In this regard, reports of adverse events in human newborns have raised concerns about the safety of glucocorticoid treatment; synthetic glucocorticoids have detrimental effects on fetal growth and development, childhood cognition, and long-term behavioral outcomes. Experimental evidence supports a link between prenatal exposure to synthetic glucocorticoids and alterations in fetal development and changes in placental function, and many of these alterations

appear to be permanent. Because the placenta is the conduit between the maternal and fetal environments, it is likely that placental function plays a key role in mediating effects of fetal glucocorticoid exposure on hypothalamic-pituitary-adrenal axis development and long-term disease risk. Here we review recent insights into how the placenta responds to changes in the intrauterine glucocorticoid environment and discuss possible KU-55933 inhibitor mechanisms by which the placenta mediates fetal hypothalamic-pituitary-adrenal

development, metabolism, cardiovascular function, and reproduction.”
“During colonization of germfree mice with the total fecal microbial community of their conventionally born and raised siblings (conventionalization), the intestinal mucosal immune system initiates and maintains a balanced immune response. However, the genetic regulation of these balanced, appropriate responses to the microbiota is obscure. Here, combined analysis of germfree and conventionalized mice revealed that the major molecular responses could be detected PHA-739358 chemical structure initiating at day 4 post conventionalization, with a strong induction of innate immune functions followed by stimulation of adaptive immune responses and development and expansion of adaptive immune cells at later stages of conventionalization. This study provides a comprehensive overview of mouse find more developmental and immune-related cellular pathways and processes that were co-mediated by the commensal microbiota and suggests which mechanisms were involved in this reprogramming. The dynamic, region-dependent mucosal responses to the colonizing microbiota revealed potential

transcriptional signatures for the control of intestinal homeostasis in healthy mice, which may help to decipher the genetic basis of pathway dysregulation in human intestinal inflammatory diseases.”
“Population density can profoundly influence fitness-related traits and population dynamics, and density dependence plays a key role in many prominent ecological and evolutionary hypotheses. Here, we evaluated how individual-level changes in population density affect growth rate and embryo production early in reproductive maturity in two different asexual lineages of Potamopyrgus antipodarum, a New Zealand freshwater snail that is an important model system for ecotoxicology and the evolution of sexual reproduction as well as a potentially destructive worldwide invader.

Both groups showed 100% specificity

compared with amyloid P immunohistochemical staining. The results show that CRF is a sensitive method to analyze trephine bone marrow biopsy specimens for amyloid deposits.”
“We investigated the effect of pH on macrophage apoptosis induced by oxidized low density lipoprotein (OxLDL), as human atherosclerotic lesions have regions of low pH. Hydroperoxide-rich and oxysterol-rich LDL caused 38% and 74% apoptosis of J774 macrophages, respectively, at 24 h, as measured by the externalization of phosphatidylserine. Native LDL, however, did not cause apoptosis. Reducing the pH of the culture medium from 7.4 to 7.0 inhibited apoptosis induced by hydroperoxide-rich or oxysterol-rich OxLDL www.selleckchem.com/products/ly2090314.html by 61% and 46%, respectively (P < 0.001). These data were confirmed by semiquantitative analysis of cytochrome c release from mitochondria. Decreasing the extracellular pH to 7.0 reduced the uptake of hydroperoxide-rich and oxysterol-rich I-125-labeled LDL by 82% and 42%, respectively, and reduced cell surface binding of oxysterol-rich find more LDL by 31%. This may

explain the reduced apoptosis. Additionally, low pH did not affect OxLDI-induced apoptosis of human monocytes, which do not possess scavenger receptors for OxLDL, but reduced apoptosis of human monocyte-derived macrophages, which do possess them. Our investigations suggest that the presence of areas of low pH within atherosclerotic lesions may reduce the uptake of OxLDL and reduce macrophage apoptosis, thus affecting lesion progression.”
“Blinking, a motor act consisting of a closing and an opening eyelid movement, can be performed voluntarily, spontaneously, and reflexly. In this study we investigated the kinematic features of voluntary, spontaneous, and reflex blinking in

patients with Parkinson’s GSK2118436 chemical structure disease (PD), OFF and ON dopaminergic treatment. Patients were asked to blink voluntarily as fast as possible. Spontaneous blinking was recorded for a minute during which the subjects just relaxed. Reflex blinking was evoked by electrical stimulation on the supraorbital nerve. Eyelid movements were recorded with the SMART analyzer motion system. Patients OFF therapy paused longer than controls during voluntary blinking but not during spontaneous and reflex blinking. The blink rate tended to be lower in patients OFF therapy than in controls and the spontaneous blinking had abnormally low amplitude and peak velocity. Finally, in patients OFF therapy the excitability of the neural circuit mediating the closing phase of the reflex blinking was enhanced. Dopaminergic treatment shortened the pause during voluntary blinking and increased the blink rate. In PD patients the longer pauses between the closing and opening phase in comparison to normal subjects, suggest bradykinesia of voluntary blinking. PD patients also display kinematic abnormalities of spontaneous blinking and changes in the excitability of the closing phase of reflex blinking.

“
“Our previous study indicated that consuming (-)-epigallocatechin gallate (EGCG) before or after traumatic brain injury (TBI) eliminated free radical generation in rats, resulting in inhibition of neuronal degeneration and apoptotic death, and improvement of cognitive impairment. Here we investigated the

effects of administering EGCG at various times pre- and post-TBI on cerebral function and morphology. Wistar rats were divided into five groups and were allowed access to (1) normal drinking water, (2) EGCG pre-TBI, (3) EGCG pre- and post-TBI, (4) EGCG post-TBI, and (5) sham-operated VS-6063 research buy group with access to normal drinking water. TBI was induced with a pneumatic controlled injury device at 10 weeks of age. Immunohistochemistry and lipid peroxidation studies revealed that at 1, 3, and 7 days post-TBI, the number of 8-Hydroxy-2′-deoxyguanosine-, 4-Hydroxy-2-nonenal- and single-stranded DNA (ssDNA)-positive cells, and levels of malondialdehyde around the damaged area were significantly decreased in all EGCG treatment groups compared with the water group (P < 0.05). Although there was a significant increase in the number of surviving neurons after TBI in each EGCG treatment group compared with the water group (P < 0.05), significant improvement of cognitive impairment

after TBI was only Elafibranor in vivo observed in the groups with continuous and post-TBI access to EGCG (P < 0.05). These results indicate that EGCG inhibits free radical-induced neuronal degeneration and apoptotic death around the area damaged by TBI. Importantly, continuous and post-TBI access to EGCG improved cerebral function following TBI. In summary, consumption of green tea may

be an effective therapy for TBI patients.”
“AIM: To investigate the association between epidermal growth factor (EGF) +61A/G polymorphism and susceptibility to gastric cancer, through a cross-sectional Napabucasin study.\n\nMETHODS: Polymerase chain reaction resctriction fragment lenght polymorphism analyses were used to geno-type EGF +61 in 207 patients with gastric lesions (162 patients with gastric adenocarcinomas, 45 with atrophy or intestinal metaplasia) and 984 controls. All subjects were Caucasian.\n\nRESULTS: Genotype distribution was 23.5% for GG and 76.5% for GA/AA in the control group, 18.4% for GG and 68.6% for GA/AA in the entire group with gastric lesions and 17.9% for GG and 82.1% for GA/AA in the group with gastric adenocarcinoma. No statistically significant associations were found between EGF +61 variants and risk for developing gastric cancer [odds ratios (OR) = 1.41, 95% confidence intervals (CI): 0.90-2.21, P = 0.116]. However, the stratification of individuals by gender revealed that males carrying A alleles (EGF +61A/G or AA) had an increased risk for developing gastric cancer as compared to GG homozygous males (OR = 1.55, 95% CI: 1.05-2.28, P = 0.021).

59mg/ml) over the 12 hours. However, the number of lymphocytes fluctuated widely between 0.08 +/- 0.03×10(6)/ml and 12.17 +/- 6.58×10(6)/ml. This modified animal model of thoracic duct lymph collection avoids influences of lipid intake, general anesthesia, or limited activity of animals on experimental outcomes, and therefore more accurately reflects lymph flow and composition under normal physiological

conditions.”
“The electrochemiluminescence (ECL) of tris(2,2-bipyridyl)ruthenium [Ru(bpy)(3)](2+) has received much attention. By immobilizing [Ru(bpy)(3)](2+) on an electrode surface, solid-state ECL has several advantages over solution-phase ECL, such as reduced amounts of costly reagent and a simplified experimental design. Herein, different types of solid-state ECL sensors were fabricated and the performances of paraffin oil selleck compound and two ionic liquids (ILs) as the binders were compared for the construction of solid-state ECL. Scanning electron microscopy (SEM), CCD camera, UV-vis, fluorescence spectroscopy, electrochemistry and ECL were applied to characterize and evaluate the performance of

the solid-state composites. According to the obtained results, Ru-graphite/IL octyl pyridinium hexaflurophosphate (OPPF6) was introduced as a new solid-state ECL with excellent properties such as simple preparation, low background buy Torin 2 current, fast electron-transfer rate and good reproducibility and stability. Moreover, for a study of the effect of carbon structure on the performance of the electrode, graphite was replaced by multi-walled carbon nanotubes (MWCNTs) and Ru-MWCNT/OPPF6 was constructed and its efficiency was compared with Ru-graphite/OPPF6 composite electrode. Copyright (c) 2013 John Wiley & Sons, Ltd.”
“Background and purpose: Health-related quality of life (HRQOL) is as important as survival to Quisinostat solubility dmso patients with heart failure (HF).

Perceptions of loss of control are common in HF and negatively affect HRQOL. Knowledge of modifiable factors associated with perceived control could guide the development of interventions to improve perceived control and thus HRQOL. Accordingly, this study examined factors related to perceived control and the relationship between perceived control and HRQOL. Methods: Patients (N=232, mean age 6112, 67% male, 78% Caucasian) provided data on HRQOL (Minnesota Living with Heart Failure questionnaire), perceived control (Control Attitudes Scale-Revised), and factors possibly associated with perceived control (knowledge and barriers (Heart Failure Knowledge and Barriers to Adherence Scale), attitudes (Dietary Sodium Restriction Questionnaire), and social support (Multidimensional Scale of Perceived Social Support)). Patients also provided data on depressive symptoms, which were a covariate of HRQOL. Hierarchical multiple regression analysis was used to analyze the data.

All rights reserved.”
“Sexual selection theory makes clear predictions regarding male spermatogenic investment. To test these predictions we used experimental sexual selection in Drosophila pseudoobscura, a sperm heteromorphic species in

which males produce find more both fertile and sterile sperm, the latter of which may function in postmating competition. Specifically, we determined whether the number and size of both sperm types, as well as relative testis mass and accessory gland size, increased with increased sperm competition risk and whether any fitness benefits could accrue from such changes. We found no effect of sexual selection history on either the number or size of either sperm morph, or on relative testis mass. However, males experiencing 3-Methyladenine nmr a greater opportunity for sexual selection evolved the largest accessory glands, had the greatest mating capacity, and sired the most progeny. These findings suggest that sterile sperm are not direct targets of sexual selection and that accessory gland size, rather than testis mass, appears to be an important determinant of male reproductive success. We briefly review the data from experimental sexual selection studies and find that testis mass may not be a frequent target

of postcopulatory sexual selection and, even when it is, the resulting changes do not always improve fitness.”
“Adolf Remane is widely considered to have been one of the most influential German zoologists of the 20th Century, yet Ernst Mayr persistently characterized Napabucasin datasheet him as an idealistic morphologist, that is, a typologist unable to understand population genetics or indeed Darwinian theory. This stands in sharp contrast to Mayr’s praise

for Bernhard Rensch as one of the most important German contributors to the Modern Synthesis of evolutionary theory. Remane’s style of scientific reasoning is analysed in his writings on microsystematics, ecology, comparative morphology and phylogenetics and found to be highly consistent throughout these varied fields of research, while differing fundamentally from the eminently statistical foundations of both population genetics and natural selection theory that were embraced by Mayr. A comparative analysis of Rensch’s understanding of science in general, and biology in particular, shows him to share core values with Remane, both authors rooted in the Mandarin tradition of the German professoriate. Biographical and socio-political factors appear to have influenced Mayr’s contrasting perception of Remane and Rensch, one that would influence later biologists and historians of science.”
“This article is about nursing leadership, workforce diversity, and under-representation in nursing. It is about long-term care, specifically the nursing home, the nurses, and the certified nursing assistants. The nursing shortage, the shortage of nurse educators, and curricular changes in the colleges and universities are not the focus of this work.

\n\nResults\n\nBetween 1995 and 2006, 346 Fer-1 patients were diagnosed with MCC.

Of these, 213 underwent resection of the primary lesion and evaluation of the draining lymph node basin. Fifty-four patients (25%) had tumors <= 1.0 cm in diameter. Average tumor diameter was 0.7 cm, and 63% were located on the head or neck. Only two patients (4%) with tumors <= 1.0 cm had regional lymph node metastasis, compared with 51 (24%) of 213 patients with tumors more than 1.0 cm (P < .0001). Both patients had clinically evident nodal disease at presentation and underwent CLND. Both have remained recurrence-free for 40 months. Thirteen (25%) of 51 patients with nodal metastasis and tumors more than 1 cm had occult nodal metastasis.\n\nConclusion\n\nIn this

series, patients with MCC <= 1.0 cm were unlikely to have regional lymph node metastasis, suggesting that regional nodal evaluation may reasonably be avoided in these patients. However, these data support SLNB for MCC more than 1 cm in diameter.”
“Ultrasound-mediated destruction of microbubbles has been proposed as an innovative non-invasive drug delivery system for cancer therapy. We developed a specific drug delivery system for squamous cell carcinoma that uses sonoporation with the anti-epidermal growth factor receptor (EGFR) antibody. Administration of a low dose of bleomycin (BLM) by sonoporation with the anti-EGFR antibody produced a marked growth inhibition of Ca9-22 cells in vitro. In addition, scanning electron microscopic analysis revealed AZD1208 molecular weight apparent surface deformation of Ca9-22 cells treated with sonoporation

in the presence of the antibody. Interestingly, the population of apoptotic cells was remarkably increased when a low dose of BLM was delivered using sonoporation with the Fab fragment of the anti-EGFR antibody. These findings indicate that sonoporation with the Fab fragment makes it possible to administer drugs into cells more efficiently and specifically, suggesting a novel application for chemotherapy and gene therapy treatments for oral squamous S3I-201 solubility dmso cell carcinoma.”
“OBJECTIVES The proportion of tuberculosis cases in a population that are clustered (i.e. share identical strains of Mycobacterium tuberculosis) reflects ongoing M. tuberculosis transmission. It varies markedly, but it is unclear how much of this variation reflects measurable differences in study design, setting and the patient population. We aimed to assess the relative impact of these factors and develop a tool to improve interpretation of the proportion clustered from an individual study.\n\nMETHODS We systematically reviewed all population-based TB clustering studies that used IS6110 RFLP as their main DNA fingerprinting technique. Meta-regression was used to see how much of the variation in the proportion clustered between studies could be explained by variables describing study design, setting and population.

0.0005 mg l(-1); 0.137 U ml(-1) vs. 0.055 U ml(-1), respectively). Fe level, CAT activity and TAS were lower in

serum of volunteers from polluted area (0.442 g l(-1) vs. 0.476 gl(-1); 3.336 nmol min-1 ml(-1) vs. 6.017 nmol min(-1) ml(-1); 0.731 Trolox-equivalents vs. 0.936 Trolox-equivalents, respectively), whilst differences in FRT concentration were not significant (66.109 pg l(-1) vs. 37.667 pgl(-1), p=0.3972). Positive correlations between Pb (r=0.206), Cd (r=0.602) and SOD in the inhabitants of polluted area, and between Cd and SOD in the control (r=0.639) were shown. In volunteers from both studied NCT-501 environments TAS-FRT (polluted: r=0.625 vs. control: r=0.837) and Fe-FRT (polluted area: r=0.831 vs. control: r=0.407) correlations, and Pb-FRT (r=0.360) and Pb-TAS (r=0.283) in the control were stated.\n\nThe higher lead and cadmium concentrations in blood cause an increase of SOD activity. It Selleckchem Salubrinal suggests that

this is one of the defense mechanisms of an organism against oxidative stress caused by environmental factors, whilst non-enzymatic mechanisms marked by TAS are the main antioxidant defense system in relation with Pb concentration in humans from unpolluted area. Simultaneously, the higher CAT activity and TAS can indicate that these mechanisms play a key role in the antioxidant protection in non-stressed environments. (C) 2011 Elsevier Inc. All rights reserved.”
“The purpose of this meta-analysis was to determine whether genetic variants of the interleukin-1 beta[+3954 C>T (rs1143634)] (IL-1 beta +3954 C>T) gene polymorphisms were associated with orthodontic

external apical root resorption (EARR). A meta-analysis was carried out using data entered into the PubMed and Embase electronic databases before October 5, 2012. A total of 7 studies were identified for meta-analysis. The strength of the relationship between IL-1 beta +3954 C>T polymorphism and the risk of EARR was assessed using odds ratio (OR). The studies provided overall OR estimates for EARR. Overall, the variant genotypes (CC and CT) of the IL-1 beta +3954 C>T polymorphism were unassociated with EARR risk compared with the TT homozygote [CC Selleckchem 3-Methyladenine vs TT, OR = 1.28, 95% confidence interval (95%CI) = 0.27-6.08; CT vs TT, OR = 0.74, 95% CI = 0.11-5.02]. Similarly, no associations were found in the dominant and recessive models (dominant model, OR = 1.08, 95% CI = 0.24-4.86; recessive model, OR = 1.85, 95% CI = 0.87-3.93). No publication bias was found, and no association was apparent between the IL-1 beta +3954 C>T polymorphism and risk of EARR in orthodontic treatment patients. Further multicenter and better-controlled studies are required to confirm these findings.”
“Methods: Use of the coronary sinus (CS) for left ventricular (LV) shocking electrode placement resulted in acceptable DFTs in each patient. The position of the shocking coil in all three patients was posterior, and in two patients alongside a left ventricular CS pacing lead.

In conclusion, chronic exposure to aldosterone improves the function of cardiomyocytes under basal conditions and electrolyte disturbances that mimic the situation found in heart failure patients.”
“The in vitro activity of 22 antibiotics (including novobiocin) and beta-lactam/gentamicin combinations was assessed against 11

multidrug-resistant pneumococcal strains. Among orally administered drugs, only telithromycin, levofloxacin, and linezolid were active against all isolates, but their use is not indicated in pediatrics. Novobiocin could be a potential therapeutic alternative. (C) 2010 Elsevier Inc. All rights reserved.”
“Objective To investigate the involvement of the leukotriene B4 (LTB4) pathway in polymyositis (PM) and dermatomyositis (DM) and the effect of immunosuppressive treatment on the LTB4 pathway.\n\nMethods 5-lipoxygenase (5-LO), 5-LO activating protein (FLAP) and LTB4 receptor-1 (BLT1) expression was Selleckchem LCL161 analysed by immunohistochemistry in muscle tissue from patients with PM/DM before and after immunosuppressive treatment and from healthy individuals. In

vivo LTB4 in thigh muscle was measured by microdialysis at rest and after acute exercise in another cohort of patients and healthy controls.\n\nResults The number of CT99021 5-LO-positive cells and BLT1-positive capillaries was higher in patients with PM/DM than in healthy individuals. The number of FLAP-expressing cells divided the patients into two groups (high/low expression). Treatment reduced the number of FLAP-positive cells in the group with initial high levels, however the expression remained high compared with healthy individuals. The number of BLT1-positive cells was also reduced while staining for 5-LO was unchanged. An P5091 in vivo inverse correlation was observed between the number of 5-LO or FLAP-positive cells in muscle tissue and muscle performance. LTB4 could be detected in dialysate of muscle tissue in vivo in both patients and healthy controls and was significantly increased after exercise in patients.\n\nConclusion The LTB4 pathway is upregulated

in muscle tissue from patients with PM/DM and this upregulation correlated negatively to muscle performance, suggesting a role for LTB4 in myositis muscle weakness. The immunosuppressive treatment was insufficient on the LTB4 pathway and, for patients with high expression of FLAP, FLAP inhibitors may be considered as possible therapy.”
“The inhibitory effect of amphotericin B (AMPH) on the growth of fungi during the isolation of thraustochytrids was examined. The growth of fungi was significantly inhibited by addition of AMPH, and therefore colonies of thraustochytrids were not overlaid with fungal mycelia, which resulted in increased efficiency of thraustochytrids isolation. (C) 2010, The Society for Biotechnology, Japan. All rights reserved.

“
“Over the past decade, comprehensive genomic studies demonstrated that leiomyosarcomas and most of the tumors previously labeled as ‘malignant fibrous histiocytomas’ share complex karyotypes and genomic profiles, and can be referred to as ‘sarcomas with complex genomics’. We recently reported a series of 160 sarcomas with complex genomics such as leiomyosarcomas, myxofibrosarcomas, selleck kinase inhibitor pleomorphic liposarcomas/rhabdomyosarcomas and undifferentiated pleomorphic sarcomas. These tumors present with a frequent loss of chromosome 10 region encompassing

the tumor suppressor gene PTEN. In the present study, we assessed PTEN genomic level and protein expression in this large series of sarcomas with complex genomics, as well as activation of downstream pathways. PTEN partial genomic loss was observed in only 46% of tumors, especially in well-differentiated leiomyosarcomas, whereas up to 68% of these tumors demonstrate a loss of protein expression

Ro-3306 on western blot analysis. Specific discrepancies in PTEN immunohistochemical results suggested bias in this latter technique. PTEN mutations were rare, with only 4 point mutations in the 65 samples studied. Subsequent activation of AKT and mTOR pathways was only observed in 2 out of 3 of PTEN-deleted tumors. On the other hand, RICTOR, a major component of the mTOR complex 2, was significantly overexpressed in well-differentiated leiomyosarcomas. These results, confirmed on tissue micro-array immunohistochemical analysis

of 459 sarcomas, could suggest a link between RICTOR overexpression and leiomyosarcomas oncogenesis. As therapeutics directed against the mTOR pathway are assessed in sarcomas, RICTOR overexpression in sarcomas and its links to therapeutic response need to be assessed. Modern Pathology (2012) 25, 197-211; doi:10.1038/modpathol.2011.163; published online 11 November 2011″
“The neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) contribute to the regulation of diverse cognitive and physiological functions including nociception. Indeed, OXT has been reported to be analgesic when administered directly into the brain, the spinal cord, or systemically. Here, we characterized the phenotype of oxytocin receptor (OTR) and vasopressin-1A p38 MAPK assay receptor (V1AR) null mutant mice in a battery of pain assays. Surprisingly, OTR knock-out mice displayed a pain phenotype identical to their wild-type littermates. Moreover, systemic administration of OXT dose-dependently produced analgesia in both wild-type and OTR knock-out mice in three different assays, the radiant-heat paw withdrawal test, the von Frey test of mechanical sensitivity, and the formalin test of inflammatory nociception. In contrast, OXT-induced analgesia was completely absent in V1AR knock-out mice. In wild-type mice, OXT-induced analgesia could be fully prevented by pretreatment with a V1AR but not an OTR antagonist.

The primary outcome was survival to hospital discharge.\n\nResults: Among the 2867 patients enrolled in the basic life-support (n= 1373) and advanced life-support

( n= 1494) phases, characteristics were similar, including mean age (44.8 v. 47.5 years), BLZ945 mw frequency of blunt injury (92.0% v. 91.4%), median injury severity score ( 24 v. 22) and percentage of patients with Glasgow Coma Scale score less than 9 (27.2% v. 22.1%). Survival did not differ overall (81.1% among patients in the advanced life-support phase v. 81.8% among those in the basic life-support phase; p=0.65). Among patients with Glasgow Coma Scale score less than 9, survival was lower among those in the

advanced life-support phase (50.9% v. 60.0%; p= 0.02). The adjusted odds of death for the advanced life-support v. basic life-support phases were nonsignificant (1.2, 95% confidence interval 0.9-1.7; mTOR inhibitor p= 0.16).\n\nInterpretation: The OPALS Major Trauma Study showed that systemwide implementation of full advanced life-support programs did not decrease mortality or morbidity for major trauma patients. We also found that during the advanced life-support phase, mortality was greater among patients with Glasgow Coma Scale scores less than 9. We believe that emergency medical services should carefully re-evaluate the indications for and application of prehospital advanced life-support measures for patients who have experienced major trauma.”
“BRIT1 protein (also known as MCPH1) contains 3 BRCT domains which are conserved in BRCA1, BRCA2, and other important molecules involved in DNA damage signaling, DNA repair, and tumor suppression. BRIT1 mutations or aberrant expression are found in primary microcephaly patients as well as in cancer patients. Recent MK-2206 inhibitor in vitro studies suggest that BRIT1/MCPH1 functions as a novel key regulator in the DNA

damage response pathways. To investigate its physiological role and dissect the underlying mechanisms, we generated BRIT1(-/-) mice and identified its essential roles in mitotic and meiotic recombination DNA repair and in maintaining genomic stability. Both BRIT1(-/-) mice and mouse embryonic fibroblasts(MEFs) were hypersensitive to gamma-irradiation. BRIT1(-/-) MEFs and T lymphocytes exhibited severe chromatid breaks and reduced RAD51 foci formation after irradiation. Notably, BRIT1(-/-) mice were infertile and meiotic homologous recombination was impaired. BRIT1-deficient spermatocytes exhibited a failure of chromosomal synapsis, and meiosis was arrested at late zygotene of prophase I accompanied by apoptosis. In mutant spermatocytes, DNA double-strand breaks (DSBs) were formed, but localization of RAD51 or BRCA2 to meiotic chromosomes was severely impaired.