated. This ability to replace a differential-equation-based model with a peridynamic one may prove useful when numerically studying more complicated problems such as those involving multiple and interacting defects.

The effect of myotonic dystrophy transcript levels and location on muscle differentiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mastroyiannopoulos, Nikolaos P.; Chrysanthou, Elina; Kyriakides, Tassos C.

2008-12-12

In myotonic dystrophy type I (DM1), nuclear retention of mutant DMPK transcripts compromises muscle cell differentiation. Although several reports have identified molecular defects in myogenesis, it remains still unclear how exactly the retention of the mutant transcripts induces this defect. We have recently created a novel cellular model in which the mutant DMPK 3' UTR transcripts were released to the cytoplasm of myoblasts by using the WPRE genetic element. As a result, muscle cell differentiation was repaired. In this paper, this cellular model was further exploited to investigate the effect of the levels and location of the mutant transcripts onmore » muscle differentiation. Results show that the levels of these transcripts were proportional to the inhibition of both the initial fusion of myoblasts and the maturity of myotubes. Moreover, the cytoplasmic export of the mutant RNAs to the cytoplasm caused less inhibition only in the initial fusion of myoblasts.« less

Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency

PubMed Central

Shen, Siming; Sandoval, Juan; Swiss, Victoria A; Li, Jiadong; Dupree, Jeff; Franklin, Robin J M; Casaccia-Bonnefil, Patrizia

2009-01-01

The efficiency of remyelination decreases with age, but the molecular mechanisms responsible for this decline remain only partially understood. In this study, we show that remyelination is regulated by age-dependent epigenetic control of gene expression. In demyelinated young brains, new myelin synthesis is preceded by downregulation of oligodendrocyte differentiation inhibitors and neural stem cell markers, and this is associated with recruitment of histone deacetylases (HDACs) to promoter regions. In demyelinated old brains, HDAC recruitment is inefficient, and this allows the accumulation of transcriptional inhibitors and prevents the subsequent surge in myelin gene expression. Defective remyelination can be recapitulated in vivo in mice receiving systemic administration of pharmacological HDAC inhibitors during cuprizone treatment and is consistent with in vitro results showing defective differentiation of oligodendrocyte progenitors after silencing specific HDAC isoforms. Thus, we suggest that inefficient epigenetic modulation of the oligodendrocyte differentiation program contributes to the age-dependent decline in remyelination efficiency. PMID:19160500

Single Ventricle Defects

MedlinePlus

... Your Risk • Symptoms & Diagnosis • Care & Treatment • Tools & Resources Web Booklets on Congenital Heart Defects These online publications ... to you or your child’s defect and concerns. Web Booklet: Adults With Congenital Heart Defects Web Booklet: ...

Laser-directed hierarchical assembly of liquid crystal defects and control of optical phase singularities

PubMed Central

Ackerman, Paul J.; Qi, Zhiyuan; Lin, Yiheng; Twombly, Christopher W.; Laviada, Mauricio J.; Lansac, Yves; Smalyukh, Ivan I.

2012-01-01

Topological defect lines are ubiquitous and important in a wide variety of fascinating phenomena and theories in many fields ranging from materials science to early-universe cosmology, and to engineering of laser beams. However, they are typically hard to control in a reliable manner. Here we describe facile erasable “optical drawing” of self-assembled defect clusters in liquid crystals. These quadrupolar defect clusters, stabilized by the medium's chirality and the tendency to form twisted configurations, are shaped into arbitrary two-dimensional patterns, including reconfigurable phase gratings capable of generating and controlling optical phase singularities in laser beams. Our findings bridge the studies of defects in condensed matter physics and optics and may enable applications in data storage, singular optics, displays, electro-optic devices, diffraction gratings, as well as in both optically- and electrically-addressed pixel-free spatial light modulators. PMID:22679553

Human cytomegalovirus infection interferes with the maintenance and differentiation of trophoblast progenitor cells of the human placenta.

PubMed

Tabata, Takako; Petitt, Matthew; Zydek, Martin; Fang-Hoover, June; Larocque, Nicholas; Tsuge, Mitsuru; Gormley, Matthew; Kauvar, Lawrence M; Pereira, Lenore

2015-05-01

Human cytomegalovirus (HCMV) is a major cause of birth defects that include severe neurological deficits, hearing and vision loss, and intrauterine growth restriction. Viral infection of the placenta leads to development of avascular villi, edema, and hypoxia associated with symptomatic congenital infection. Studies of primary cytotrophoblasts (CTBs) revealed that HCMV infection impedes terminal stages of differentiation and invasion by various molecular mechanisms. We recently discovered that HCMV arrests earlier stages involving development of human trophoblast progenitor cells (TBPCs), which give rise to the mature cell types of chorionic villi-syncytiotrophoblasts on the surfaces of floating villi and invasive CTBs that remodel the uterine vasculature. Here, we show that viral proteins are present in TBPCs of the chorion in cases of symptomatic congenital infection. In vitro studies revealed that HCMV replicates in continuously self-renewing TBPC lines derived from the chorion and alters expression and subcellular localization of proteins required for cell cycle progression, pluripotency, and early differentiation. In addition, treatment with a human monoclonal antibody to HCMV glycoprotein B rescues differentiation capacity, and thus, TBPCs have potential utility for evaluation of the efficacies of novel antiviral antibodies in protecting and restoring placental development. Our results suggest that HCMV replicates in TBPCs in the chorion in vivo, interfering with the earliest steps in the growth of new villi, contributing to virus transmission and impairing compensatory development. In cases of congenital infection, reduced responsiveness of the placenta to hypoxia limits the transport of substances from maternal blood and contributes to fetal growth restriction. Human cytomegalovirus (HCMV) is a leading cause of birth defects in the United States. Congenital infection can result in permanent neurological defects, mental retardation, hearing loss, visual

Lnx2 ubiquitin ligase is essential for exocrine cell differentiation in the early zebrafish pancreas

PubMed Central

Won, Minho; Ro, Hyunju; Dawid, Igor B.

2015-01-01

The gene encoding the E3 ubiquitin ligase Ligand of Numb protein-X (Lnx)2a is expressed in the ventral-anterior pancreatic bud of zebrafish embryos in addition to its expression in the brain. Knockdown of Lnx2a by using an exon 2/intron 2 splice morpholino resulted in specific inhibition of the differentiation of ventral bud derived exocrine cell types, with little effect on endocrine cell types. A frame shifting null mutation in lnx2a did not mimic this phenotype, but a mutation that removed the exon 2 splice donor site did. We found that Lnx2b functions in a redundant manner with its paralog Lnx2a. Inhibition of lnx2a exon 2/3 splicing causes exon 2 skipping and leads to the production of an N-truncated protein that acts as an interfering molecule. Thus, the phenotype characterized by inhibition of exocrine cell differentiation requires inactivation of both Lnx2a and Lnx2b. Human LNX1 is known to destabilize Numb, and we show that inhibition of Numb expression rescues the Lnx2a/b-deficient phenotype. Further, Lnx2a/b inhibition leads to a reduction in the number of Notch active cells in the pancreas. We suggest that Lnx2a/b function to fine tune the regulation of Notch through Numb in the differentiation of cell types in the early zebrafish pancreas. Further, the complex relationships among genotype, phenotype, and morpholino effect in this case may be instructive in the ongoing consideration of morpholino use. PMID:26392552

Lnx2 ubiquitin ligase is essential for exocrine cell differentiation in the early zebrafish pancreas.

PubMed

Won, Minho; Ro, Hyunju; Dawid, Igor B

2015-10-06

The gene encoding the E3 ubiquitin ligase Ligand of Numb protein-X (Lnx)2a is expressed in the ventral-anterior pancreatic bud of zebrafish embryos in addition to its expression in the brain. Knockdown of Lnx2a by using an exon 2/intron 2 splice morpholino resulted in specific inhibition of the differentiation of ventral bud derived exocrine cell types, with little effect on endocrine cell types. A frame shifting null mutation in lnx2a did not mimic this phenotype, but a mutation that removed the exon 2 splice donor site did. We found that Lnx2b functions in a redundant manner with its paralog Lnx2a. Inhibition of lnx2a exon 2/3 splicing causes exon 2 skipping and leads to the production of an N-truncated protein that acts as an interfering molecule. Thus, the phenotype characterized by inhibition of exocrine cell differentiation requires inactivation of both Lnx2a and Lnx2b. Human LNX1 is known to destabilize Numb, and we show that inhibition of Numb expression rescues the Lnx2a/b-deficient phenotype. Further, Lnx2a/b inhibition leads to a reduction in the number of Notch active cells in the pancreas. We suggest that Lnx2a/b function to fine tune the regulation of Notch through Numb in the differentiation of cell types in the early zebrafish pancreas. Further, the complex relationships among genotype, phenotype, and morpholino effect in this case may be instructive in the ongoing consideration of morpholino use.

Off-stoichiometric defect clustering in irradiated oxides

NASA Astrophysics Data System (ADS)

Khalil, Sarah; Allen, Todd; EL-Azab, Anter

2017-04-01

A cluster dynamics model describing the formation of vacancy and interstitial clusters in irradiated oxides has been developed. The model, which tracks the composition of the oxide matrix and the defect clusters, was applied to the early stage formation of voids and dislocation loops in UO2, and the effects of irradiation temperature and dose rate on the evolution of their densities and composition was investigated. The results show that Frenkel defects dominate the nucleation process in irradiated UO2. The results also show that oxygen vacancies drive vacancy clustering while the migration energy of uranium vacancies is a rate-limiting factor for the nucleation and growth of voids. In a stoichiometric UO2 under irradiation, off-stoichiometric vacancy clusters exist with a higher concentration of hyper-stoichiometric clusters. Similarly, off-stoichiometric interstitial clusters form with a higher concentration of hyper-stoichiometric clusters. The UO2 matrix was found to be hyper-stoichiometric due to the accumulation of uranium vacancies.

Geologically Controlled Isotope-Time Patterns Reveal Early Differentiation and Crust Formation Processes

NASA Astrophysics Data System (ADS)

Bennett, V. C.; Nutman, A. P.

2014-12-01

The mechanisms of continental crust production and evolution in the early Earth remain controversial, as are questions of the relative roles of early differentiation versus subsequent tectonic procssing in creating Earth's chemical signatures. Here we present geologic observations integrated with whole rock major, trace element and Sm-Nd isotopic signatures and combined with U-Pb and Lu-Hf isotopic compositions of zircon populations from the same rocks, from the most extensive early rock record comprising the 3.9 Ga to 3.6 Ga terranes of southwest Greenland. These data reveal repeated patterns of formation of juvenile TTG crust and associated mafic and ultramafic rocks in convergent margin settings followed by formation of more evolved granites [1]. Our new zircon Lu-Hf data from rare 3.6-3.7 Ga tonalites within the Itsaq Gneiss Complex, obtained from single component, non-migmatitic gneisses with simple zircon populations, limited within sample Hf isotopic variability and accurate U-Pb ages, now document extraction of juvenile tonalites from a near chondritic mantle source between 3.9 Ga and 3.6 Ga. The more evolved, granitic rocks in each area show slightly negative initial ɛHf in accord with crustal reworking of the older (3.8-3.9 Ga) gniesses. There is no evidence for Hadean material in the sources of the granitoids. The Hf isotope-time patterns are consistent with juvenile crust production from a mantle source that experienced only modest amounts of prior crustal extraction. They are distinct from those predicted by reprocessing of an enriched Hadean mafic crust, as has been proposed for this region [2] and for the source of the Hadean Jack Hills zircons [3]. The well-documented, time decreasing, positive 142Nd anomalies [e.g., 4] from these rocks are further evidence of crustal derivation from a convecting mantle source, rather than reworking of an enriched mafic lithosphere. The 143Nd isotopic -time patterns are more complex, reflecting the interplay

Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET.

PubMed

Shalom-Feuerstein, Ruby; Serror, Laura; Aberdam, Edith; Müller, Franz-Josef; van Bokhoven, Hans; Wiman, Klas G; Zhou, Huiqing; Aberdam, Daniel; Petit, Isabelle

2013-02-05

Ectodermal dysplasia is a group of congenital syndromes affecting a variety of ectodermal derivatives. Among them, ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome is caused by single point mutations in the p63 gene, which controls epidermal development and homeostasis. Phenotypic defects of the EEC syndrome include skin defects and limbal stem-cell deficiency. In this study, we designed a unique cellular model that recapitulated major embryonic defects related to EEC. Fibroblasts from healthy donors and EEC patients carrying two different point mutations in the DNA binding domain of p63 were reprogrammed into induced pluripotent stem cell (iPSC) lines. EEC-iPSC from both patients showed early ectodermal commitment into K18(+) cells but failed to further differentiate into K14(+) cells (epidermis/limbus) or K3/K12(+) cells (corneal epithelium). APR-246 (PRIMA-1(MET)), a small compound that restores functionality of mutant p53 in human tumor cells, could revert corneal epithelial lineage commitment and reinstate a normal p63-related signaling pathway. This study illustrates the relevance of iPSC for p63 related disorders and paves the way for future therapy of EEC.

Combined perventricular septal defect closure and patent ductus arteriosus ligation via the lower ministernotomy approach.

PubMed

Voitov, Alexey; Omelchenko, Alexander; Gorbatykh, Yuriy; Bogachev-Prokophiev, Alexander; Karaskov, Alexander

2018-02-01

Over the past decade, minimally invasive approaches have been advocated for surgical correction of congenital defects to reduce costs related to hospitalization and for improved cosmesis. Minimal skin incisions and partial sternotomy reduce surgical trauma, however these techniques might not be successful in treating a number of congenital pathological conditions, particularly for combined congenital defects. We focused on cases with a combined presentation of ventricular septal defect and patent ductus arteriosus. We studied 12 infants who successfully underwent surgical treatment for a combined single-stage ventricular septal defect and patent ductus arteriosus closure through a lower ministernotomy without using cardiopulmonary bypass and X-rays. No intraoperative and early postoperative complications or mortality were noted. Postoperative echocardiography did not reveal residual shunts. The proposed technique is safe and reproducible in infants. © Crown copyright 2017.

Lubrication of dislocation glide in MgO by hydrous defects

NASA Astrophysics Data System (ADS)

Skelton, Richard; Walker, Andrew M.

2018-02-01

Water-related defects, principally in the form of protonated cation vacancies, are potentially able to weaken minerals under high-stress or low-temperature conditions by reducing the Peierls stress required to initiate dislocation glide. In this study, we use the Peierls-Nabarro (PN) model to determine the effect of protonated Mg vacancies on the 1/2<110>{110} and 1/2<110>{100} slip systems in MgO. This PN model is parameterized using generalized stacking fault energies calculated using plane-wave density functional theory, with and without protonated Mg vacancies present at the glide plane. It found that these defects increase dislocation core widths and reduce the Peierls stress over the entire pressure range 0-125 GPa. Furthermore, 1/2<110>{110} slip is found to be more sensitive to the presence of protonated vacancies which increases in the pressure at which {100} becomes the easy glide plane for 1/2<110> screw dislocations. These results demonstrate, for a simple mineral system, that water-related defects can alter the deformation behavior of minerals in the glide-creep regime by reducing the stress required to move dislocations by glide. (Mg, Fe)O is the most anisotropic mineral in the Earth's lower mantle, so the differential sensitivity of the major slip systems in MgO to hydrous defects has potential implications for the interpretation of the seismic anisotropy in this region.

Congenital heart disease in relation to maternal use of Bendectin and other drugs in early pregnancy.

PubMed

Zierler, S; Rothman, K J

1985-08-08

To clarify the association of Bendectin and other drugs used in early pregnancy with the occurrence of congenital heart disease, we interviewed 298 mothers of children with congenital heart disease and 738 mothers of healthy controls. Differential recall of drug use by mothers of affected children and mothers of controls was evaluated by comparison of information collected by interview with that recorded in the prenatal record. Data derived from maternal interviews were generally consistent with the record data. Reported Bendectin use was minimally associated with congenital heart disease (prevalence odds ratio, 1.1; 90 per cent confidence interval, 0.8 to 1.5). The data from this study were consistent with previously reported associations of other drugs with congenital heart disease. In particular, aspirin use in early pregnancy was associated with about a twofold increase in the frequency of defects in septation of the truncus arteriosus (prevalence odds ratio, 2.1; 90 per cent confidence interval, 1.1 to 3.9).

Polycomb-like 2 Associates with PRC2 and Regulates Transcriptional Networks during Mouse Embryonic Stem Cell Self-Renewal and Differentiation

PubMed Central

Walker, Emily; Chang, Wing Y.; Hunkapiller, Julie; Cagney, Gerard; Garcha, Kamal; Torchia, Joseph; Krogan, Nevan J.; Reiter, Jeremy F.; Stanford, William L.

2010-01-01

Summary Polycomb group (PcG) proteins are conserved epigenetic transcriptional repressors that control numerous developmental gene expression programs and have recently been implicated in modulating embryonic stem cell (ESC) fate. We identified the PcG protein PCL2 (polycomb-like 2) in a genome-wide screen for regulators of self-renewal and pluripotency and predicted that it would play an important role in mouse ESC fate determination. Using multiple biochemical strategies, we provide evidence that PCL2 is a Polycomb Repressive Complex 2 (PRC2)-associated protein in mouse ESCs. Knockdown of Pcl2 in ESCs resulted in heightened self-renewal characteristics, defects in differentiation and altered patterns of histone methylation. Integration of global gene expression and promoter occupancy analyses allowed us to identify PCL2 and PRC2 transcriptional targets and draft regulatory networks. We describe the role of PCL2 in both modulating transcription of ESC self-renewal genes in undifferentiated ESCs as well as developmental regulators during early commitment and differentiation. PMID:20144788

Use of Antihistamine Medications During Early Pregnancy and Isolated Major Malformations

PubMed Central

Gilboa, Suzanne M.; Strickland, Matthew J.; Olshan, Andrew F.; Werler, Martha M.; Correa, Adolfo

2013-01-01

BACKGROUND Antihistamines are commonly used during pregnancy. There is little evidence that they have teratogenic effects, but there are knowledge gaps with respect to newer products, as well as the relationship between specific antihistamines and specific birth defects. METHODS Using the National Birth Defects Prevention Study (1997-2003), the authors examined associations between maternal use of 14 antihistamines during early pregnancy and 26 isolated major birth defects. A Bayesian analysis incorporating prior knowledge about the relationships between the antihistamines, birth defects, and measured covariates was conducted. RESULTS Of the 364 associations investigated, 24 had 95% posterior intervals excluding 1.0. All 24 associations were positive; 23 associations were of weak to moderate magnitude (posterior odds ratio [OR] < 3.0) and one was strong (OR > 6.0) but very imprecise. Of the 24 associations, 20 were with non-cardiac defects. Eight associations involved the antihistamine diphenhydramine. CONCLUSIONS The results of this study generally were consistent with no association between birth defects and antihistamine use during early pregnancy. Several of the findings might warrant further investigation, although the observed elevated associations should be interpreted in the context of the number of associations investigated and the analysis of retrospective, self-reported data. PMID:19161158

Racial/ethnic variations in the prevalence of selected major birth defects, metropolitan Atlanta, 1994-2005.

PubMed

Kucik, James E; Alverson, Clinton J; Gilboa, Suzanne M; Correa, Adolfo

2012-01-01

Birth defects are the leading cause of infant mortality and are responsible for substantial child and adult morbidity. Documenting the variation in prevalence of birth defects among racial/ethnic subpopulations is critical for assessing possible variations in diagnosis, case ascertainment, or risk factors among such groups. We used data from the Metropolitan Atlanta Congenital Defects Program, a population-based birth defects registry with active case ascertainment. We estimated the racial/ethnic variation in prevalence of 46 selected major birth defects among live births, stillbirths, and pregnancy terminations at >20 weeks gestation among mothers residing in the five central counties of metropolitan Atlanta between 1994 and 2005, adjusting for infant sex, maternal age, gravidity, and socioeconomic status (SES). We also explored SES as a potential effect measure modifier. Compared with births to non-Hispanic white women, births to non-Hispanic black women had a significantly higher prevalence of five birth defects and a significantly lower prevalence of 10 birth defects, while births to Hispanic women had a significantly higher prevalence of four birth defects and a significantly lower prevalence of six birth defects. The racial/ethnic disparities in the prevalence of some defects varied by SES, but no clear pattern emerged. Racial/ethnic disparities were suggested in 57% of included birth defects. Disparities in the prevalence of birth defects may result from different underlying genetic susceptibilities; exposure to risk factors; or variability in case diagnosis, ascertainment, or reporting among the subpopulations examined. Policies that improve early diagnosis of birth defects could reduce associated morbidity and mortality.

Characterization of Oxygen Defect Clusters in UO2+ x Using Neutron Scattering and PDF Analysis.

PubMed

Ma, Yue; Garcia, Philippe; Lechelle, Jacques; Miard, Audrey; Desgranges, Lionel; Baldinozzi, Gianguido; Simeone, David; Fischer, Henry E

2018-06-18

In hyper-stoichiometric uranium oxide, both neutron diffraction work and, more recently, theoretical analyses report the existence of clusters such as the 2:2:2 cluster, comprising two anion vacancies and two types of anion interstitials. However, little is known about whether there exists a region of low deviation-from-stoichiometry in which defects remain isolated, or indeed whether at high deviation-from-stoichiometry defect clusters prevail that contain more excess oxygen atoms than the di-interstitial cluster. In this study, we report pair distribution function (PDF) analyses of UO 2 and UO 2+ x ( x ≈ 0.007 and x ≈ 0.16) samples obtained from high-temperature in situ neutron scattering experiments. PDF refinement for the lower deviation from stoichiometry sample suggests the system is too dilute to differentiate between isolated defects and di-interstitial clusters. For the UO 2.16 sample, several defect structures are tested, and it is found that the data are best represented assuming the presence of center-occupied cuboctahedra.

Box 6: Nanoscale Defects

NASA Astrophysics Data System (ADS)

Alves, Eduardo; Breese, Mark

Defects affect virtually all properties of crystalline materials, and their role is magnified in nanoscale structures. In this box we describe the different type of defects with particular emphasis on point and linear defects. Above zero Kelvin all real materials have a defect population within their structure, which affects either their crystalline, electronic or optical properties. It is common to attribute a negative connotation to the presence of defects. However, a perfect silicon crystal or any other defect-free semiconductor would have a limited functionality and might even be useless.

Reactive impinging-flow technique for polymer-electrolyte-fuel-cell electrode-defect detection

DOE PAGES

Zenyuk, Iryna V.; Englund, Nicholas; Bender, Guido; ...

2016-09-29

Reactive impinging flow (RIF) is a novel quality-control method for defect detection (i.e., reduction in Pt catalyst loading) in gas-diffusion electrodes (GDEs) on weblines. The technique uses infrared thermography to detect temperature of a nonflammable (<4% H 2) reactive mixture of H 2/O 2 in N 2 impinging and reacting on a Pt catalytic surface. In this article, different GDE size defects (with catalyst-loading reductions of 25, 50, and 100%) are detected at various webline speeds (3.048 and 9.144 m min -1) and gas flowrates (32.5 or 50 standard L min -1). Furthermore, a model is developed and validated formore » the technique, and it is subsequently used to optimize operating conditions and explore the applicability of the technique to a range of defects. The model suggests that increased detection can be achieved by recting more of the impinging H 2, which can be accomplished by placing blocking substrates on the top, bottom, or both of the GDE; placing a substrate on both results in a factor of four increase in the temperature differential, which is needed for smaller defect detection. Lastly, overall, the RIF technique is shown to be a promising route for in-line, high-speed, large-area detection of GDE defects on moving weblines.« less

Effects of Stone-Wales and vacancy defects in atomic-scale friction on defective graphite

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Xiao-Yu; Key Laboratory of Hubei Province for Water Jet Theory and New Technology, Wuhan University, Wuhan 430072; Wu, RunNi

2014-05-05

Graphite is an excellent solid lubricant for surface coating, but its performance is significantly weakened by the vacancy or Stone-Wales (SW) defect. This study uses molecular dynamics simulations to explore the frictional behavior of a diamond tip sliding over a graphite which contains a single defect or stacked defects. Our results suggest that the friction on defective graphite shows a strong dependence on defect location and type. The 5-7-7-5 structure of SW defect results in an effectively negative slope of friction. For defective graphite containing a defect in the surface, adding a single vacancy in the interior layer will decreasemore » the friction coefficients, while setting a SW defect in the interior layer may increase the friction coefficients. Our obtained results may provide useful information for understanding the atomic-scale friction properties of defective graphite.« less

Propagation of damage in the rat brain following sarin exposure: Differential progression of early processes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lazar, Shlomi; Egoz, Inbal; Brandeis, Rachel

Sarin is an irreversible organophosphate cholinesterase inhibitor and a highly toxic warfare agent. Following the overt, dose-dependent signs (e.g. tremor, hyper secretion, seizures, respiratory depression and eventually death), brain damage is often reported. The goal of the present study was to characterize the early histopathological and biochemical events leading to this damage. Rats were exposed to 1LD50 of sarin (80 μg/kg, i.m.). Brains were removed at 1, 2, 6, 24 and 48 h and processed for analysis. Results showed that TSPO (translocator protein) mRNA increased at 6 h post exposure while TSPO receptor density increased only at 24 h. Inmore » all brain regions tested, bax mRNA decreased 1 h post exposure followed by an increase 24 h later, with only minor increase in bcl2 mRNA. At this time point a decrease was seen in both anti-apoptotic protein Bcl2 and pro-apoptotic Bax, followed by a time and region specific increase in Bax. An immediate elevation in ERK1/2 activity with no change in JNK may indicate an endogenous “first response” mechanism used to attenuate the forthcoming apoptosis. The time dependent increase in the severity of brain damage included an early bi-phasic activation of astrocytes, a sharp decrease in intact neuronal cells, a time dependent reduction in MAP2 and up to 15% of apoptosis. Thus, neuronal death is mostly due to necrosis and severe astrocytosis. The data suggests that timing of possible treatments should be determined by early events following exposure. For example, the biphasic changes in astrocytes activity indicate a possible beneficial effects of delayed anti-inflammatory intervention. - Highlights: • The severity of brain damage post 1LD50 sarin exposure is time dependent. • Sarin induce differential progression of early processes in the rat brain. • Potential treatments should be timed according to early events following exposure. • The biphasic astrocytes activity suggests a delay in anti

C/EBPα and C/EBPβ Are Required for Sebocyte Differentiation and Stratified Squamous Differentiation in Adult Mouse Skin

PubMed Central

House, John S.; Zhu, Songyun; Ranjan, Rakesh; Linder, Keith; Smart, Robert C.

2010-01-01

C/EBPα and C/EBPβ are bZIP transcription factors that are highly expressed in the interfollicular epidermis and sebaceous glands of skin and yet germ line deletion of either family member alone has only mild or no effect on keratinocyte biology and their role in sebocyte biology has never been examined. To address possible functional redundancies and reveal functional roles of C/EBPα and C/EBPβ in postnatal skin, mouse models were developed in which either family member could be acutely ablated alone or together in the epidermis and sebaceous glands of adult mice. Acute removal of either C/EBPα or C/EBPβ alone in adult mouse skin revealed modest to no discernable changes in epidermis or sebaceous glands. In contrast, co-ablation of C/EBPα and C/EBPβ in postnatal epidermis resulted in disruption of stratified squamous differentiation characterized by hyperproliferation of basal and suprabasal keratinocytes and a defective basal to spinous keratinocyte transition involving an expanded basal compartment and a diminished and delayed spinous compartment. Acute co-ablation of C/EBPα and C/EBPβ in sebaceous glands resulted in severe morphological defects, and sebocyte differentiation was blocked as determined by lack of sebum production and reduced expression of stearoyl-CoA desaturase (SCD3) and melanocortin 5 receptor (MC5R), two markers of terminal sebocyte differentiation. Specialized sebocytes of Meibomian glands and preputial glands were also affected. Our results indicate that in adult mouse skin, C/EBPα and C/EBPβ are critically involved in regulating sebocyte differentiation and epidermal homeostasis involving the basal to spinous keratinocyte transition and basal cell cycle withdrawal. PMID:20352127

C/EBPalpha and C/EBPbeta are required for Sebocyte differentiation and stratified squamous differentiation in adult mouse skin.

PubMed

House, John S; Zhu, Songyun; Ranjan, Rakesh; Linder, Keith; Smart, Robert C

2010-03-23

C/EBPalpha and C/EBPbeta are bZIP transcription factors that are highly expressed in the interfollicular epidermis and sebaceous glands of skin and yet germ line deletion of either family member alone has only mild or no effect on keratinocyte biology and their role in sebocyte biology has never been examined. To address possible functional redundancies and reveal functional roles of C/EBPalpha and C/EBPbeta in postnatal skin, mouse models were developed in which either family member could be acutely ablated alone or together in the epidermis and sebaceous glands of adult mice. Acute removal of either C/EBPalpha or C/EBPbeta alone in adult mouse skin revealed modest to no discernable changes in epidermis or sebaceous glands. In contrast, co-ablation of C/EBPalpha and C/EBPbeta in postnatal epidermis resulted in disruption of stratified squamous differentiation characterized by hyperproliferation of basal and suprabasal keratinocytes and a defective basal to spinous keratinocyte transition involving an expanded basal compartment and a diminished and delayed spinous compartment. Acute co-ablation of C/EBPalpha and C/EBPbeta in sebaceous glands resulted in severe morphological defects, and sebocyte differentiation was blocked as determined by lack of sebum production and reduced expression of stearoyl-CoA desaturase (SCD3) and melanocortin 5 receptor (MC5R), two markers of terminal sebocyte differentiation. Specialized sebocytes of Meibomian glands and preputial glands were also affected. Our results indicate that in adult mouse skin, C/EBPalpha and C/EBPbeta are critically involved in regulating sebocyte differentiation and epidermal homeostasis involving the basal to spinous keratinocyte transition and basal cell cycle withdrawal.

Maternal Antihypertensive Medication Use and Congenital Heart Defects: Updated Results From the National Birth Defects Prevention Study.

PubMed

Fisher, Sarah C; Van Zutphen, Alissa R; Werler, Martha M; Lin, Angela E; Romitti, Paul A; Druschel, Charlotte M; Browne, Marilyn L

2017-05-01

Previous NBDPS (National Birth Defects Prevention Study) findings from 1997 to 2003 suggested that maternal antihypertensive use was associated with congenital heart defects (CHDs). We re-examined associations between specific antihypertensive medication classes and specific CHDs with additional NBDPS data from 2004 to 2011. After excluding mothers missing hypertension information or who reported pregestational diabetes mellitus, a multiple birth, or antihypertensive use but no hypertension, we compared self-reported maternal exposure data on 10 625 CHD cases and 11 137 nonmalformed controls. We calculated adjusted odds ratios [95% confidence intervals] to estimate the risk of specific CHDs associated with antihypertensive use during the month before conception through the third month of pregnancy, controlling for maternal age, race/ethnicity, body mass index, first trimester cigarette smoking, and NBDPS site. Overall, 164 (1.5%) case mothers and 102 (0.9%) control mothers reported early pregnancy antihypertensive use for their hypertension. We observed increased risk of 4 CHD phenotypes, regardless of antihypertensive medication class reported: coarctation of the aorta (2.50 [1.52-4.11]), pulmonary valve stenosis (2.19 [1.44-3.34]), perimembranous ventricular septal defect (1.90 [1.09-3.31]), and secundum atrial septal defect (1.94 [1.36-2.79]). The associations for these phenotypes were statistically significant for mothers who reported β-blocker use or renin-angiotensin system blocker use; estimates for other antihypertensive medication classes were generally based on fewer exposed cases and were less stable but remained elevated. Our results support and expand on earlier NBDPS findings that antihypertensive medication use may be associated with increased risk of specific CHDs, although we cannot completely rule out confounding by underlying disease characteristics. © 2017 American Heart Association, Inc.

Multiscale simulations of defect dipole-enhanced electromechanical coupling at dilute defect concentrations

NASA Astrophysics Data System (ADS)

Liu, Shi; Cohen, R. E.

2017-08-01

The role of defects in solids of mixed ionic-covalent bonds such as ferroelectric oxides is complex. Current understanding of defects on ferroelectric properties at the single-defect level remains mostly at the empirical level, and the detailed atomistic mechanisms for many defect-mediated polarization-switching processes have not been convincingly revealed quantum mechanically. We simulate the polarization-electric field (P-E) and strain-electric field (ɛ-E) hysteresis loops for BaTiO3 in the presence of generic defect dipoles with large-scale molecular dynamics and provide a detailed atomistic picture of the defect dipole-enhanced electromechanical coupling. We develop a general first-principles-based atomistic model, enabling a quantitative understanding of the relationship between macroscopic ferroelectric properties and dipolar impurities of different orientations, concentrations, and dipole moments. We find that the collective orientation of dipolar defects relative to the external field is the key microscopic structure feature that strongly affects materials hardening/softening and electromechanical coupling. We show that a small concentration (≈0.1 at. %) of defect dipoles dramatically improves electromechanical responses. This offers the opportunity to improve the performance of inexpensive polycrystalline ferroelectric ceramics through defect dipole engineering for a range of applications including piezoelectric sensors, actuators, and transducers.

Osteoblast differentiation and skeletal development are regulated by Mdm2–p53 signaling

PubMed Central

Lengner, Christopher J.; Steinman, Heather A.; Gagnon, James; Smith, Thomas W.; Henderson, Janet E.; Kream, Barbara E.; Stein, Gary S.; Lian, Jane B.; Jones, Stephen N.

2006-01-01

Mdm2 is required to negatively regulate p53 activity at the peri-implantation stage of early mouse development. However, the absolute requirement for Mdm2 throughout embryogenesis and in organogenesis is unknown. To explore Mdm2–p53 signaling in osteogenesis, Mdm2-conditional mice were bred with Col3.6-Cre–transgenic mice that express Cre recombinase in osteoblast lineage cells. Mdm2-conditional Col3.6-Cre mice die at birth and display multiple skeletal defects. Osteoblast progenitor cells deleted for Mdm2 have elevated p53 activity, reduced proliferation, reduced levels of the master osteoblast transcriptional regulator Runx2, and reduced differentiation. In contrast, p53-null osteoprogenitor cells have increased proliferation, increased expression of Runx2, increased osteoblast maturation, and increased tumorigenic potential, as mice specifically deleted for p53 in osteoblasts develop osteosarcomas. These results demonstrate that p53 plays a critical role in bone organogenesis and homeostasis by negatively regulating bone development and growth and by suppressing bone neoplasia and that Mdm2-mediated inhibition of p53 function is a prerequisite for Runx2 activation, osteoblast differentiation, and proper skeletal formation. PMID:16533949

Difficulties in distinguishing between an atlas fracture and a congenital posterior atlas arch defect in postmortem analysis.

PubMed

Sanchis-Gimeno, Juan A; Blanco-Perez, Esther; Aparicio, Luis; Martinez-Soriano, Francisco; Martinez-Sanjuan, Vicente

2014-09-01

We found one atlas from a sample of 148 skeletons (0.67%) that presented different anatomical variations which made it difficult to determine whether the vertebra had an atlas fracture, an unusual Type B posterior atlas arch defect, or a combination of both. We carried out a stereomicroscopy, radiographic, and computerized tomography scan study that revealed that the dry atlas we found presented a very uncommon congenital Type B posterior atlas arch defect, simulating a fracture. In short, the present paper has revealed that differentiating Type B posterior atlas arch defects from fractures in post-mortem dry vertebrae is more difficult than expected. Thus we believe that it can be easier than expected to mistake Type B posterior arch defects for fractures and vice versa in postmortem studies. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells

PubMed Central

Saito, Masako; Nagasawa, Masayuki; Takada, Hidetoshi; Hara, Toshiro; Tsuchiya, Shigeru; Agematsu, Kazunaga; Yamada, Masafumi; Kawamura, Nobuaki; Ariga, Tadashi; Tsuge, Ikuya; Nonoyama, Shigeaki; Karasuyama, Hajime

2011-01-01

Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by recurrent staphylococcal infections and atopic dermatitis associated with elevated serum IgE levels. Although defective differentiation of IL-17–producing CD4+ T cells (Th17) partly accounts for the susceptibility to staphylococcal skin abscesses and pneumonia, the pathogenesis of atopic manifestations in HIES still remains an enigma. In this study, we examined the differentiation and function of Th1, Th2, regulatory T cells (Treg cells), and dendritic cells (DCs) in HIES patients carrying either STAT3 or TYK2 mutations. Although the in vitro differentiation of Th1 and Th2 cells and the number and function of Treg cells in the peripheral blood were normal in HIES patients with STAT3 mutations, primary and monocyte-derived DCs showed defective responses to IL-10 and thus failed to become tolerogenic. When treated with IL-10, patient DCs showed impaired up-regulation of inhibitory molecules on their surface, including PD-L1 and ILT-4, compared with control DCs. Moreover, IL-10–treated DCs from patients displayed impaired ability to induce the differentiation of naive CD4+ T cells to FOXP3+ induced Treg cells (iTreg cells). These results suggest that the defective generation of IL-10–induced tolerogenic DCs and iTreg cells may contribute to inflammatory changes in HIES. PMID:21300911

Facts about Birth Defects

MedlinePlus

... Defects Language: English (US) Español (Spanish) Recommend on Facebook Tweet Share Compartir On This Page Birth Defects are Common Identifying Birth Defects Causes Prevention References Birth defects are common, costly, and critical conditions that affect 1 in every 33 babies born in the ...

Functional Defects in Color Vision in Patients With Choroideremia.

PubMed

Jolly, Jasleen K; Groppe, Markus; Birks, Jacqueline; Downes, Susan M; MacLaren, Robert E

2015-10-01

To characterize defects in color vision in patients with choroideremia. Prospective cohort study. Thirty patients with choroideremia (41 eyes) and 10 age-matched male controls (19 eyes) with visual acuity of ≥6/36 attending outpatient clinics in Oxford Eye Hospital underwent color vision testing with the Farnsworth-Munsell 100 hue test, visual acuity testing, and autofluorescence imaging. To exclude changes caused by degeneration of the fovea, a subgroup of 14 patients with a visual acuity ≥6/6 was analyzed. Calculated color vision total error scores were compared between the groups and related to a range of factors using a random-effects model. Mean color vision total error scores were 120 (95% confidence interval [CI] 92, 156) in the ≥6/6 choroideremia group, 206 (95% CI 161, 266) in the <6/6 visual acuity choroideremia group, and 47 (95% CI 32, 69) in the control group. Covariate analysis showed a significant difference in color vision total error score between the groups (P < .001 between each group). Patients with choroideremia have a functional defect in color vision compared with age-matched controls. The color vision defect deteriorates as the degeneration encroaches on the fovea. The presence of an early functional defect in color vision provides a useful biomarker against which to assess successful gene transfer in gene therapy trials. Copyright © 2015 Elsevier Inc. All rights reserved.

Laser-Directed Hierarchical Assembly of Liquid Crystal Defects and Control of Optical Phase Singularities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ackerman, P. J.; Qi, Z. Y.; Lin, Y. H.

2012-06-07

Topological defect lines are ubiquitous and important in a wide variety of fascinating phenomena and theories in many fields ranging from materials science to early-universe cosmology, and to engineering of laser beams. However, they are typically hard to control in a reliable manner. Here we describe facile erasable 'optical drawing' of self-assembled defect clusters in liquid crystals. These quadrupolar defect clusters, stabilized by the medium's chirality and the tendency to form twisted configurations, are shaped into arbitrary two-dimensional patterns, including reconfigurable phase gratings capable of generating and controlling optical phase singularities in laser beams. Our findings bridge the studies ofmore » defects in condensed matter physics and optics and may enable applications in data storage, singular optics, displays, electro-optic devices, diffraction gratings, as well as in both optically- and electrically-addressed pixel-free spatial light modulators.« less

Complex cardiac defects after ethanol exposure during discrete cardiogenic events in zebrafish: Prevention with folic acid

PubMed Central

Sarmah, Swapnalee; Marrs, James A.

2014-01-01

BACKGROUND Fetal alcohol spectrum disorder (FASD) describes a range of birth defects including various congenital heart defects (CHDs). Mechanisms of FASD-associated CHDs are not understood. Whether alcohol interferes with a single critical event or with multiple events in heart formation is not known. RESULTS Our zebrafish embryo experiments showed that ethanol interrupts different cardiac regulatory networks and perturbed multiple steps of cardiogenesis (specification, myocardial migration, looping, chamber morphogenesis and endocardial cushion formation). Ethanol exposure during gastrulation until cardiac specification or during myocardial midline migration did not produce severe or persistent heart development defects. However, exposure comprising gastrulation until myocardial precursor midline fusion or during heart patterning stages produced aberrant heart looping and defective endocardial cushions. Continuous exposure during entire cardiogenesis produced complex cardiac defects leading to severely defective myocardium, endocardium, and endocardial cushions. Supplementation of retinoic acid with ethanol partially rescued early heart developmental defects, but the endocardial cushions did not form correctly. In contrast, supplementation of folic acid rescued normal heart development, including the endocardial cushions. CONCLUSIONS Our results indicate that ethanol exposure interrupted divergent cardiac morphogenesis events causing heart defects. Folic acid supplementation was effective in preventing a wide spectrum of ethanol-induced heart developmental defects. PMID:23832875

Tutorial: Junction spectroscopy techniques and deep-level defects in semiconductors

NASA Astrophysics Data System (ADS)

Peaker, A. R.; Markevich, V. P.; Coutinho, J.

2018-04-01

The term junction spectroscopy embraces a wide range of techniques used to explore the properties of semiconductor materials and semiconductor devices. In this tutorial review, we describe the most widely used junction spectroscopy approaches for characterizing deep-level defects in semiconductors and present some of the early work on which the principles of today's methodology are based. We outline ab-initio calculations of defect properties and give examples of how density functional theory in conjunction with formation energy and marker methods can be used to guide the interpretation of experimental results. We review recombination, generation, and trapping of charge carriers associated with defects. We consider thermally driven emission and capture and describe the techniques of Deep Level Transient Spectroscopy (DLTS), high resolution Laplace DLTS, admittance spectroscopy, and scanning DLTS. For the study of minority carrier related processes and wide gap materials, we consider Minority Carrier Transient Spectroscopy (MCTS), Optical DLTS, and deep level optical transient spectroscopy together with some of their many variants. Capacitance, current, and conductance measurements enable carrier exchange processes associated with the defects to be detected. We explain how these methods are used in order to understand the behaviour of point defects and the determination of charge states and negative-U (Hubbard correlation energy) behaviour. We provide, or reference, examples from a wide range of materials including Si, SiGe, GaAs, GaP, GaN, InGaN, InAlN, and ZnO.

Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors.

PubMed

Kobayashi, Michihiro; Nabinger, Sarah C; Bai, Yunpeng; Yoshimoto, Momoko; Gao, Rui; Chen, Sisi; Yao, Chonghua; Dong, Yuanshu; Zhang, Lujuan; Rodriguez, Sonia; Yashiro-Ohtani, Yumi; Pear, Warren S; Carlesso, Nadia; Yoder, Mervin C; Kapur, Reuben; Kaplan, Mark H; Daniel Lacorazza, Hugo; Zhang, Zhong-Yin; Liu, Yan

2017-04-01

The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow hematopoietic stem and progenitor cells (HSPCs) that continuously feed thymic progenitors remain largely unknown. While Notch signal is indispensable for T cell specification and differentiation, the downstream effectors are not well understood. PRL2, a protein tyrosine phosphatase that regulates hematopoietic stem cell proliferation and self-renewal, is highly expressed in murine thymocyte progenitors. Here we demonstrate that protein tyrosine phosphatase PRL2 and receptor tyrosine kinase c-Kit are critical downstream targets and effectors of the canonical Notch/RBPJ pathway in early T cell progenitors. While PRL2 deficiency resulted in moderate defects of thymopoiesis in the steady state, de novo generation of T cells from Prl2 null hematopoietic stem cells was significantly reduced following transplantation. Prl2 null HSPCs also showed impaired T cell differentiation in vitro. We found that Notch/RBPJ signaling upregulated PRL2 as well as c-Kit expression in T cell progenitors. Further, PRL2 sustains Notch-mediated c-Kit expression and enhances stem cell factor/c-Kit signaling in T cell progenitors, promoting effective DN1-DN2 transition. Thus, we have identified a critical role for PRL2 phosphatase in mediating Notch and c-Kit signals in early T cell progenitors. Stem Cells 2017;35:1053-1064. © 2016 AlphaMed Press.

Pathobiology and genetics of neural tube defects.

PubMed

Finnell, Richard H; Gould, Amy; Spiegelstein, Ofer

2003-01-01

Neural tube defects (NTDs), including spina bifida and anencephaly, are common congenital malformations that occur when the neural tube fails to achieve proper closure during early embryogenesis. Based on epidemiological and clinical data obtained over the last few decades, it is apparent that these multifactorial defects have a significant genetic component to their etiology that interacts with specific environmental risk factors. The purpose of this review article is to synthesize the existing literature on the genetic factors contributing to NTD risk. To date, there is evidence that closure of the mammalian neural tube initiates and fuses intermittently at four discrete locations. Disruption of this process at any of these four sites may lead to an NTD, possibly arising through closure site-specific genetic mechanisms. Candidate genes involved in neural tube closure include genes of the folate metabolic pathway, as well as those involved in folate transport. Although extensive efforts have focused on elucidating the genetic risk factors contributing to the etiology of NTDs, the population burden for these malformations remains unknown. One group at high risk for having children with NTDs is epileptic women receiving antiepileptic medications during pregnancy. Efforts to better understand the genetic factors that may contribute to their heightened risk, as well as the pathogenesis of neural tube closure defects, are reviewed herein.

Exploiting Defect Clustering to Screen Bare Die for Infant Mortality Failure: An Experimental Study

NASA Technical Reports Server (NTRS)

Lakin, David R., II; Singh, Adit D.

1999-01-01

We present the first experimental results to establish that a binning strategy based on defect clustering can be used to screen bare die for early life failures. The data for this study comes from the SEMATECH test methods experiment.

Redefining early gastric cancer.

PubMed

Barreto, Savio G; Windsor, John A

2016-01-01

The problem is that current definitions of early gastric cancer allow the inclusion of regional lymph node metastases. The increasing use of endoscopic submucosal dissection to treat early gastric cancer is a concern because regional lymph nodes are not addressed. The aim of the study was thus to critically evaluate current evidence with regard to tumour-specific factors associated with lymph node metastases in "early gastric cancer" to develop a more precise definition and improve clinical management. A systematic and comprehensive search of major reference databases (MEDLINE, EMBASE, PubMed and the Cochrane Library) was undertaken using a combination of text words "early gastric cancer", "lymph node metastasis", "factors", "endoscopy", "surgery", "lymphadenectomy" "mucosa", "submucosa", "lymphovascular invasion", "differentiated", "undifferentiated" and "ulcer". All available publications that described tumour-related factors associated with lymph node metastases in early gastric cancer were included. The initial search yielded 1494 studies, of which 42 studies were included in the final analysis. Over time, the definition of early gastric cancer has broadened and the indications for endoscopic treatment have widened. The mean frequency of lymph node metastases increased on the basis of depth of infiltration (mucosa 6% vs. submucosa 28%), presence of lymphovascular invasion (absence 9% vs. presence 53%), tumour differentiation (differentiated 13% vs. undifferentiated 34%) and macroscopic type (elevated 13% vs. flat 26%) and tumour diameter (≤2 cm 8% vs. >2 cm 25%). There is a need to re-examine the diagnosis and staging of early gastric cancer to ensure that patients with one or more identifiable risk factor for lymph node metastases are not denied appropriate chemotherapy and surgical resection.

Improving surveillance for injuries associated with potential motor vehicle safety defects

PubMed Central

Whitfield, R; Whitfield, A

2004-01-01

Objective: To improve surveillance for deaths and injuries associated with potential motor vehicle safety defects. Design: Vehicles in fatal crashes can be studied for indications of potential defects using an "early warning" surveillance statistic previously suggested for screening reports of adverse drug reactions. This statistic is illustrated with time series data for fatal, tire related and fire related crashes. Geographic analyses are used to augment the tire related statistics. Results: A statistical criterion based on the Poisson distribution that tests the likelihood of an expected number of events, given the number of events that actually occurred, is a promising method that can be readily adapted for use in injury surveillance. Conclusions: Use of the demonstrated techniques could have helped to avert a well known injury surveillance failure. This method is adaptable to aid in the direction of engineering and statistical reviews to prevent deaths and injuries associated with potential motor vehicle safety defects using available databases. PMID:15066972

An open-architecture approach to defect analysis software for mask inspection systems

NASA Astrophysics Data System (ADS)

Pereira, Mark; Pai, Ravi R.; Reddy, Murali Mohan; Krishna, Ravi M.

2009-04-01

possible for the end-users to make use of their collected knowledge through the years of experience in mask inspection process by encapsulating the knowledge into software utilities and plugging them into NxDAT. The plug-in interface is designed with the intent of enabling the pro-active mask defect analysis teams to build competitive differentiation into their defect analysis process while protecting their knowledge internally within their company. By providing interface with all major standard layout and mask data formats, NxDAT enables correlation of defect data on reticles with design and mask databases, further extending the effectiveness of defect analysis for D2DB inspection. NxDAT also includes many other advanced features for easy and fast navigation, visual display of defects, defect selection, multi-tier classification, defect clustering and gridding, sophisticated CD and contact measurement analysis, repeatability analysis such as adder analysis, defect trend, capture rate etc.

Threshold-dependent cooperativity of Pdx1 and Oc1 in pancreatic progenitors establishes competency for endocrine differentiation and β-cell function

PubMed Central

Wright, Christopher V.E.; Won, Kyoung-Jae

2016-01-01

Summary Pdx1 and Oc1 are co-expressed in multipotent pancreatic progenitors and regulate the pro-endocrine gene Neurog3. Their expression diverges in later organogenesis, with Oc1 absent from hormone+ cells and Pdx1 maintained in mature β cells. In a classical genetic test for cooperative functional interactions, we derived mice with combined Pdx1 and Oc1 heterozygosity. Endocrine development in double-heterozygous pancreata was normal at embryonic day (e)13.5, but defects in specification and differentiation were apparent at e15.5, the height of the second wave of differentiation. Pancreata from double heterozygotes showed alterations in the expression of genes crucial for β-cell development and function, decreased numbers and altered allocation of Neurog3-expressing endocrine progenitors, and defective endocrine differentiation. Defects in islet gene expression and β-cell function persisted in double heterozygous neonates. These results suggest that Oc1 and Pdx1 cooperate prior to their divergence, in pancreatic progenitors, to allow for proper differentiation and functional maturation of β cells. PMID:27292642

Defective lysosomal targeting of activated fibroblast growth factor receptor 3 in achondroplasia.

PubMed

Cho, Jay Y; Guo, Changsheng; Torello, Monica; Lunstrum, Gregory P; Iwata, Tomoko; Deng, Chuxia; Horton, William A

2004-01-13

Mutations of fibroblast growth factor receptor 3 (FGFR3) are responsible for achondroplasia (ACH) and related dwarfing conditions in humans. The pathogenesis involves constitutive activation of FGFR3, which inhibits proliferation and differentiation of growth plate chondrocytes. Here we report that activating mutations in FGFR3 increase the stability of the receptor. Our results suggest that the mutations disrupt c-Cbl-mediated ubiquitination that serves as a targeting signal for lysosomal degradation and termination of receptor signaling. The defect allows diversion of actively signaling receptors from lysosomes to a recycling pathway where their survival is prolonged, and, as a result, their signaling capacity is increased. The lysosomal targeting defect is additive to other mechanisms proposed to explain the pathogenesis of ACH.

Multiple prethymic defects underlie age-related loss of T progenitor competence

PubMed Central

Zediak, Valerie P.; Maillard, Ivan

2007-01-01

Aging in mice and humans is characterized by declining T-lymphocyte production in the thymus, yet it is unclear whether aging impacts the T-lineage potential of hematopoietic progenitors. Although alterations in the lymphoid progenitor content of aged mouse bone marrow (BM) have been described, irradiation-reconstitution experiments have failed to reveal defects in T-lineage potential of BM hematopoietic progenitors or purified hematopoietic stem cells (HSCs) from aged mice. Here, we assessed T-progenitor potential in unmanipulated recipient mice without conditioning irradiation. T-progenitor potential was reduced in aged BM compared with young BM, and this reduction was apparent at the earliest stages of intrathymic differentiation. Further, enriched populations of aged HSCs or multipotent progenitors (MPPs) gave rise to fewer T-lineage cells than their young counterparts. Whereas the T-precursor frequency within the MPP pool was unchanged, there was a 4-fold decline in T-precursor frequency within the HSC pool. In addition, among the T-competent HSC clones, there were fewer highly proliferative clones in the aged HSC pool than in the young HSC pool. These results identify T-compromised aged HSCs and define the nature and cellular sites of prethymic, age-related defects in T-lineage differentiation potential. PMID:17456721

Anatomy of the ventricular septal defect in outflow tract defects: similarities and differences.

PubMed

Mostefa-Kara, Meriem; Bonnet, Damien; Belli, Emre; Fadel, Elie; Houyel, Lucile

2015-03-01

The study objective was to analyze the anatomy of the ventricular septal defect found in various phenotypes of outflow tract defects. We reviewed 277 heart specimens with isolated outlet ventricular septal defect without subpulmonary stenosis (isolated outlet ventricular septal defect, 19); tetralogy of Fallot (71); tetralogy of Fallot with pulmonary atresia (51); common arterial trunk (54); double outlet right ventricle (65) with subaortic, doubly committed, or subpulmonary ventricular septal defect; and interrupted aortic arch type B (17). Special attention was paid to the rims of the ventricular septal defect viewed from the right ventricular side and the relationships between the tricuspid and aortic valves. The ventricular septal defect was always located in the outlet of the right ventricle, between the 2 limbs of the septal band. There was a fibrous continuity between the tricuspid and aortic valves in 74% of specimens with isolated outlet ventricular septal defect, 66% of specimens with tetralogy of Fallot, 39% of specimens with tetralogy of Fallot with pulmonary atresia, 4.6% of specimens with double outlet right ventricle, 1.8% of specimens with common arterial trunk, and zero of specimens with interrupted aortic arch type B (P < .005). When present, this continuity always involved the anterior tricuspid leaflet. The ventricular septal defect in outflow tract defects is always an outlet ventricular septal defect, cradled between the 2 limbs of the septal band. However, there are some differences regarding the posteroinferior and superior rims of the ventricular septal defect. These differences suggest an anatomic continuum from the isolated outlet ventricular septal defect to the interrupted aortic arch type B rather than distinct physiologic phenotypes, related to various degrees of abnormal rotation of the outflow tract during heart development: minimal in isolated outlet ventricular septal defect; incomplete in tetralogy of Fallot, tetralogy of Fallot

Relative stability of deep- versus shallow-side bone levels in angular proximal infrabony defects.

PubMed

Heins, P; Hartigan, M; Low, S; Chace, R

1989-01-01

The relative changes with time, in the position of the coronal margin of the mesial and distal bone of proximal, angular infrabony defects, were investigated. Tracings of the radiographs of 51 mandibular posterior sites, treated by flap curettage, with a mean post-surgical duration of 11.8 years, were measured using a digitizer pad. The group consisting of shallow-side sites (N = 51), exhibited no significant change in the bone height with time; however, there was a significant decrease in bone height in the deep-side group (N = 51). The mean area of proximal bone decreased significantly with time. The defects were divided into early (N = 25) and advanced (N = 26) angular groups, and then into deep- and shallow-side subgroups. In the early defect group, there was a significant decrease in the mean bone height of the deep-side subgroup. There were no differences in the changes of mean bone level of the remaining 3 subgroups with time. There was no correlation between changes in bone levels of adjacent mesial and distal sides of angular defects with time (r = 0.27). There was no difference between the deep- and shallow-side groups in the number of sites which gained, lost or evidenced no change in bone height. In the study population, the bone height of 73% of the deep-side, and 84% of the shallow-side sites was either unchanged or in a more coronal position.(ABSTRACT TRUNCATED AT 250 WORDS)

Cats, frogs, and snakes: early concepts of neural tube defects.

PubMed

Obladen, Michael

2011-11-01

Disturbed neurulation fascinated scientists of all times. In Egypt, anencephalic infants were venerated as animal-headed gods. Roman law required them to be killed. The medieval world held the mother responsible, either because of assumed imagination or "miswatching," or because of suspected intercourse with animals or devils. Modern embryology and teratology began with the use of the microscope by Malpighi in 1672. Details of neural tube closure were described by Koelliker in 1861 and by His in 1874. From 1822, genetic disease and familial recurrence due to insufficient nutrition were discerned and lower social class identified as a risk factor. It took a century to define the malnutrition as insufficient folate intake. The mandatory supplementation of folate in staple foods successfully reduced the incidence of neural tube defects in the United States, Australia, Canada, and Chile, but it was not adopted by most European countries.

Cost-Sensitive Radial Basis Function Neural Network Classifier for Software Defect Prediction

PubMed Central

Venkatesan, R.

2016-01-01

Effective prediction of software modules, those that are prone to defects, will enable software developers to achieve efficient allocation of resources and to concentrate on quality assurance activities. The process of software development life cycle basically includes design, analysis, implementation, testing, and release phases. Generally, software testing is a critical task in the software development process wherein it is to save time and budget by detecting defects at the earliest and deliver a product without defects to the customers. This testing phase should be carefully operated in an effective manner to release a defect-free (bug-free) software product to the customers. In order to improve the software testing process, fault prediction methods identify the software parts that are more noted to be defect-prone. This paper proposes a prediction approach based on conventional radial basis function neural network (RBFNN) and the novel adaptive dimensional biogeography based optimization (ADBBO) model. The developed ADBBO based RBFNN model is tested with five publicly available datasets from the NASA data program repository. The computed results prove the effectiveness of the proposed ADBBO-RBFNN classifier approach with respect to the considered metrics in comparison with that of the early predictors available in the literature for the same datasets. PMID:27738649

Cost-Sensitive Radial Basis Function Neural Network Classifier for Software Defect Prediction.

PubMed

Kumudha, P; Venkatesan, R

Effective prediction of software modules, those that are prone to defects, will enable software developers to achieve efficient allocation of resources and to concentrate on quality assurance activities. The process of software development life cycle basically includes design, analysis, implementation, testing, and release phases. Generally, software testing is a critical task in the software development process wherein it is to save time and budget by detecting defects at the earliest and deliver a product without defects to the customers. This testing phase should be carefully operated in an effective manner to release a defect-free (bug-free) software product to the customers. In order to improve the software testing process, fault prediction methods identify the software parts that are more noted to be defect-prone. This paper proposes a prediction approach based on conventional radial basis function neural network (RBFNN) and the novel adaptive dimensional biogeography based optimization (ADBBO) model. The developed ADBBO based RBFNN model is tested with five publicly available datasets from the NASA data program repository. The computed results prove the effectiveness of the proposed ADBBO-RBFNN classifier approach with respect to the considered metrics in comparison with that of the early predictors available in the literature for the same datasets.

Predictive factors for lymph node metastasis in poorly differentiated early gastric cancer and their impact on the surgical strategy

PubMed Central

Li, Hua; Lu, Ping; Lu, Yang; Liu, Cai-Gang; Xu, Hui-Mian; Wang, Shu-Bao; Chen, Jun-Qing

2008-01-01

AIM: To identify the predictive clinicopathological factors for lymph node metastasis (LNM) in poorly differentiated early gastric cancer (EGC) and to further expand the possibility of using endoscopic mucosal resection (EMR) for the treatment of poorly differentiated EGC. METHODS: Data were collected from 85 poorly-differentiated EGC patients who were surgically treated. Association between the clinicopathological factors and the presence of LNM was retrospectively analyzed by univariate and multivariate logistic regression analyses. RESULTS: Univariate analysis showed that tumor size (OR = 5.814, 95% CI = 1.050 - 32.172, P = 0.044), depth of invasion (OR = 10.763, 95% CI = 1.259 - 92.026, P = 0.030) and lymphatic vessel involvement (OR = 61.697, 95% CI = 2.144 - 175.485, P = 0.007) were the significant and independent risk factors for LNM. The LNM rate was 5.4%, 42.9% and 50%, respectively, in poorly differentiated EGC patients with one, two and three of the risk factors, respectively. No LNM was found in 25 patients without the three risk factors. Forty-four lymph nodes were found to have metastasis, 29 (65.9%) and 15 (34.1%) of the lymph nodes involved were within N1 and beyond N1, respectively, in 12 patients with LNM. CONCLUSION: Endoscopic mucosal resection alone may be sufficient to treat poorly differentiated intramucosal EGC (≤ 2.0 cm in diameter) with no histologically-confirmed lymphatic vessel involvement. When lymphatic vessels are involved, lymph node dissection beyond limited (D1) dissection or D1+ lymph node dissection should be performed depending on the tumor location. PMID:18636670

Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects

PubMed Central

Jacobs, Russell E.; Lopez-Burks, Martha E.; Choi, Hojae; Wikenheiser, Jamie; Hallgrimsson, Benedikt; Jamniczky, Heather A.; Fraser, Scott E.; Lander, Arthur D.; Calof, Anne L.

2016-01-01

Elucidating the causes of congenital heart defects is made difficult by the complex morphogenesis of the mammalian heart, which takes place early in development, involves contributions from multiple germ layers, and is controlled by many genes. Here, we use a conditional/invertible genetic strategy to identify the cell lineage(s) responsible for the development of heart defects in a Nipbl-deficient mouse model of Cornelia de Lange Syndrome, in which global yet subtle transcriptional dysregulation leads to development of atrial septal defects (ASDs) at high frequency. Using an approach that allows for recombinase-mediated creation or rescue of Nipbl deficiency in different lineages, we uncover complex interactions between the cardiac mesoderm, endoderm, and the rest of the embryo, whereby the risk conferred by genetic abnormality in any one lineage is modified, in a surprisingly non-additive way, by the status of others. We argue that these results are best understood in the context of a model in which the risk of heart defects is associated with the adequacy of early progenitor cell populations relative to the sizes of the structures they must eventually form. PMID:27606604

Treatment of open tibial shaft fracture with soft tissue and bone defect caused by aircraft bomb--case report.

PubMed

Golubović, Zoran; Vidić, Goran; Trenkić, Srbobran; Vukasinović, Zoran; Lesić, Aleksandar; Stojiljković, Predrag; Stevanović, Goran; Golubović, Ivan; Visnjić, Aleksandar; Najman, Stevo

2010-01-01

Aircraft bombs can cause severe orthopaedic injuries. Tibia shaft fractures caused by aircraft bombs are mostly comminuted and followed by bone defects, which makes the healing process extremely difficult and prone to numerous complications. The goal of this paper is to present the method of treatment and the end results of treatment of a serious open tibial fracture with soft and bone tissue defects resulting from aircraft bomb shrapnel wounds. A 26-year-old patient presented with a tibial fracture as the result of a cluster bomb shrapnel wound. He was treated applying the method of external bone fixation done two days after wounding, as well as of early coverage of the lower leg soft tissue defects done on the tenth day after the external fixation of the fracture. The external fixator was removed after five months, whereas the treatment was continued by means of functional plaster cast for another two months. The final functional result was good. Radical wound debridement, external bone fixation of the fracture, and early reconstruction of any soft tissue and bone defects are the main elements of the treatment of serious fractures.

Impairment of social and moral behavior related to early damage in human prefrontal cortex.

PubMed

Anderson, S W; Bechara, A; Damasio, H; Tranel, D; Damasio, A R

1999-11-01

The long-term consequences of early prefrontal cortex lesions occurring before 16 months were investigated in two adults. As is the case when such damage occurs in adulthood, the two early-onset patients had severely impaired social behavior despite normal basic cognitive abilities, and showed insensitivity to future consequences of decisions, defective autonomic responses to punishment contingencies and failure to respond to behavioral interventions. Unlike adult-onset patients, however, the two patients had defective social and moral reasoning, suggesting that the acquisition of complex social conventions and moral rules had been impaired. Thus early-onset prefrontal damage resulted in a syndrome resembling psychopathy.

The scaffold protein Nde1 safeguards the brain genome during S phase of early neural progenitor differentiation

PubMed Central

Houlihan, Shauna L; Feng, Yuanyi

2014-01-01

Successfully completing the S phase of each cell cycle ensures genome integrity. Impediment of DNA replication can lead to DNA damage and genomic disorders. In this study, we show a novel function for NDE1, whose mutations cause brain developmental disorders, in safeguarding the genome through S phase during early steps of neural progenitor fate restrictive differentiation. Nde1 mutant neural progenitors showed catastrophic DNA double strand breaks concurrent with the DNA replication. This evoked DNA damage responses, led to the activation of p53-dependent apoptosis, and resulted in the reduction of neurons in cortical layer II/III. We discovered a nuclear pool of Nde1, identified the interaction of Nde1 with cohesin and its associated chromatin remodeler, and showed that stalled DNA replication in Nde1 mutants specifically occurred in mid-late S phase at heterochromatin domains. These findings suggest that NDE1-mediated heterochromatin replication is indispensible for neuronal differentiation, and that the loss of NDE1 function may lead to genomic neurological disorders. DOI: http://dx.doi.org/10.7554/eLife.03297.001 PMID:25245017

Effect of calcium citrate on bone integration in a rabbit femur defect model.

PubMed

Zhang, Wei; Wang, Wei; Chen, Qing-Yu; Lin, Zhong-Qin; Cheng, Shao-Wen; Kou, Dong-Quan; Ying, Xiao-Zhou; Shen, Yue; Cheng, Xiao-Jie; Nie, Peng-Fei; Li, Xiu-Cui; Rompis, Ferdinand An; Huang, Hang; Zhang, Hua; Mu, Zhong-Lin; Peng, Lei

2012-04-01

To explore effect of calcium citrate on bone integration in a rabbit femur defect model, and to compare the bone formation with different sizes by radiological and histological study. Twenty-four male Japanese white rabbits were randomly divided into three groups (Group A, B, C) in this study. Under anesthesia, defects of four sizes (1.2, 1.5, 2.0 and 2.5 mm) were created in each of the rabbits. Commercially pure calcium citrate powder was placed inside the medullary compartment of the femur (Experimental), while in the contralateral femur (Control) nothing was implanted. The defects were analyzed using radiography and histological analysis by using Imagepro-Plus 6.0 software after animal was sacrificed at 4th(Group A), 6th(Group B) and 8th(Group C) weeks postoperatively. Four samples were analyzed for each size of defect and each healing period. The histological and the radiologic evaluation were performed after sacrification of all rabbits on postoperative 4th and 6th weeks, It showed significant difference between the experimental group and the control group when these defects were less than or equal to 2.0 mm. No statistical difference was observed when these defects were larger than 2.0 mm at all healing periods except at the 4th week. Calcium citrate affects the early periods of bone defects healing mechanism in Japanese white rabbits positively, especially when the defect is not too large. We suggest further studies on calcium citrate to determine the effects of various dosages, administration ways and the experimental time on the bone defects. Copyright © 2012 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

Signaling Cascades Governing Cdc42-Mediated Chondrogenic Differentiation and Mensenchymal Condensation.

PubMed

Wang, Jirong R; Wang, Chaojun J; Xu, Chengyun Y; Wu, Xiaokai K; Hong, Dun; Shi, Wei; Gong, Ying; Chen, Haixiao X; Long, Fanxin; Wu, Ximei M

2016-03-01

Endochondral ossification consists of successive steps of chondrocyte differentiation, including mesenchymal condensation, differentiation of chondrocytes, and hypertrophy followed by mineralization and ossification. Loss-of-function studies have revealed that abnormal growth plate cartilage of the Cdc42 mutant contributes to the defects in endochondral bone formation. Here, we have investigated the roles of Cdc42 in osteogenesis and signaling cascades governing Cdc42-mediated chondrogenic differentiation. Though deletion of Cdc42 in limb mesenchymal progenitors led to severe defects in endochondral ossification, either ablation of Cdc42 in limb preosteoblasts or knockdown of Cdc42 in vitro had no obvious effects on bone formation and osteoblast differentiation. However, in Cdc42 mutant limb buds, loss of Cdc42 in mesenchymal progenitors led to marked inactivation of p38 and Smad1/5, and in micromass cultures, Cdc42 lay on the upstream of p38 to activate Smad1/5 in bone morphogenetic protein-2-induced mesenchymal condensation. Finally, Cdc42 also lay on the upstream of protein kinase B to transactivate Sox9 and subsequently induced the expression of chondrocyte differential marker in transforming growth factor-β1-induced chondrogenesis. Taken together, by using biochemical and genetic approaches, we have demonstrated that Cdc42 is involved not in osteogenesis but in chondrogenesis in which the BMP2/Cdc42/Pak/p38/Smad signaling module promotes mesenchymal condensation and the TGF-β/Cdc42/Pak/Akt/Sox9 signaling module facilitates chondrogenic differentiation. Copyright © 2016 by the Genetics Society of America.

The ubiquitin ligase LIN41/TRIM71 targets p53 to antagonize cell death and differentiation pathways during stem cell differentiation

PubMed Central

Nguyen, Duong Thi Thuy; Richter, Daniel; Michel, Geert; Mitschka, Sibylle; Kolanus, Waldemar; Cuevas, Elisa; Gregory Wulczyn, F

2017-01-01

Rapidity and specificity are characteristic features of proteolysis mediated by the ubiquitin-proteasome system. Therefore, the UPS is ideally suited for the remodeling of the embryonic stem cell proteome during the transition from pluripotent to differentiated states and its inverse, the generation of inducible pluripotent stem cells. The Trim-NHL family member LIN41 is among the first E3 ubiquitin ligases to be linked to stem cell pluripotency and reprogramming. Initially discovered in C. elegans as a downstream target of the let-7 miRNA, LIN41 is now recognized as a critical regulator of stem cell fates as well as the timing of neurogenesis. Despite being indispensable for embryonic development and neural tube closure in mice, the underlying mechanisms for LIN41 function in these processes are poorly understood. To better understand the specific contributions of the E3 ligase activity for the stem cell functions of LIN41, we characterized global changes in ubiquitin or ubiquitin-like modifications using Lin41-inducible mouse embryonic stem cells. The tumor suppressor protein p53 was among the five most strongly affected proteins in cells undergoing neural differentiation in response to LIN41 induction. We show that LIN41 interacts with p53, controls its abundance by ubiquitination and antagonizes p53-dependent pro-apoptotic and pro-differentiation responses. In vivo, the lack of LIN41 is associated with upregulation of Grhl3 and widespread caspase-3 activation, two downstream effectors of p53 with essential roles in neural tube closure. As Lin41-deficient mice display neural tube closure defects, we conclude that LIN41 is critical for the regulation of p53 functions in cell fate specification and survival during early brain development. PMID:28430184

Rare copy number variants in patients with congenital conotruncal heart defects.

PubMed

Xie, Hongbo M; Werner, Petra; Stambolian, Dwight; Bailey-Wilson, Joan E; Hakonarson, Hakon; White, Peter S; Taylor, Deanne M; Goldmuntz, Elizabeth

2017-03-01

Previous studies using different cardiac phenotypes, technologies and designs suggest a burden of large, rare or de novo copy number variants (CNVs) in subjects with congenital heart defects. We sought to identify disease-related CNVs, candidate genes, and functional pathways in a large number of cases with conotruncal and related defects that carried no known genetic syndrome. Cases and control samples were divided into two cohorts and genotyped to assess each subject's CNV content. Analyses were performed to ascertain differences in overall CNV prevalence and to identify enrichment of specific genes and functional pathways in conotruncal cases relative to healthy controls. Only findings present in both cohorts are presented. From 973 total conotruncal cases, a burden of rare CNVs was detected in both cohorts. Candidate genes from rare CNVs found in both cohorts were identified based on their association with cardiac development or disease, and/or their reported disruption in published studies. Functional and pathway analyses revealed significant enrichment of terms involved in either heart or early embryonic development. Our study tested one of the largest cohorts specifically with cardiac conotruncal and related defects. These results confirm and extend previous findings that CNVs contribute to disease risk for congenital heart defects in general and conotruncal defects in particular. As disease heterogeneity renders identification of single recurrent genes or loci difficult, functional pathway and gene regulation network analyses appear to be more informative. Birth Defects Research 109:271-295, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

The TEL-AML1 fusion protein of acute lymphoblastic leukemia modulates IRF3 activity during early B-cell differentiation.

PubMed

de Laurentiis, A; Hiscott, J; Alcalay, M

2015-12-03

The t(12;21) translocation is the most common genetic rearrangement in childhood acute lymphoblastic leukemia (ALL) and gives rise to the TEL-AML1 fusion gene. Many studies on TEL-AML1 describe specific properties of the fusion protein, but a thorough understanding of its function is lacking. We exploited a pluripotent hematopoietic stem/progenitor cell line, EML1, and generated a cell line (EML-TA) stably expressing the TEL-AML1 fusion protein. EML1 cells differentiate to mature B-cells following treatment with IL7; whereas EML-TA display an impaired differentiation capacity and remain blocked at an early stage of maturation. Global gene expression profiling of EML1 cells at different stages of B-lymphoid differentiation, compared with EML-TA, identified the interferon (IFN)α/β pathway as a primary target of repression by TEL-AML1. In particular, expression and phosphorylation of interferon-regulatory factor 3 (IRF3) was decreased in EML-TA cells; strikingly, stable expression of IRF3 restored the capacity of EML-TA cells to differentiate into mature B-cells. Similarly, IRF3 silencing in EML1 cells by siRNA was sufficient to block B-lymphoid differentiation. The ability of TEL-AML1 to block B-cell differentiation and downregulate the IRF3-IFNα/β pathway was confirmed in mouse and human primary hematopoietic precursor cells (Lin- and CD34+ cells, respectively), and in a patient-derived cell line expressing TEL-AML1 (REH). Furthermore, treatment of TEL-AML1 expressing cells with IFNα/β was sufficient to overcome the maturation block. Our data provide new insight on TEL-AML1 function and may offer a new therapeutic opportunity for B-ALL.

Synthetic Defects for Vibrothermography

NASA Astrophysics Data System (ADS)

Renshaw, Jeremy; Holland, Stephen D.; Thompson, R. Bruce; Eisenmann, David J.

2010-02-01

Synthetic defects are an important tool used for characterizing the performance of nondestructive evaluation techniques. Viscous material-filled synthetic defects were developed for use in vibrothermography (also known as sonic IR) as a tool to improve inspection accuracy and reliability. This paper describes how the heat-generation response of these VMF synthetic defects is similar to the response of real defects. It also shows how VMF defects can be applied to improve inspection accuracy for complex industrial parts and presents a study of their application in an aircraft engine stator vane.

Early Evaluation of the Fetal Heart.

PubMed

Hernandez-Andrade, Edgar; Patwardhan, Manasi; Cruz-Lemini, Mónica; Luewan, Suchaya

2017-01-01

Evaluation of the fetal heart at 11-13 + 6 weeks of gestation is indicated for women with a family history of congenital heart defects (CHD), a previous child with CDH, or an ultrasound finding associated with cardiac anomalies. The accuracy for early detection of CHD is highly related to the experience of the operator. The 4-chamber view and outflow tracts are the most important planes for identification of an abnormal heart, and can be obtained in the majority of fetuses from 11 weeks of gestation onward. Transvaginal ultrasound is the preferred route for fetal cardiac examination prior to 12 weeks of gestation, whereas, after 12 weeks, the fetal heart can be reliably evaluated by transabdominal ultrasound. Cardiac defects, such as ventricular septal defects, tetralogy of Fallot, Ebstein's anomaly, or cardiac tumors, are unlikely to be identified at ≤14 weeks of gestation. Additional ultrasound techniques such as spatiotemporal image correlation and the evaluation of volumes by a fetal-heart expert can improve the detection of congenital heart disease. The evaluation of the fetal cardiac function at 11-13 + 6 weeks of gestation can be useful for early identification of fetuses at risk of anemia due to hemoglobinopathies, such as hemoglobin Bart's disease. © 2017 S. Karger AG, Basel.

In vivo differentiation of human periodontal ligament cells leads to formation of dental hard tissue.

PubMed

Wolf, M; Lossdörfer, S; Abuduwali, N; Meyer, R; Kebir, S; Götz, W; Jäger, A

2013-11-01

Following trauma, periodontal disease, or orthodontic tooth movement, residual periodontal ligament (PDL) cells at the defect site are considered mandatory for successful regeneration of the injured structures. Recent developments in tissue engineering focus, as one pillar, on the transplantation of PDL cells to support periodontal regeneration processes. Here, we examined the ability of osteogenically predifferentiated PDL cells to undergo further osteoblastic or cementoblastic differentiation and to mineralize their extracellular matrix when transplanted in an in vivo microenvironment. Using collagen sponges as carriers, osteogenically predifferentiated human PDL cells were transplanted subcutaneously into six immunocompromised CD-1® nude mice. Following explantation after 28 days, osteogenic and cementogenic marker protein expression was visualized immunohistochemically. After 28 days, transplanted PDL cells revealed both cellular, cytoplasmatic and extracellular immunoreactivity for the chosen markers alkaline phosphatase, osteopontin, PTH-receptor 1, and osteocalcin. Specific osteogenic and cementoblastic differentiation was demonstrated by RUNX2 and CEMP1 immunoreactivity. Early stages of mineralization were demonstrated by calcium and phosphate staining. Our results reinforce the previously published reports of PDL cell mineralization in vivo and further demonstrate the successful induction of specific osteogenic and cementogenic differentiation of transplanted human PDL cells in vivo. These findings reveal promising possibilities for supporting periodontal remodeling and regeneration processes with PDL cells being potential target cells with which to influence the process of orthodontically induced root resorption.

Cutaneous vascular anomalies associated with neural tube defects: nomenclature and pathology revisited.

PubMed

Maugans, Todd; Sheridan, Rachel M; Adams, Denise; Gupta, Anita

2011-07-01

Lumbosacral cutaneous vascular anomalies associated with neural tube defects are frequently described in the literature as "hemangiomas." The classification system for pediatric vascular anomalies developed by the International Society for the Study of Vascular Anomalies provides a framework to accurately diagnose these lesions. To apply this classification to vascular cutaneous anomalies overlying myelodysplasias. A retrospective analysis of patients with neural tube defects and lumbosacral cutaneous vascular lesions was performed. All eligible patients had detailed histopathologic analysis of skin and spinal cord/placode lesions. Clinical and radiologic features were analyzed. Conventional histology and GLUT-1 immunostaining were performed to differentiate infantile capillary hemangiomas from capillary vascular malformations. Ten cases with cutaneous lesions associated with neural tube defects were reviewed. Five lesions were diagnosed as infantile capillary hemangiomas based upon histology and positive GLUT-1 endothelial reactivity. These lesions had a strong association with dermal sinus tracts. No reoperations were required for residual intraspinal vascular lesions, and overlying cutaneous vascular anomalies involuted with time. The remaining 5 lesions were diagnosed as capillary malformations. These occurred with both open and closed neural tube defects, did not involute, and demonstrated enlargement and darkening due to vascular congestion. The International Society for the Study of Vascular Anomalies scheme should be used to describe the cutaneous vascular lesions associated with neural tube defects: infantile capillary hemangiomas and capillary malformations. We advocate that these lesions be described as "vascular anomalies" or "stains" pending accurate diagnosis by clinical, histological, and immunohistochemical evaluations.

Topological Defects in Liquid Crystals: Studying the Correlation between Defects and Curvature

NASA Astrophysics Data System (ADS)

Melton, Charles

2015-03-01

Topological defects have recently been the subject of many fascinating studies in soft condensed matter physics. In particular, linking the evolution of topological defects to curvature changes has been a focus, leading possible applications in the areas such as cosmetics, pharmaceuticals, and electronics. In this study, defects in nematic liquid crystal droplets are investigated via laboratory and theoretical techniques. Nematic liquid crystal defects are reproduced via Monte Carlo simulations using a modified 2D XY-Model Hamiltonian. The simulation is performed on a curved surface to replicate a nematic droplet and examine possible defect configurations. To complement this theoretical work, we have trapped nematic droplets inside a dual-beam optical trap. This system allows controllable non-contact droplet deformation on a microscope based platform. Future work will focus on using the trap to stretch nematic droplets, correlating the changing topological defects with theoretical predictions.

Bone Marrow Aspirate Concentrate for Cartilage Defects of the Knee: From Bench to Bedside Evidence.

PubMed

Cotter, Eric J; Wang, Kevin C; Yanke, Adam B; Chubinskaya, Susan

2018-04-01

Objective To critically evaluate the current basic science, translational, and clinical data regarding bone marrow aspirate concentrate (BMAC) in the setting of focal cartilage defects of the knee and describe clinical indications and future research questions surrounding the clinical utility of BMAC for treatment of these lesions. Design A literature search was performed using the PubMed and Ovid MEDLINE databases for studies in English (1980-2017) using keywords, including ["bone marrow aspirate" and "cartilage"], ["mesenchymal stem cells" and "cartilage"], and ["bone marrow aspirate" and "mesenchymal stem cells" and "orthopedics"]. A total of 1832 articles were reviewed by 2 independent authors and additional literature found through scanning references of cited articles. Results BMAC has demonstrated promising results in the clinical application for repair of chondral defects as an adjuvant procedure or as an independent management technique. A subcomponent of BMAC, bone marrow derived-mesenchymal stem cells (MSCs) possess the ability to differentiate into cells important for osteogenesis and chondrogenesis. Modulation of paracrine signaling is perhaps the most important function of BM-MSCs in this setting. In an effort to increase the cellular yield, authors have shown the ability to expand BM-MSCs in culture while maintaining phenotype. Conclusions Translational studies have demonstrated good clinical efficacy of BMAC both concomitant with cartilage restoration procedures, at defined time points after surgery, and as isolated injections. Early clinical data suggests BMAC may help stimulate a more robust hyaline cartilage repair tissue response. Numerous questions remain regarding BMAC usage, including cell source, cell expansion, optimal pathology, and injection timing and quantity.

Geometrically unrestricted, topologically constrained control of liquid crystal defects using simultaneous holonomic magnetic and holographic optical manipulation.

PubMed

Varney, Michael C M; Jenness, Nathan J; Smalyukh, Ivan I

2014-02-01

Despite the recent progress in physical control and manipulation of various condensed matter, atomic, and particle systems, including individual atoms and photons, our ability to control topological defects remains limited. Recently, controlled generation, spatial translation, and stretching of topological point and line defects have been achieved using laser tweezers and liquid crystals as model defect-hosting systems. However, many modes of manipulation remain hindered by limitations inherent to optical trapping. To overcome some of these limitations, we integrate holographic optical tweezers with a magnetic manipulation system, which enables fully holonomic manipulation of defects by means of optically and magnetically controllable colloids used as "handles" to transfer forces and torques to various liquid crystal defects. These colloidal handles are magnetically rotated around determined axes and are optically translated along three-dimensional pathways while mechanically attached to defects, which, combined with inducing spatially localized nematic-isotropic phase transitions, allow for geometrically unrestricted control of defects, including previously unrealized modes of noncontact manipulation, such as the twisting of disclination clusters. These manipulation capabilities may allow for probing topological constraints and the nature of defects in unprecedented ways, providing the foundation for a tabletop laboratory to expand our understanding of the role defects play in fields ranging from subatomic particle physics to early-universe cosmology.

Defects in oxide surfaces studied by atomic force and scanning tunneling microscopy

PubMed Central

König, Thomas; Simon, Georg H; Heinke, Lars; Lichtenstein, Leonid

2011-01-01

Summary Surfaces of thin oxide films were investigated by means of a dual mode NC-AFM/STM. Apart from imaging the surface termination by NC-AFM with atomic resolution, point defects in magnesium oxide on Ag(001) and line defects in aluminum oxide on NiAl(110), respectively, were thoroughly studied. The contact potential was determined by Kelvin probe force microscopy (KPFM) and the electronic structure by scanning tunneling spectroscopy (STS). On magnesium oxide, different color centers, i.e., F0, F+, F2+ and divacancies, have different effects on the contact potential. These differences enabled classification and unambiguous differentiation by KPFM. True atomic resolution shows the topography at line defects in aluminum oxide. At these domain boundaries, STS and KPFM verify F2+-like centers, which have been predicted by density functional theory calculations. Thus, by determining the contact potential and the electronic structure with a spatial resolution in the nanometer range, NC-AFM and STM can be successfully applied on thin oxide films beyond imaging the topography of the surface atoms. PMID:21977410

Birth defects among a cohort of infants born to HIV-infected women on antiretroviral medication

PubMed Central

Watts, D. Heather; Huang, Sharon; Culnane, Mary; Kaiser, Kathleen A.; Scheuerle, Angela; Mofenson, Lynne; Stanley, Kenneth; Newell, Marie-Louise; Mandelbrot, Laurent; Delfraissy, Jean-Francois; Cunningham, Coleen K.

2011-01-01

Objective To determine rate of and risk factors for birth defects in infants born to HIV-infected women receiving nucleoside and protease inhibitor antiretroviral (ARV) therapy. Methods Birth defects were evaluated among infants on the Pediatric AIDS Clinical Trials Group 316 trial that studied addition of peripartum nevirapine to established ARV regimen for prevention of mother-to-child transmission. Maternal therapy was categorized by trimester of earliest exposure. Birth defects were coded using conventions of the Antiretroviral Pregnancy Registry. Results Birth defects were detected in 60/1414 (4.2%; 95% CI 3.3–5.4%) infants including 30/636 (4.7%; 95% CI 3.2–6.7%) with first trimester ARV exposure and 30/778 (3.9%; 95% CI 2.6–5.5%) with exposure only after the first trimester (P=0.51). Rates of classes of defects were similar between first trimester compared to later exposure groups except heart defects which occurred in 16 (2.5%; 95% CI 1.4–4.1%) with first trimester ARV exposure and in six (0.8%; 95% CI 0.3–1.7%) infants with later exposure (P=0.02). Exposure to ARV was not associated with specific types of heart defects. Two cases of cardiomyopathy were noted. Conclusion ARV use in early pregnancy was not associated with an increased risk of birth defects overall. The possible association of ARV exposure with heart defects requires further surveillance. PMID:21142844

Defects in Mitochondrial DNA Replication and Human Disease

PubMed Central

Copeland, William C.

2011-01-01

Mitochondrial DNA (mtDNA) is replicated by the DNA polymerase γ in concert with accessory proteins such as the mitochondrial DNA helicase, single stranded DNA binding protein, topoisomerase, and initiating factors. Nucleotide precursors for mtDNA replication arise from the mitochondrial salvage pathway originating from transport of nucleosides, or alternatively from cytoplasmic reduction of ribonucleotides. Defects in mtDNA replication or nucleotide metabolism can cause mitochondrial genetic diseases due to mtDNA deletions, point mutations, or depletion which ultimately cause loss of oxidative phosphorylation. These genetic diseases include mtDNA depletion syndromes (MDS) such as Alpers or early infantile hepatocerebral syndromes, and mtDNA deletion disorders, such as progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). This review focuses on our current knowledge of genetic defects of mtDNA replication (POLG, POLG2, C10orf2) and nucleotide metabolism (TYMP, TK2, DGOUK, and RRM2B) that cause instability of mtDNA and mitochondrial disease. PMID:22176657

Application of metal magnetic memory technology on defects detection of jack-up platform

NASA Astrophysics Data System (ADS)

Xu, Changhang; Cheng, Liping; Xie, Jing; Yin, Xiaokang; Chen, Guoming

2016-02-01

Metal magnetic memory test (MMMT), which is an effective way in evaluating early damages of ferrimagnets, can determine the existence of material stresses concentration and premature defects. As one of offshore oil exploration and development equipment, jack-up platform always generate stress concentration during its life-cycle due to complicated loading condition and the hash marine environment, which will decline the bearing capacity and cause serious consequences. The paper conducts in situ experiments of defects detection on some key structural components of jack-up platform using MMMT. The signals acquired by MMM-System are processed for feature extraction to evaluate the severity of structure stress concentration. The results show that the method presented in this paper based on MMMT can provide an effective and convenient way of defect detection and structural health monitoring for Jack-up Platform.

Defects formation and wave emitting from defects in excitable media

NASA Astrophysics Data System (ADS)

Ma, Jun; Xu, Ying; Tang, Jun; Wang, Chunni

2016-05-01

Abnormal electrical activities in neuronal system could be associated with some neuronal diseases. Indeed, external forcing can cause breakdown even collapse in nervous system under appropriate condition. The excitable media sometimes could be described by neuronal network with different topologies. The collective behaviors of neurons can show complex spatiotemporal dynamical properties and spatial distribution for electrical activities due to self-organization even from the regulating from central nervous system. Defects in the nervous system can emit continuous waves or pulses, and pacemaker-like source is generated to perturb the normal signal propagation in nervous system. How these defects are developed? In this paper, a network of neurons is designed in two-dimensional square array with nearest-neighbor connection type; the formation mechanism of defects is investigated by detecting the wave propagation induced by external forcing. It is found that defects could be induced under external periodical forcing under the boundary, and then the wave emitted from the defects can keep balance with the waves excited from external forcing.

Porous CaP/silk composite scaffolds to repair femur defects in an osteoporotic model

PubMed Central

Cheng, Ning; Dai, Jing; Cheng, Xiangrong; Li, Shu’e; Miron, Richard J.; Wu, Tao; Chen, Wenli; Zhang, Yufeng

2018-01-01

The most common complication for patients with postmenopausal osteoporosis is bone-related defects and fractures. While routine medication has a high probability of undesirable side effects, new approaches have aimed to develop regeneration procedures that stimulate new bone formation while reversing bone loss. Recently, we have synthesized a new hybrid CaP/silk scaffold with a CaP-phase distribution and pore architecture better suited to facilitate cell differentiation and bone formation. The aim of the present study was to compare the involved remodeling process and therapeutic effect of porous CaP/silk composite scaffolds upon local implantation into osteoporotic defects. Wistar rats were used to induce postmenopausal osteoporotic model by bilateral ovariectomy. The pure silk and hybrid CaP/silk scaffolds were implanted into critical sized defects created in distal femoral epiphysis. After 14 and 28 days, the in vivo osteogenetic efficiency was evaluated by μCT analysis, hematoxylin and eosin staining, Safranin O staining, tartrate-resistant acid phosphatase staining, and immunohistochemical assessment. Animals with or without critical-sized defects were used as drill or blank controls, respectively. The osteoporotic defect model was well established with significantly decreased μCT parameters of BV/TV, Tb.N and increased Tb.Sp, porosity, combined with changes in histological observations. During the healing process, the critical-sized drill control defects failed to regenerate appreciable bone tissue, while more significantly increased bone formation and mineralization with dynamic scaffold degradation and decreased osteoclastic bone resorption could be detected within defects with hybrid CaP/silk scaffolds compared to pure silk scaffolds. PMID:23674058

Porous CaP/silk composite scaffolds to repair femur defects in an osteoporotic model.

PubMed

Cheng, Ning; Dai, Jing; Cheng, Xiangrong; Li, Shu'e; Miron, Richard J; Wu, Tao; Chen, Wenli; Zhang, Yufeng; Shi, Bin

2013-08-01

The most common complication for patients with postmenopausal osteoporosis is bone-related defects and fractures. While routine medication has a high probability of undesirable side effects, new approaches have aimed to develop regeneration procedures that stimulate new bone formation while reversing bone loss. Recently, we have synthesized a new hybrid CaP/silk scaffold with a CaP-phase distribution and pore architecture better suited to facilitate cell differentiation and bone formation. The aim of the present study was to compare the involved remodeling process and therapeutic effect of porous CaP/silk composite scaffolds upon local implantation into osteoporotic defects. Wistar rats were used to induce postmenopausal osteoporotic model by bilateral ovariectomy. The pure silk and hybrid CaP/silk scaffolds were implanted into critical sized defects created in distal femoral epiphysis. After 14 and 28 days, the in vivo osteogenetic efficiency was evaluated by μCT analysis, hematoxylin and eosin staining, Safranin O staining, tartrate-resistant acid phosphatase staining, and immunohistochemical assessment. Animals with or without critical-sized defects were used as drill or blank controls, respectively. The osteoporotic defect model was well established with significantly decreased μCT parameters of BV/TV, Tb.N and increased Tb.Sp, porosity, combined with changes in histological observations. During the healing process, the critical-sized drill control defects failed to regenerate appreciable bone tissue, while more significantly increased bone formation and mineralization with dynamic scaffold degradation and decreased osteoclastic bone resorption could be detected within defects with hybrid CaP/silk scaffolds compared to pure silk scaffolds.

Integration of DNA sample collection into a multi-site birth defects case-control study.

PubMed

Rasmussen, Sonja A; Lammer, Edward J; Shaw, Gary M; Finnell, Richard H; McGehee, Robert E; Gallagher, Margaret; Romitti, Paul A; Murray, Jeffrey C

2002-10-01

Advances in quantitative analysis and molecular genotyping have provided unprecedented opportunities to add biological sampling and genetic information to epidemiologic studies. The purpose of this article is to describe the incorporation of DNA sample collection into the National Birth Defects Prevention Study (NBDPS), an ongoing case-control study in an eight-state consortium with a primary goal to identify risk factors for birth defects. Babies with birth defects are identified through birth defects surveillance systems in the eight participating centers. Cases are infants with one or more of over 30 major birth defects. Controls are infants without defects from the same geographic area. Epidemiologic information is collected through an hour-long interview with mothers of both cases and controls. We added the collection of buccal cytobrush DNA samples for case-infants, control-infants, and their parents to this study. We describe here the methods by which the samples have been collected and processed, establishment of a centralized resource for DNA banking, and quality control, database management, access, informed consent, and confidentiality issues. Biological sampling and genetic analyses are important components to epidemiologic studies of birth defects aimed at identifying risk factors. The DNA specimens collected in this study can be used for detection of mutations, study of polymorphic variants that confer differential susceptibility to teratogens, and examination of interactions among genetic risk factors. Information on the methods used and issues faced by the NBDPS may be of value to others considering the addition of DNA sampling to epidemiologic studies.

Dopaminergic differentiation of neural progenitors derived from placental mesenchymal stem cells in the brains of Parkinson's disease model rats and alleviation of asymmetric rotational behavior.

PubMed

Park, Saeyoung; Kim, Eungpil; Koh, Seong-Eun; Maeng, Sungho; Lee, Won-Don; Lim, Jinho; Shim, Insop; Lee, Young-Jay

2012-07-23

Parkinson's disease (PD) is caused by the progressive loss of dopaminergic neurons in the mesencephalic substantia nigra and is accompanied by behavioral abnormalities. Pharmacological administration of L-dihydroxyphenylalanine (l-dopa) improves the abnormalities in the early phase of the illness, but numerous adverse effects hinder long-term administration. Transplantation of fetal mesencephalic tissues has been suggested as an alternative to l-dopa treatment; however, the use of human fetal tissues is controversial. Mesenchymal stem cells (MSCs) are capable of self-renewal and differentiation and are thus a promising substitute for fetal tissue for the replacement of diseased tissues or organs. Previously, this group isolated 17 independent MSCs from the first trimester human placenta (termed first trimester placental MSCs, or fPMSCs) and reported their successful in vitro differentiation into fPMSC-derived neural progenitors (fPMSC-NPs) (Park et al., Placenta 2011; 32:269-276). In the current study, the in vitro-generated fPMSC-NPs were transplanted into the striatum of a rat model of PD to evaluate whether they could undergo terminal differentiation and mediate behavioral recovery. As early as 2 weeks after transplantation, a minor but significant amelioration of rotational asymmetry was observed, and near-normal motor function was achieved at 24weeks. Immunohistochemical and positron emission tomography (PET) analyses provided experimental evidence for the dopaminergic differentiation of the transplanted progenitors. These results show that in vitro-generated fPMSC-NPs are capable of terminal differentiation in vivo and can attenuate motor defects associated with PD. Hence, the placenta is an auspicious source of stem cells for the therapeutic treatment of neurological disorders. Copyright © 2012 Elsevier B.V. All rights reserved.

Early inner solar system origin for anomalous sulfur isotopes in differentiated protoplanets.

PubMed

Antonelli, Michael A; Kim, Sang-Tae; Peters, Marc; Labidi, Jabrane; Cartigny, Pierre; Walker, Richard J; Lyons, James R; Hoek, Joost; Farquhar, James

2014-12-16

Achondrite meteorites have anomalous enrichments in (33)S, relative to chondrites, which have been attributed to photochemistry in the solar nebula. However, the putative photochemical reactions remain elusive, and predicted accompanying (33)S depletions have not previously been found, which could indicate an erroneous assumption regarding the origins of the (33)S anomalies, or of the bulk solar system S-isotope composition. Here, we report well-resolved anomalous (33)S depletions in IIIF iron meteorites (<-0.02 per mil), and (33)S enrichments in other magmatic iron meteorite groups. The (33)S depletions support the idea that differentiated planetesimals inherited sulfur that was photochemically derived from gases in the early inner solar system (<∼2 AU), and that bulk inner solar system S-isotope composition was chondritic (consistent with IAB iron meteorites, Earth, Moon, and Mars). The range of mass-independent sulfur isotope compositions may reflect spatial or temporal changes influenced by photochemical processes. A tentative correlation between S isotopes and Hf-W core segregation ages suggests that the two systems may be influenced by common factors, such as nebular location and volatile content.

Analysis of the SWI/SNF chromatin-remodeling complex during early heart development and BAF250a repression cardiac gene transcription during P19 cell differentiation

PubMed Central

Singh, Ajeet Pratap; Archer, Trevor K.

2014-01-01

The regulatory networks of differentiation programs and the molecular mechanisms of lineage-specific gene regulation in mammalian embryos remain only partially defined. We document differential expression and temporal switching of BRG1-associated factor (BAF) subunits, core pluripotency factors and cardiac-specific genes during post-implantation development and subsequent early organogenesis. Using affinity purification of BRG1 ATPase coupled to mass spectrometry, we characterized the cardiac-enriched remodeling complexes present in E8.5 mouse embryos. The relative abundance and combinatorial assembly of the BAF subunits provides functional specificity to Switch/Sucrose NonFermentable (SWI/SNF) complexes resulting in a unique gene expression profile in the developing heart. Remarkably, the specific depletion of the BAF250a subunit demonstrated differential effects on cardiac-specific gene expression and resulted in arrhythmic contracting cardiomyocytes in vitro. Indeed, the BAF250a physically interacts and functionally cooperates with Nucleosome Remodeling and Histone Deacetylase (NURD) complex subunits to repressively regulate chromatin structure of the cardiac genes by switching open and poised chromatin marks associated with active and repressed gene expression. Finally, BAF250a expression modulates BRG1 occupancy at the loci of cardiac genes regulatory regions in P19 cell differentiation. These findings reveal specialized and novel cardiac-enriched SWI/SNF chromatin-remodeling complexes, which are required for heart formation and critical for cardiac gene expression regulation at the early stages of heart development. PMID:24335282

Searching for “Defect-Tolerant” Photovoltaic Materials: Combined Theoretical and Experimental Screening

DOE PAGES

Brandt, Riley E.; Poindexter, Jeremy R.; Gorai, Prashun; ...

2017-05-09

Recently, we and others have proposed screening criteria for 'defect-tolerant' photovoltaic (PV) absorbers, identifying several classes of semiconducting compounds with electronic structures similar to those of hybrid lead-halide perovskites. In this work, we reflect on the accuracy and prospects of these new design criteria through a combined experimental and theoretical approach. We construct a model to extract photoluminescence lifetimes of six of these candidate PV absorbers, including four (InI, SbSI, SbSeI, and BiOI) for which time-resolved photoluminescence has not been previously reported. The lifetimes of all six candidate materials exceed 1 ns, a threshold for promising early stage PV devicemore » performance. However, there are variations between these materials, and none achieve lifetimes as high as those of the hybrid lead-halide perovskites, suggesting that the heuristics for defect-tolerant semiconductors are incomplete. Here, we explore this through first-principles point defect calculations and Shockley-Read-Hall recombination models to describe the variation between the measured materials. In light of these insights, we discuss the evolution of screening criteria for defect tolerance and high-performance PV materials.« less

The neuroregenerative mechanism mediated by the Hsp90-binding immunophilin FKBP52 resembles the early steps of neuronal differentiation

PubMed Central

Quintá, HR; Galigniana, MD

2012-01-01

BACKGROUND AND PURPOSE The immunosuppressive macrolide FK506 (tacrolimus) shows neuroregenerative action by a mechanism that appears to involve the Hsp90-binding immunophilin FKBP52. This study analyses some aspects of the early steps of neuronal differentiation and neuroregeneration. EXPERIMENTAL APPROACH Undifferentiated murine neuroblastoma cells and hippocampal neurones isolated from embryonic day-17 rat embryos were induced to differentiate with FK506. Subcellular relocalization of FKBP52, Hsp90 and its co-chaperone p23 was analysed by indirect immunofluorescence confocal microscopy and by Western blots of axonal fractions isolated from cells grown on a porous transwell cell culture chamber. Neuroregeneration was evaluated using a scratch-wound assay. KEY RESULTS In undifferentiated cells, FKBP52, Hsp90 and p23 are located in the cell nucleus, forming an annular structure that disassembles when the differentiation process is triggered by FK506. This was observed in the N2a cell line and in hippocampal neurones. More importantly, the annular structure of chaperones is reassembled after damaging the neurones, whereas FK506 prompts their rapid regeneration, a process linked to the subcellular redistribution of the heterocomplex. CONCLUSIONS AND IMPLICATIONS There is a direct relationship between the disassembly of the chaperone complex and the progression of neuronal differentiation upon stimulation with the immunophilin ligand FK506. Both neuronal differentiation and neuroregeneration appear to be mechanistically linked, so the elucidation of one mechanism may lead to unravel the properties of the other. This study also implies that the discovery of FK506 derivatives, devoid of immunosuppressive action, would be therapeutically significant for neurotrophic use. PMID:22091865

Bone Marrow Aspirate Concentrate-Enhanced Marrow Stimulation of Chondral Defects

PubMed Central

Eichler, Hermann; Orth, Patrick

2017-01-01

Mesenchymal stem cells (MSCs) from bone marrow play a critical role in osteochondral repair. A bone marrow clot forms within the cartilage defect either as a result of marrow stimulation or during the course of the spontaneous repair of osteochondral defects. Mobilized pluripotent MSCs from the subchondral bone migrate into the defect filled with the clot, differentiate into chondrocytes and osteoblasts, and form a repair tissue over time. The additional application of a bone marrow aspirate (BMA) to the procedure of marrow stimulation is thought to enhance cartilage repair as it may provide both an additional cell population capable of chondrogenesis and a source of growth factors stimulating cartilage repair. Moreover, the BMA clot provides a three-dimensional environment, possibly further supporting chondrogenesis and protecting the subchondral bone from structural alterations. The purpose of this review is to bridge the gap in our understanding between the basic science knowledge on MSCs and BMA and the clinical and technical aspects of marrow stimulation-based cartilage repair by examining available data on the role and mechanisms of MSCs and BMA in osteochondral repair. Implications of findings from both translational and clinical studies using BMA concentrate-enhanced marrow stimulation are discussed. PMID:28607559

Iodine-Containing Mass-Defect-Tuned Dendrimers for Use as Internal Mass Spectrometry Calibrants

NASA Astrophysics Data System (ADS)

Giesen, Joseph A.; Diament, Benjamin J.; Grayson, Scott M.

2018-03-01

Calibrants based on synthetic dendrimers have been recently proposed as a versatile alternative to peptides and proteins for both MALDI and ESI mass spectrometry calibration. Because of their modular synthetic platform, dendrimer calibrants are particularly amenable to tailoring for specific applications. Utilizing this versatility, a set of dendrimers has been designed as an internal calibrant with a tailored mass defect to differentiate them from the majority of natural peptide analytes. This was achieved by incorporating a tris-iodinated aromatic core as an initiator for the dendrimer synthesis, thereby affording multiple calibration points ( m/z range 600-2300) with an optimized mass-defect offset relative to all peptides composed of the 20 most common proteinogenic amino acids. [Figure not available: see fulltext.

Differentiation of Effector CD4 T Cell Populations*

PubMed Central

Zhu, Jinfang; Yamane, Hidehiro; Paul, William E.

2012-01-01

CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation. PMID:20192806

FGF-2 signal promotes proliferation of cerebellar progenitor cells and their oligodendrocytic differentiation at early postnatal stage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Naruse, Masae; Shibasaki, Koji; Ishizaki, Yasuki, E-mail: yasukiishizaki@gunma-u.ac.jp

The origins and developmental regulation of cerebellar oligodendrocytes are largely unknown, although some hypotheses of embryonic origins have been suggested. Neural stem cells exist in the white matter of postnatal cerebellum, but it is unclear whether these neural stem cells generate oligodendrocytes at postnatal stages. We previously showed that cerebellar progenitor cells, including neural stem cells, widely express CD44 at around postnatal day 3. In the present study, we showed that CD44-positive cells prepared from the postnatal day 3 cerebellum gave rise to neurospheres, while CD44-negative cells prepared from the same cerebellum did not. These neurospheres differentiated mainly into oligodendrocytesmore » and astrocytes, suggesting that CD44-positive neural stem/progenitor cells might generate oligodendrocytes in postnatal cerebellum. We cultured CD44-positive cells from the postnatal day 3 cerebellum in the presence of signaling molecules known as mitogens or inductive differentiation factors for oligodendrocyte progenitor cells. Of these, only FGF-2 promoted survival and proliferation of CD44-positive cells, and these cells differentiated into O4+ oligodendrocytes. Furthermore, we examined the effect of FGF-2 on cerebellar oligodendrocyte development ex vivo. FGF-2 enhanced proliferation of oligodendrocyte progenitor cells and increased the number of O4+ and CC1+ oligodendrocytes in slice cultures. These results suggest that CD44-positive cells might be a source of cerebellar oligodendrocytes and that FGF-2 plays important roles in their development at an early postnatal stage. - Highlights: • CD44 is expressed in cerebellar neural stem/progenitor cells at postnatal day 3 (P3). • FGF-2 promoted proliferation of CD44-positive progenitor cells from P3 cerebellum. • FGF-2 promoted oligodendrocytic differentiation of CD44-positive progenitor cells. • FGF-2 increased the number of oligodendrocytes in P3 cerebellar slice culture.« less

In vitro and in vivo study of additive manufactured porous Ti6Al4V scaffolds for repairing bone defects

NASA Astrophysics Data System (ADS)

Li, Guoyuan; Wang, Lei; Pan, Wei; Yang, Fei; Jiang, Wenbo; Wu, Xianbo; Kong, Xiangdong; Dai, Kerong; Hao, Yongqiang

2016-09-01

Metallic implants with a low effective modulus can provide early load-bearing and reduce stress shielding, which is favorable for increasing in vivo life-span. In this research, porous Ti6Al4V scaffolds with three pore sizes (300~400, 400~500, and 500~700 μm) were manufactured by Electron Beam Melting, with an elastic modulus range of 3.7 to 1.7 GPa. Cytocompatibility in vitro and osseointegration ability in vivo of scaffolds were assessed. hBMSCs numbers increased on all porous scaffolds over time. The group with intended pore sizes of 300 to 400 μm was significantly higher than that of the other two porous scaffolds at days 5 and 7. This group also had higher ALP activity at day 7 in osteogenic differentiation experiment. The scaffold with pore size of 300 to 400 μm was implanted into a 30-mm segmental defect of goat metatarsus. In vivo evaluations indicated that the depth of bone ingrowth increased over time and no implant dislocation occurred during the experiment. Based on its better cytocompatibility and favorable bone ingrowth, the present data showed the capability of the additive manufactured porous Ti6Al4V scaffold with an intended pore size of 300 to 400 μm for large segmental bone defects.

[Conservative therapy of cartilage defects of the upper ankle joint].

PubMed

Smolenski, U C; Best, N; Bocker, B

2008-03-01

Cartilage defects of the upper ankle joint reflect the problem that great force is transmitted and balanced out over a relatively small surface area. As a pathophysiological factor, cartilage-bone contusions play a significant role in the development of cartilage defects of the upper ankle joint. Physiotherapeutic procedures belong to the standard procedures of conservative therapy. The use and selection of the type of therapy is based on empirical considerations and experience and investigations on effectiveness of particular therapies are relatively rare. At present a symptom-oriented therapy of cartilage defects of the upper ankle joint seems to be the most sensible approach. It can be assumed that it makes sense that the symptomatic treatment of cartilage defects or initial stages of arthritis also includes the subsequent symptoms of pain, irritated condition and limited function. This leads to starting points for physiotherapy with respect to pain therapy, optimisation of pressure relationships, avoidance of pressure points, improvement of diffusion and pressure release. In addition to the differential physiotherapeutic findings, the determination of a curative, preventive or rehabilitative procedure is especially important. In physical therapy special importance is placed on a scheduled serial application corresponding to the findings, employing the necessary methods, such as physiotherapy, sport therapy, medical mechanics, manual therapy, massage, electrotherapy and warmth therapy. From this the findings-related therapy is proposed as a practical therapy concept: locomotive apparatus pain therapy, optimisation of pressure relationships, improvement of diffusion and decongestion therapy. Therapy options have been selected base on the current literature and are summarised in tabular form. The art of symptomatic therapy of cartilage defects of the upper ankle joint does not lie in the multitude of sometimes speculative procedures, but in the targeted selection

Intestinal development and differentiation

PubMed Central

Noah, Taeko K.; Donahue, Bridgitte; Shroyer, Noah F.

2011-01-01

In this review, we present an overview of intestinal development and cellular differentiation of the intestinal epithelium. The review is separated into two sections: Section one summarizes organogenesis of the small and large intestines, including endoderm and gut tube formation in early embryogenesis, villus morphogenesis, and crypt formation. Section two reviews cell fate specification and differentiation of each cell type within the intestinal epithelium. Growth factor and transcriptional networks that regulate these developmental processes are summarized. PMID:21978911

Implementation of Chaotic Gaussian Particle Swarm Optimization for Optimize Learning-to-Rank Software Defect Prediction Model Construction

NASA Astrophysics Data System (ADS)

Buchari, M. A.; Mardiyanto, S.; Hendradjaya, B.

2018-03-01

Finding the existence of software defect as early as possible is the purpose of research about software defect prediction. Software defect prediction activity is required to not only state the existence of defects, but also to be able to give a list of priorities which modules require a more intensive test. Therefore, the allocation of test resources can be managed efficiently. Learning to rank is one of the approach that can provide defect module ranking data for the purposes of software testing. In this study, we propose a meta-heuristic chaotic Gaussian particle swarm optimization to improve the accuracy of learning to rank software defect prediction approach. We have used 11 public benchmark data sets as experimental data. Our overall results has demonstrated that the prediction models construct using Chaotic Gaussian Particle Swarm Optimization gets better accuracy on 5 data sets, ties in 5 data sets and gets worse in 1 data sets. Thus, we conclude that the application of Chaotic Gaussian Particle Swarm Optimization in Learning-to-Rank approach can improve the accuracy of the defect module ranking in data sets that have high-dimensional features.

Automated retinal nerve fiber layer defect detection using fundus imaging in glaucoma.

PubMed

Panda, Rashmi; Puhan, N B; Rao, Aparna; Padhy, Debananda; Panda, Ganapati

2018-06-01

Retinal nerve fiber layer defect (RNFLD) provides an early objective evidence of structural changes in glaucoma. RNFLD detection is currently carried out using imaging modalities like OCT and GDx which are expensive for routine practice. In this regard, we propose a novel automatic method for RNFLD detection and angular width quantification using cost effective redfree fundus images to be practically useful for computer-assisted glaucoma risk assessment. After blood vessel inpainting and CLAHE based contrast enhancement, the initial boundary pixels are identified by local minima analysis of the 1-D intensity profiles on concentric circles. The true boundary pixels are classified using random forest trained by newly proposed cumulative zero count local binary pattern (CZC-LBP) and directional differential energy (DDE) along with Shannon, Tsallis entropy and intensity features. Finally, the RNFLD angular width is obtained by random sample consensus (RANSAC) line fitting on the detected set of boundary pixels. The proposed method is found to achieve high RNFLD detection performance on a newly created dataset with sensitivity (SN) of 0.7821 at 0.2727 false positives per image (FPI) and the area under curve (AUC) value is obtained as 0.8733. Copyright © 2018 Elsevier Ltd. All rights reserved.

Zebrafish numb and numblike are involved in primitive erythrocyte differentiation.

PubMed

Bresciani, Erica; Confalonieri, Stefano; Cermenati, Solei; Cimbro, Simona; Foglia, Efrem; Beltrame, Monica; Di Fiore, Pier Paolo; Cotelli, Franco

2010-12-13

Notch signaling is an evolutionarily conserved regulatory circuitry implicated in cell fate determination in various developmental processes including hematopoietic stem cell self-renewal and differentiation of blood lineages. Known endogenous inhibitors of Notch activity are Numb-Nb and Numblike-Nbl, which play partially redundant functions in specifying and maintaining neuronal differentiation. Nb and Nbl are expressed in most tissues including embryonic and adult hematopoietic tissues in mice and humans, suggesting possible roles for these proteins in hematopoiesis. We employed zebrafish to investigate the possible functional role of Numb and Numblike during hematopoiesis, as this system allows a detailed analysis even in embryos with severe defects that would be lethal in other organisms. Here we describe that nb/nbl knockdown results in severe reduction or absence of embryonic erythrocytes in zebrafish. Interestingly, nb/nbl knocked-down embryos present severe downregulation of the erythroid transcription factor gata1. This results in erythroblasts which fail to mature and undergo apoptosis. Our results indicate that Notch activity is increased in embryos injected with nb/nbl morpholino, and we show that inhibition of Notch activation can partially rescue the hematopoietic phenotype. Our results provide the first in vivo evidence of an involvement of Numb and Numblike in zebrafish erythroid differentiation during primitive hematopoiesis. Furthermore, we found that, at least in part, the nb/nbl morphant phenotype is due to enhanced Notch activation within hematopoietic districts, which in turn results in primitive erythroid differentiation defects.

Elementary defects in graphane

NASA Astrophysics Data System (ADS)

Podlivaev, A. I.; Openov, L. A.

2017-07-01

The main zero-dimensional defects in graphane, a completely hydrogenated single-layer graphene, having the chair-type conformation have been numerically simulated. The hydrogen and carbon-hydrogen vacancies, Stone-Wales defect, and "transmutation defect" resulting from the simultaneous hoppings of two hydrogen atoms between the neighboring carbon atoms have been considered. The energies of formations of these defects have been calculated and their effect on the electronic structure, phonon spectra, and Young modulus has been studied.

Complications related to bone augmentation procedures of localized defects in the alveolar ridge. A retrospective clinical study.

PubMed

Jensen, Anders Torp; Jensen, Simon Storgård; Worsaae, Nils

2016-06-01

This retrospective clinical study aims to evaluate complications after augmentation of localized bone defects of the alveolar ridge. From standardized registrations, the following complications related to bone augmentation procedures were recorded: soft tissue dehiscence, infection, sensory disturbance, additional augmentation procedures needed, and early implant failure. A total of 223 patients (132 women, 91 men; mean age 23.5 years; range 17-65 years) with 331 bone defects had bone augmentation performed into which 350 implants were placed. Soft tissue dehiscence occurred in 1.7 % after GBR procedures, 25.9 % after staged horizontal ridge augmentation, and 18.2 % after staged vertical ridge augmentation. Infections were diagnosed in 2 % after GBR procedures, 12.5 % after sinus floor elevation (SFE) (transcrestal technique), 5 % after staged SFE, 11 % after staged horizontal ridge augmentation, and 9 % after staged vertical ridge augmentation. Additional augmentation procedures were needed in 2 % after GBR procedures, 37 % after staged horizontal ridge augmentation, and 9 % after staged vertical ridge augmentation. A total of six early implant failures occurred (1.7 %), four after GBR procedures (1.6 %), and two (12 %) after staged vertical ridge augmentation. Predictable methods exist to augment localized defects in the alveolar ridge, as documented by low complication rates and high early implant survival rates.

Intrinsic electronic defects and multiple-atom processes in the oxidic semiconductor Ga2O3

NASA Astrophysics Data System (ADS)

Schmeißer, Dieter; Henkel, Karsten

2018-04-01

We report on the electronic structure of gallium oxide (Ga2O3) single crystals as studied by resonant photoelectron spectroscopy (resPES). We identify intrinsic electronic defects that are formed by mixed-atomic valence states. We differentiate three coexisting defect states that differ in their electronic correlation energy and their spatial localization lengths. Their relative abundance is described by a fractional ionicity with covalent and ionic bonding contributions. For Ga2O3, our analyses of the resPES data enable us to derive two main aspects: first, experimental access is given to determine the ionicity based on the original concepts of Pauling and Phillips. Second, we report on multi-atomic energy loss processes in the Ga2p core level and X-ray absorption data. The two experimental findings can be explained consistently in the same context of mixed-atomic valence states and intrinsic electronic defects.

Stress responsiveness and anxiety-like behavior: The early social environment differentially shapes stability over time in a small rodent.

PubMed

Sangenstedt, Susanne; Jaljuli, Iman; Sachser, Norbert; Kaiser, Sylvia

2017-04-01

The early social environment can profoundly affect behavioral and physiological phenotypes. We investigated how male wild cavy offspring, whose mothers had either lived in a stable (SE) or an unstable social environment (UE) during pregnancy and lactation, differed in their anxiety-like behavior and stress responsiveness. At two different time points in life, we tested the offspring's anxiety-like behavior in a dark-light test and their endocrine reaction to challenge in a cortisol reactivity test. Furthermore, we analyzed whether individual traits remained stable over time. There was no effect of the early social environment on anxiety-like behavior and stress responsiveness. However, at an individual level, anxiety-like behavior was stable over time in UE- but not in SE-sons. Stress responsiveness, in turn, was rather inconsistent in UE-sons and temporally stable in SE-sons. Conclusively, we showed for the first time that the early social environment differentially shapes the stability of behavioral and endocrine traits. At first glance, these results may be surprising, but they can be explained by the different functions anxiety-like behavior and stress responsiveness have. Copyright © 2017 Elsevier Inc. All rights reserved.

Overexpression of tropomyosin receptor kinase A improves the survival and Schwann-like cell differentiation of bone marrow stromal cells in nerve grafts for bridging rat sciatic nerve defects.

PubMed

Zheng, Meige; Duan, Junxiu; He, Zhendan; Wang, Zhiwei; Mu, Shuhua; Zeng, Zhiwen; Qu, Junle; Zhang, Jian; Wang, Dong

2016-10-01

Bone marrow stromal cells (BMSCs) can differentiate into Schwann-like cells in vivo and effectively promote nerve regeneration and functional recovery as the seed cells for peripheral nerve repair. However, the survival rate and neural differentiation rate of the transplanted BMSCs are very low, which would limit their efficacy. In this work, rat BMSCs were infected by recombinant lentiviruses to construct tropomyosin receptor kinase A (TrkA)-overexpressing BMSCs and TrkA-shRNA-expressing BMSCs, which were then used in transplantation for rat sciatic nerve defects. We showed that lentivirus-mediated overexpression of TrkA in BMSCs can promote cell survival and protect against serum-starve-induced apoptosis in vitro. At 8 weeks after transplantation, the Schwann-like differentiated ratio of the existing implanted cells had reached 74.8 ± 1.6% in TrkA-overexpressing BMSCs-laden nerve grafts, while 40.7 ± 2.3% and 42.3 ± 1.5% in vector and control BMSCs-laden nerve grafts, but only 8.2 ± 1.8% in TrkA-shRNA-expressing BMSCs-laden nerve grafts. The cell apoptosis ratio of the existing implanted cells in TrkA-overexpressing BMSCs-laden nerve grafts was 16.5 ± 1.2%, while 33.9 ± 1.9% and 42.6 ± 2.9% in vector and control BMSCs-laden nerve grafts, but 87.2 ± 2.5% in TrkA-shRNA-expressing BMSCs-laden nerve grafts. These results demonstrate that TrkA overexpression can improve the survival and Schwann-like cell differentiation of BMSCs and prevent cell death in nerve grafts, which may have potential implication in advancing cell transplantation for peripheral nerve repair. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Influence of chemical disorder on energy dissipation and defect evolution in concentrated solid solution alloys

PubMed Central

Zhang, Yanwen; Stocks, G. Malcolm; Jin, Ke; Lu, Chenyang; Bei, Hongbin; Sales, Brian C.; Wang, Lumin; Béland, Laurent K.; Stoller, Roger E.; Samolyuk, German D.; Caro, Magdalena; Caro, Alfredo; Weber, William J.

2015-01-01

A grand challenge in materials research is to understand complex electronic correlation and non-equilibrium atomic interactions, and how such intrinsic properties and dynamic processes affect energy transfer and defect evolution in irradiated materials. Here we report that chemical disorder, with an increasing number of principal elements and/or altered concentrations of specific elements, in single-phase concentrated solid solution alloys can lead to substantial reduction in electron mean free path and orders of magnitude decrease in electrical and thermal conductivity. The subsequently slow energy dissipation affects defect dynamics at the early stages, and consequentially may result in less deleterious defects. Suppressed damage accumulation with increasing chemical disorder from pure nickel to binary and to more complex quaternary solid solutions is observed. Understanding and controlling energy dissipation and defect dynamics by altering alloy complexity may pave the way for new design principles of radiation-tolerant structural alloys for energy applications. PMID:26507943

Esophageal peristaltic defects in adults with functional dysphagia.

PubMed

Ratuapli, Shiva K; Hansel, Stephanie L; Umar, Sarah B; Burdick, George E; Ramirez, Francisco C; Fleischer, David E; Harris, Lucinda A; Lacy, Brian E; DiBaise, John K; Crowell, Michael D

2014-08-01

Functional dysphagia (FD) is characterized by the presence of dysphagia without evidence of mechanical esophageal obstruction, GERD, and histopathology-based esophageal motor disorders. Dysphagia is common in older patients; however, there is a paucity of information regarding the type and frequency of peristaltic abnormalities compared to younger patients. Based on recently validated criteria for classification of weak peristalsis using high-resolution manometry (HRM), we hypothesized that older patients with FD would have more peristaltic defects detected by HRM compared to younger FD patients. A retrospective review of our motility database yielded 65 patients that met inclusion criteria. Patients were divided into two groups based on age (younger: <70 years; older: ≥70 years). Patients were interviewed, completed a quality-of-life questionnaire, and underwent solid-state HRM. The two groups differed in age but in no other demographic characteristics, severity of dysphagia, or quality of life. Dyspeptic symptoms, including nausea (p < 0.001), early satiety (p = 0.01), bloating (p = 0.02), and belching (p = 0.01), were also more prevalent in younger FD patients. Older age was associated with weak peristalsis involving frequent failed peristalsis, small proximal peristaltic defects (2-5 cm), and large proximal peristaltic defects (>5 cm) (p < 0.001). The mean contraction amplitude was also lower in the older group (p < 0.05). These data support the hypothesis that older patients with FD have a higher frequency of peristaltic abnormalities on HRM compared to younger patients. Older age was associated with increased frequency of weak peristalsis with small and large peristaltic defects.

Investigation of membranous ventricular septal defect complicated with tricuspid regurgitation in ventricular septal defect occlusion