To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to ...the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
Abstract
During flavivirus maturation, the structural proteins prM (pre-membrane) and E (envelope) undergo extensive low pH-mediated conformational changes, transitioning from spiky trimeric to ...smooth dimeric prM/E heterodimers which allow for furin cleavage of prM into pr and M and forms the irreversible mature conformation of smooth M/E heterodimers. The mechanisms of irreversible conformational changes to E protein following the pr cleavage are not understood. Utilizing cryo-EM structures of immature virus and structure-based mutagenesis of Zika virus, we identified two critical “latching and locking” interactions mediated by M protein residues Arg38 and Trp19, respectively, that stabilize the E protein structure in the smooth mature stage. M protein thus latches and locks the E protein in an irreversible mature structure, preventing premature fusion in the secretory pathway. Our studies provide mechanistic insights into the reversible structural transition of immature trimeric spikes and the irreversible transition of smooth dimeric M/E heterodimers critical for virus infectivity.
Male African elephants experience intense intrasexual selection in gaining access to oestrous females, who represent a very scarce and highly mobile resource. An unusual combination of behavioural ...and physiological traits in males probably reflects this intense selection pressure. Males show prolonged growth, growing throughout much or perhaps all of their long life span (ca. 60–65 years), and they show musth, a physiological and behavioural condition exclusive to elephants, which is manifested by bouts of elevated testosterone and aggression and heightened sexual activity. Most observed matings are by males over 35 years of age and in musth, suggesting that age and musth are both important factors contributing to male reproductive success. Here we report the results of a genetic paternity analysis of a well-studied population of wild African elephants. Patterns of paternity for 119 calves born over a 22-year period showed significant effects of both age and musth on paternity success. Among males in musth, paternity success increased significantly with age until the very oldest age classes, when it modestly declined. When not in musth, males experienced relatively constant, low levels of paternity success at all ages. Thus, despite the importance of both musth and age in determining male paternity success, adult males both in and out of musth, and of all ages, produced calves. In general, however, older males had markedly elevated paternity success compared with younger males, suggesting the possibility of sexual selection for longevity in this species.
The behavioral theory constructs most often used to study mammography utilization—perceived benefit, perceived susceptibility, self-efficacy, intention, and subjective norms—have neither been ...developed nor sufficiently tested among diverse racial/ethnic subgroups. The authors explored these constructs and their underlying assumptions relating to the social context of Filipina and Latina women. The mixed-methods study included testing construct measures in the multilingual surveys of a concurrent intervention study of 1,463 women from five ethnic groups. An intensive inductive investigation then targeted Latina and Filipina women to elucidate connections between social context and individual screening behavior. In-depth interviews were conducted with 11 key informant scholars, 13 community gatekeepers, and 29 lay women, and a supplemental study videotaped and interviewed 9 mother-daughter dyads. Three social context domains emerged: relational culture, social capital, and transculturation and transmigration. The meaning and appropriateness of the five behavioral constructs were analyzed in relation to these domains. In contradistinction to tenets of behavioral theory, the authors found that social context can influence behavior directly, circumventing or attenuating the influence of individual beliefs; contextual influences, synthesized from multiple perspectives, can operate at an unconscious level not accessible to the individual; and contextual influences are dynamic, contingent on distal and proximal forces coming together in a given moment and are thus not consistent with an exclusive focus at the individual level. This article describes the study methods, summarizes main findings, and previews the detailed results presented in the other articles in this issue.
Rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) is common in patients with RA and leads to significant morbidity and mortality. No randomized, placebo-controlled data are ...available that support the role of immunosuppression to treat RA-associated ILD, despite being widely used in clinical practice.
How does immunosuppression impact pulmonary function trajectory in a multisite retrospective cohort of patients with RA-associated ILD?
Patients with RA who started treatment for ILD with mycophenolate, azathioprine, or rituximab were identified retrospectively from five ILD centers. Change in lung function before and after treatment was analyzed using a linear spline mixed-effect model with random intercept. Prespecified secondary analyses examined the impact of radiologic pattern of ILD (ie, usual interstitial pneumonia UIP vs non-UIP) on treatment trajectory.
Two hundred twelve patients were included in the analysis: 92 patients (43.4%) were treated with azathioprine, 77 patients (36.3%) were treated with mycophenolate mofetil, and 43 patients (20.3%) were treated with rituximab. In the combined analysis of all three agents, an improvement in FVC % predicted was found after 12 months of treatment compared with the potential 12-month response without treatment (+3.90%; P ≤ .001; 95% CI, 1.95-5.84). Diffusing capacity of the lungs for carbon monoxide (Dlco) % predicted also improved at 12 months (+4.53%; P ≤ .001; 95% CI, 2.12-6.94). Neither the UIP pattern of ILD nor choice of immunosuppressive agent significantly impacted the pulmonary function trajectory on immunosuppression.
Immunosuppression was associated with an improved trajectory in FVC and Dlco compared with the pretreatment pulmonary function trajectory. Prospective, randomized trials are required to validate these findings.
The characteristics of intracerebral hemorrhage (ICH) may vary by ICH location because of differences in the distribution of underlying cerebral small vessel diseases. Therefore, we investigated the ...incidence, characteristics, and outcome of lobar and nonlobar ICH.
In a population-based, prospective inception cohort study of ICH, we used multiple overlapping sources of case ascertainment and follow-up to identify and validate ICH diagnoses in 2010 to 2011 in an adult population of 695 335.
There were 128 participants with first-ever primary ICH. The overall incidence of lobar ICH was similar to nonlobar ICH (9.8 95% confidence interval, 7.7-12.4 versus 8.6 95% confidence interval, 6.7-11.1 per 100 000 adults/y). At baseline, adults with lobar ICH were more likely to have preceding dementia (21% versus 5%; P=0.01), lower Glasgow Coma Scale scores (median, 13 versus 14; P=0.03), larger ICHs (median, 38 versus 11 mL; P<0.001), subarachnoid extension (57% versus 5%; P<0.001), and subdural extension (15% versus 3%; P=0.02) than those with nonlobar ICH. One-year case fatality was lower after lobar ICH than after nonlobar ICH (adjusted odds ratio for death at 1 year: lobar versus nonlobar ICH 0.21; 95% confidence interval, 0.07-0.63; P=0.006, after adjustment for known predictors of outcome). There were 4 recurrent ICHs, which occurred exclusively in survivors of lobar ICH (annual risk of recurrent ICH after lobar ICH, 11.8%; 95% confidence interval, 4.6%-28.5% versus 0% after nonlobar ICH; log-rank P=0.04).
The baseline characteristics and outcome of lobar ICH differ from other locations.
The mechanism by which TG modulates osteoclast formation and apoptosis is not clear. In this study, we showed a biphasic effect of TG on osteoclast formation and apoptosis through the regulation of ...ROS production, caspase‐3 activity, cytosolic Ca2+, and RANKL‐induced activation of NF‐κB and AP‐1 activities.
Introduction: Apoptosis and differentiation are among the consequences of changes in intracellular Ca2+ levels. In this study, we investigated the effects of the endoplasmic reticular Ca2+‐ATPase inhibitor, thapsigargin (TG), on osteoclast apoptosis and differentiation.
Materials and Methods: Both RAW264.7 cells and primary spleen cells were used to examine the effect of TG on RANKL‐induced osteoclastogenesis. To determine the action of TG on signaling pathways, we used reporter gene assays for NF‐κB and activator protein‐1 (AP‐1) activity, Western blotting for phospho‐extracellular signal‐related kinase (ERK), and fluorescent probes to measure changes in levels of intracellular calcium and reactive oxygen species (ROS). To assess rates of apoptosis, we measured changes in annexin staining, caspase‐3 activity, and chromatin and F‐actin microfilament structure.
Results: At concentrations that caused a rapid rise in intracellular Ca2+, TG increased caspase‐3 activity and promoted apoptosis in osteoclast‐like cells (OLCs). Low concentrations of TG, which were insufficient to measurably alter intracellular Ca2+, unexpectedly suppressed caspase‐3 activity and enhanced RANKL‐induced osteoclastogenesis. At these lower concentrations, TG potentiated ROS production and RANKL‐induced NF‐κB activity, but suppressed RANKL‐induced AP‐1 activity and had little effect on ERK phosphorylation.
Conclusion: Our novel findings of a biphasic effect of TG are incompletely explained by our current understanding of TG action, but raise the possibility that low intensity or local changes in subcellular Ca2+ levels may regulate intracellular differentiation signaling. The extent of cross‐talk between Ca2+ and RANKL‐mediated intracellular signaling pathways might be important in determining whether cells undergo apoptosis or differentiate into OLCs.
MK-1064 was recently disclosed as a selective orexin 2 receptor antagonist (2-SORA) possessing a profile commensurate with clinical investigation for the treatment of insomnia. Two issues arose ...during preclinical profiling of MK-1064: stability in low pH media and moderate TDI of CYP3A4. A mechanistic hypothesis for low pH hydrolysis initially drove compound design and optimization of A, B, and C rings of MK-1064 resulted in the amelioration of both issues and the discovery of MK-3697.
Orexin receptor antagonists have demonstrated clinical utility for the treatment of insomnia. The majority of clinical efforts to date have focused on the development of dual orexin receptor antagonists (DORAs), small molecules that antagonize both the orexin 1 and orexin 2 receptors. Our group has recently disclosed medicinal chemistry efforts to identify highly potent, orally bioavailable selective orexin 2 receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the ‘triaryl’ amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4. These studies resulted in the discovery of 2,5-disubstituted isonicotinamide 2-SORAs such as compound 24 that demonstrated improved stability and TDI profiles as well as excellent sleep efficacy across species.
PURPOSE Preclinical studies indicate that metronomic chemotherapy is antiangiogenic and synergistic with other antiangiogenic agents. We designed a phase I/II study to evaluate the safety and ...activity of adding dalteparin and prednisone to metronomic cyclophosphamide and methotrexate in women with measurable metastatic breast cancer (MBC). PATIENTS AND METHODS Patients received daily dalteparin and oral cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP). The primary study end point was clinical benefit rate (CBR), a combination of complete response (CR), partial response (PR), and prolonged stable disease for > or = 24 weeks (pSD). Secondary end points included time to progression (TTP), duration of response, and overall survival (OS). Biomarker response to treatment was assessed by using plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptors (sVEGFRs) -1 and -2. Results Forty-one eligible patients were accrued. Sixteen (39%) had no prior chemotherapy for MBC; 15 (37%) had two or more chemotherapy regimens for MBC. Toxicities were minimal except for transient grade 3 elevation of liver transaminases in 11 patients (27%) and grade 3 vomiting in one patient (2%). One patient (2%) had CR, six (15%) had PR, and three (7%) had pSD, for a CBR of 10 (24%) of 41 patients. Median TTP was 10 weeks (95% CI, 8 to 17 weeks), and median OS was 48 weeks (95% CI, 32 to 79 weeks). VEGF levels decreased but not significantly, whereas sVEGFR-1 and -2 levels increased significantly after 2 weeks of therapy. There was no correlation between response and VEGF, sVEGFR-1, or sVEGFR-2 levels. CONCLUSION Metronomic dalCMP is safe, well tolerated, and clinically active in MBC.
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