The rockefeller university

PurposeTo investigate the effects of dehydroepiandrosterone (DHEA) supplementation on female sexual function in premenopausal infertile women of advanced ages.MethodsThis observational study was conducted in an academically affiliated private fertility center. Patients included 87 premenopausal infertile women, 50 of whom completed the study including the Female Sexual Function Index (FSFI) questionnaires and comprehensive endocrine evaluation before and 4-8 weeks after initiating 25mg of oral micronized DHEA TID.ResultsAge of patients was 41.14.2 years, BMI 24.4 +/- 6.1kg/m(2), 86% were married, and 42% were parous. Following supplementation with DHEA, all serum androgen levels increased (each P<0.0001), while FSH levels decreased by 2.6 +/- 4.4 from a baseline of 10.3 +/- 5.4mIU/mL (P=0.009). The FSFI score for the whole study group increased by 7% (from 27.2 +/- 6.9 to 29.2 +/- 5.6; P=0.0166). Domain scores for desire increased by 17% (P=0.0004) and by 12% for arousal (P=0.0122); lubrication demonstrated an 8% trend towards improvement (P=0.0551), while no changes in domain scores for orgasm, satisfaction, or pain were observed. Women in the lowest starting FSFI score quartile (<25.7), experienced a 6.1 +/- 8.0 (34%) increase in total FSFI score following DHEA supplementation. Among these women, improvements in domain categories were noted for desire (40%), arousal (46%), lubrication (33%), orgasm (54%), satisfaction (24%), and pain (25%).Conclusions p id=Par4 This uncontrolled observational study implies that supplementation with DHEA improves sexual function in older premenopausal women with low baseline FSFI scores.

Zika virus (ZIKV) targets neural progenitor cells in the brain, attenuates cell proliferation, and leads to cell death. Here, we describe a role for the ZIKV protease NS2B-NS3 heterodimer in mediating neurotoxicity through cleavage of a host protein required for neurogenesis. Similar to ZIKV infection, NS2B-NS3 expression led to cytokinesis defects and cell death in a protease activity-dependent fashion. Among binding partners, NS2B-NS3 cleaved Septin-2, a cytoskeletal factor involved in cytokinesis. Cleavage of Septin-2 occurred at residue 306 and forced expression of a non-cleavable Septin-2 restored cytokinesis, suggesting a direct mechanism of ZIKV-induced neural toxicity.

In recent years, gating and transient ion-pathway formation in the light-gated channelrhodopsins (ChRs) have been intensively studied. Despite these efforts, a profound understanding of the mechanistic details is still lacking. To track structural changes concomitant with the formation and subsequent collapse of the ion-conducting pore, we site-specifically introduced the artificial polarity-sensing probe p-azido-L-phenylalanine (azF) into several ChRs by amber stop codon suppression. The frequently used optogenetic actuator ReaChR (red-activatable ChR) exhibited the best expression properties of the wild type and the azF mutants. By exploiting the unique infrared spectral absorption of azF [nu(as) (N-3) similar to 2100 cm(-1)] and its sensitivity to polarity changes, we monitored hydration changes at various sites of the pore region and the inner gate by stationary and time-resolved infrared spectroscopy. Our data imply that channel closure coincides with a dehydration event occurring between the interface of the central and the inner gate. In contrast, the extracellular ion pathway seems to be hydrated in the open and closed states to similar extents. Mutagenesis of sites in the inner gate suggests that it acts as an intracellular entry funnel, whose architecture and composition modulate water influx and efflux within the channel pore. Our results highlight the potential of genetic code expansion technology combined with biophysical methods to investigate channel gating, particularly hydration dynamics at specific sites, with a so far unprecedented spatial resolution.

In this brief review, the authors present a history of the different aspects of the scientific puzzle leading from pioneer animal studies and astute clinical experimental observations to a mature appreciation of the deleterious role of excess of a type I interferon in human pathology.

Curing HIV infection has been impossible, with the exception of the "Berlin Patient.'' Martinez-Navio et al. (2019) in Miami herein present a rare monkey whose virus was controlled for >3 years after a single genetic intervention that led to persistent production of HIV-neutralizing antibodies in vivo.

In the four decades since the first birth by in-vitro fertilisation (IVF),1 the field has been rewarded with a Nobel prize,2 seen IVF evolve from an experimental procedure into clinical routine, and witnessed a pronounced shift in treatment utilisation from intrauterine inseminations to IVF. However, many studies have shown inferior newborn outcomes with IVF by comparison with spontaneously conceived pregnancies. These observed differences in infant outcomes have been suggested to be a bystander effect, reflective of underlying phenotypes of women who needed IVF to conceive. However, in these previous studies, researchers used random-effects models, focused only on children conceived by IVF, and included children conceived by other fertility treatments in control groups of natural conceptions. These design choices could bias results by underestimating the adverse effects of IVF.

Liposarcoma is the most common soft tissue sarcoma. Molecularly targeted therapeutics have had limited efficacy in liposarcomas, in part because of inadequate knowledge of the complex molecular alterations in these tumors. Our recent study revealed the tumor suppressive function of miR-193b in liposarcoma. Considering the biological and clinical heterogeneity of liposarcoma, here, we confirmed the under-expression of miR-193b in additional patient liposarcoma samples and cell lines. Based on STRING analysis of protein-protein interactions among the reported putative miR-193b targets, we validated three: PDGFR beta, SMAD4, and YAP1, belonging to strongly interacting pathways (focal adhesion, TGF beta, and Hippo, respectively). We show that all three are directly targeted by miR-193b in liposarcoma. Inhibition of PDGFR beta reduces liposarcoma cell viability and increases adipogenesis. Knockdown of SMAD4 promotes adipogenic differentiation. miR-193b targeting of the Hippo signaling effector YAP1 indirectly inhibits Wnt/beta-catenin signaling. Both a PDGFR inhibitor (CP-673451) and a Wnt/beta-catenin inhibitor (ICG-001) had potent inhibitory effects on liposarcoma cells, suggesting their potential application in liposarcoma treatment. In summary, we demonstrate that miR-193b controls cell growth and differentiation in liposarcoma by targeting multiple key components (PDGFR beta, SMAD4, and YAP1) in several oncogenic signaling pathways.

Background Nephrotic syndrome (NS), a chronic kidney disease, is characterized by significant loss of protein in the urine causing hypoalbuminemia and edema. In general, approximate to 15% of childhood-onset cases do not respond to steroid therapy and are classified as steroid-resistant NS (SRNS). In approximate to 30% of cases with SRNS, a causative mutation can be detected in one of 44 monogenic SRNS genes. The gene LAMA5 encodes laminin-5, an essential component of the glomerular basement membrane. Mice with a hypomorphic mutation in the orthologous gene Lama5 develop proteinuria and hematuria. Methods To identify additional monogenic causes of NS, we performed whole exome sequencing in 300 families with pediatric NS. In consanguineous families we applied homozygosity mapping to identify genomic candidate loci for the underlying recessive mutation. Results In three families, in whom mutations in known NS genes were excluded, but in whom a recessive, monogenic cause of NS was strongly suspected based on pedigree information, we identified homozygous variants of unknown significance (VUS) in the gene LAMA5. While all affected individuals had nonsyndromic NS with an early onset of disease, their clinical outcome and response to immunosuppressive therapy differed notably. Conclusion We here identify recessive VUS in the gene LAMA5 in patients with partially treatment-responsive NS. More data will be needed to determine the impact of these VUS in disease management. However, familial occurrence of disease, data from genetic mapping and a mouse model that recapitulates the NS phenotypes suggest that these genetic variants may be inherited factors that contribute to the development of NS in pediatric patients.

Taylor's law (TL), a commonly observed and applied pattern in ecology, describes variances of population densities as related to mean densities via log(variance) = log(a) + b*log(mean). Variations among datasets in the slope, b, have been associated with multiple factors of central importance in ecology, including strength of competitive interactions and demographic rates. But these associations are not transparent, and the relative importance of these and other factors for TL slope variation is poorly studied. TL is thus a ubiquitously used indicator in ecology, the understanding of which is still opaque. The goal of this study was to provide tools to help fill this gap in understanding by providing proximate determinants of TL slopes, statistical quantities that are correlated to TL slopes but are simpler than the slope itself and are more readily linked to ecological factors. Using numeric simulations and 82 multi-decadal population datasets, we here propose, test and apply two proximate statistical determinants of TL slopes which we argue can become key tools for understanding the nature and ecological causes of TL slope variation. We find that measures based on population skewness, coefficient of variation and synchrony are effective proximate determinants. We demonstrate their potential for application by using them to help explain covariation in slopes of spatial and temporal TL (two common types of TL). This study provides tools for understanding TL, and demonstrates their usefulness.