The rockefeller university

'Poor responders' is a term used to describe a subpopulation of IVF patients who do not respond well to ovarian stimulation with gonadotrophins. While there is no standard definition of a poor responder, these patients tend to be of advanced maternal age (>= 40 years), have a history of poor ovarian response with conventional stimulation protocols, and/or have low ovarian reserve. Despite the heterogeneity of this patient group, there are characteristics and needs common to many poor responders that can be addressed through a holistic approach. Stimulation during the earlier stages of follicle maturation may help synchronize follicle development for improved response to later gonadotrophin stimulation, and supplementation with dehydroepiandrosterone or human growth hormone may promote early follicle development in poor responders. IVF protocols should be specifically tailored to poor responders to complement the patient's natural cycle. Because poor responders tend to have high levels of stress and anxiety, patients should receive psychological counselling and support, both prior to and during IVF cycles, to ensure optimal outcomes and improve patients' experience. It is important to set realistic expectations with poor responders and their partners to help patients make informed decisions and better manage their distress and anxiety. (c) 2017 Published by Elsevier Ltd on behalf of Reproductive Healthcare Ltd.

Colloidal suspensions transform between fluid and disordered solid states as parameters such as the colloid volume fraction and the strength and nature of the colloidal interactions are varied. Seemingly subtle changes in the characteristics of the colloids can markedly alter the mechanical rigidity and flow behavior of these soft composite materials. This sensitivity creates both a scientific challenge and an opportunity for designing suspensions for specific applications. In this paper, we report a novel mechanism of gel formation in mixtures of weakly attractive nanocolloids with modest size ratio. Employing a combination of x-ray photon correlation spectroscopy, rheometry, and molecular dynamics simulations, we find that gels are stable at remarkably weaker attraction in mixtures with size ratio near two than in the corresponding monodisperse suspensions. In contrast with depletion-driven gelation at larger size ratio, gel formation in the mixtures is triggered by microphase demixing of the species into dense regions of immobile smaller colloids surrounded by clusters of mobile larger colloids that is not predicted by mean-field thermodynamic considerations. These results point to a new route for tailoring nanostructured colloidal solids through judicious combination of interparticle interaction and size distribution. Published by AIP Publishing.

In fibrolamellar hepatocellular carcinoma a single genetic deletion results in the fusion of the first exon of the heat shock protein 40, DNAJB1, which encodes the J domain, with exons 2-10 of the catalytic subunit of protein kinase A, PRKACA. This produces an enzymatically active chimeric protein J-PKAca. We used molecular dynamics simulations and NMR to analyze the conformational landscape of native and chimeric kinase, and found an ensemble of conformations. These ranged from having the J-domain tucked under the large lobe of the kinase, similar to what was reported in the crystal structure, to others where the J-domain was dislodged from the core of the kinase and swinging free in solution. These simulated dislodged states were experimentally captured by NMR. Modeling of the different conformations revealed no obvious steric interactions of the J-domain with the rest of the RII beta holoenzyme.

Mutations in CDCA7, the SNF2 family protein HELLS (LSH), or the DNA methyltransferase DNMT3b cause immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome. While it has been speculated that DNA methylation defects cause this disease, little is known about the molecular function of CDCA7 and its functional relationship to HELLS and DNMT3b. Systematic analysis of how the cell cycle, H3K9 methylation, and the mitotic kinase Aurora B affect proteomic profiles of chromatin in Xenopus egg extracts revealed that HELLS and CDCA7 form a stoichiometric complex on chromatin, in a manner sensitive to Aurora B. Although HELLS alone fails to remodel nucleosomes, we demonstrate that the HELLS-CDCA7 complex possesses nucleosome remodeling activity. Furthermore, CDCA7 is essential for loading HELLS onto chromatin, and CDCA7 harboring patient ICF mutations fails to recruit the complex to chromatin. Together, our study identifies a unique bipartite nucleosome remodeling complex where the functional remodeling activity is split between two proteins and thus delineates the defective pathway in ICF syndrome.

Human immunodeficiency virus type 1 (HIV-1) particle assembly requires several protein: RNA interactions that vary widely in their character, from specific recognition of highly conserved and structured viral RNA elements to less specific interactions with variable RNA sequences. Genetic, biochemical, biophysical, and structural studies have illuminated how virion morphogenesis is accompanied by dramatic changes in the interactions among the protein and RNA virion components. The 5' leader RNA element drives RNA recognition by Gag upon initiation of HIV-1 assembly and can assume variable conformations that influence translation, dimerization, and Gag recognition. As Gag multimerizes on the plasma membrane, forming immature particles, its RNA binding specificity transiently changes, enabling recognition of the A-rich composition of the viral genome. Initiation of assembly may also be regulated by occlusion of the membrane binding surface of Gag by tRNA. Finally, recent work has suggested that RNA interactions with viral enzymes may activate and ensure the accuracy of virion maturation.

Protein-protein interactions mediate essential cellular processes, however the detection of native interactions is challenging since they are often low affinity and context dependent. Here, we develop a chemical proteomics approach in vivo CLASPI [iCLASPI] (in vivo crosslinking-assisted and stable isotope labeling by amino acids in cell culture [SILAC]-based protein identification) relying upon photo-crosslinking, amber suppression, and SILAC-based quantitative proteomics to profile context-dependent protein-protein interactions in living cells. First, we use iCLASPI to profile in vivo binding partners of the N-terminal tails of soluble histone H3 or H4. We identify known histone chaperones and modifying proteins, thereby validating our approach, and find an interaction between soluble histone H3 and UBR7, an E3 ubiquitin ligase, mediated by UBR7's PHD domain. Furthermore, we apply iCLASPI to profile the context-dependent protein-protein interactions of chromatin-associated histone H3 at different cell-cycle stages, and identify ANP32A as a mitosis-specific interactor. Our results demonstrate that the iCLASPI approach can provide a general strategy for identifying native, context-dependent direct protein-protein interactions using photo-crosslinking and quantitative proteomics.

This article examines some of the assumptions and implications associated with the Belmont era context in which the concept of therapeutic misconception was forged. We argue that the justification of therapeutic misconception should be reconsidered based on less paternalistic and more participatory models of research. Finally, we identify conceptual and practical approaches that might better reflect contemporary research practice.

Since the 1990s, the International Union of Immunological Societies (IUIS) PID expert committee (EC), now called Inborn Errors of Immunity Committee, has published every other year a classification of the inborn errors of immunity. This complete catalog serves as a reference for immunologists and researchers worldwide. However, it was unadapted for clinicians at the bedside. For those, the IUIS PID EC is now publishing a phenotypical classification since 2013, which proved to be more user-friendly. There are now 320 single-gene inborn errors of immunity underlying phenotypes as diverse as infection, malignancy, allergy, auto-immunity, and auto-inflammation. We herein propose the revised 2017 phenotypic classification, based on the accompanying 2017 IUIS Inborn Errors of Immunity Committee classification.

Background: Improvements in oocyte cryopreservation techniques and establishment of cryopreserved donor oocyte banks have led to improved access to and lower cost of donor oocytes, upending the traditional practice of fresh oocyte donation. The objective of this study was to examine national trends in utilization and live birth rates with fresh versus cryopreserved donor oocytes. Methods: A retrospective analysis of 2013 through 2015 aggregate U.S. national data reported by the Society for Assisted Reproductive Technology which included 30,160 IVF cycles with either fresh or cryopreserved donor oocytes was performed. Results: During the study period utilization of fresh oocyte donations rapidly declined by 32.9%, while cryopreserved oocyte donation increased by 44.4%. Fresh donor oocytes produced significantly higher live birth rates per recipient cycle start than cryopreserved donor oocytes (51.1% vs. 39.7%). Over the three-year study period fresh donor oocytes produced stable live birth rates per recipient cycle start while those with cryopreserved oocytes significantly declined year-by-year. Conclusion: Despite rising popularity of cryopreserved donor oocytes, prospective patients should be counselled that fresh donor oocytes still represent standard of care due to higher live birth rates.