The rockefeller university

Introduction: Infertile women with severely diminished ovarian reserve who have low birth chances with in vitro fertilization (IVF) are often denied treatment with autologous oocytes. This study was designed to determine age-specific treatment efficacy and clinical characteristics of infertile women with severely diminished ovarian reserve who had live birth following IVF with autologous oocytes. Methods: This retrospective cohort study investigated 291 infertile women who underwent 482 IVF cycles with autologous oocytes during 2004 to 2016 at our academically affiliated private fertility center. All women were aged <45 years and had maximum baseline follicle-stimulating hormone (FSH) levels 20 mIU/mL. Main outcome measures included pregnancy, spontaneous abortion, and live birth rates. Patient and treatment characteristics were compared for women who achieved a live birth to those who did not. Results: Live birth rates were 8.6% per treated woman and 6% per started IVF cycle. The spontaneous abortion risk was 27% per clinical pregnancy. Age-specific live birth rates were highest at 17.2% for women <35 years and lowest at 1.9% for women >42 years. Women who achieved live birth were younger than those who did not (38.0 8.0 vs 40.0 +/- 6.0; P = .008), had lower FSH levels (25.0 +/- 20.0 vs 32.5 +/- 31.0; P = .006), and produced more oocytes (3.0 +/- 5.0 vs 1.0 +/- 2.0; P < .001), as well as transferrable embryos (2.0 +/- 2.0 vs 0.0 +/- 1.0; P < .001). Conclusion: Infertile women up to 45 years with severely diminished ovarian reserve achieve better live birth rates than previously reported and should not be denied access to IVF based on elevated FSH levels alone.

Stem cells (SCs) govern tissue homeostasis and wound repair. They reside within niches, the special microenvironments within tissues that control SC lineage outputs. Upon injury or stress, new signals emanating from damaged tissue can divert nearby cells into adopting behaviours that are not part of their homeostatic repertoire. This behaviour, known as SC plasticity, typically resolves as wounds heal. However, in cancer, it can endure. Recent studies have yielded insights into the orchestrators of maintenance and lineage commitment for SCs belonging to three mammalian tissues: the haematopoietic system, the skin epithelium and the intestinal epithelium. We delineate the multifactorial determinants and general principles underlying the remarkable facets of SC plasticity, which lend promise for regenerative medicine and cancer therapeutics.

Acquisition of mutations is central to evolution; however, the detrimental effects of most mutations on protein folding and stability limit protein evolvability. Molecular chaperones, which suppress aggregation and facilitate polypeptide folding, may alleviate the effects of destabilizing mutations thus promoting sequence diversification. To illuminate how chaperones can influence protein evolution, we examined the effect of reduced activity of the chaperone Hsp90 on poliovirus evolution. We find that Hsp90 offsets evolutionary trade-offs between protein stability and aggregation. Lower chaperone levels favor variants of reduced hydrophobicity and protein aggregation propensity but at a cost to protein stability. Notably, reducing Hsp90 activity also promotes clusters of codon-deoptimized synonymous mutations at inter-domain boundaries, likely to facilitate cotranslational domain folding. Our results reveal how a chaperone can shape the sequence landscape at both the protein and RNA levels to harmonize competing constraints posed by protein stability, aggregation propensity, and translation rate on successful protein biogenesis.

Plaque psoriasis is one of the most common autoimmune skin diseases and is characterized by erythematous, scaly plaques. Many highly effective, targeted therapies have been developed as a result of an improved understanding of the pathogenesis of psoriasis. Using agents that target the central interleukin (IL)-23/IL-17 immune axis, this once difficult-to-treat disease is now among the most effectively treated autoimmune diseases with major clinical improvements possible in around 90% of patients. In this article, we outline the immune mechanisms responsible for the development of psoriasis and provide an overview of the novel IL-23 antagonists being used to manage this chronic skin disease.

A search for resonancelike structures in the B-s(0)pi(+/-) invariant mass spectrum is performed using proton-proton collision data collected by the CMS experiment at the LHC at root s = 8 TeV, corresponding to an integrated luminosity of 19.7 fb(-1). The B-s(0) mesons are reconstructed in the decay chain B-s(0) -> J/Psi phi, with J/Psi -> mu(+) mu(-) and phi -> K+K-. The B-s(0)pi(+/-) invariant mass distribution shows no statistically significant peaks for different selection requirements on the reconstructed B-s(0) and pi(+/-) candidates. Upper limits are set on the relative production rates of the X(5568) and B-s(0) states times the branching fraction of the decay X(5568)(+/-) -> B-s(0)pi(+/-). In addition, upper limits are obtained as a function of the mass and the natural width of possible exotic states decaying into B-s(0)pi(+/-).

A search for supersymmetry (SUSY) is performed in final states comprising one or more jets and missing transverse momentum using data from proton-proton collisions at a centre-of-mass energy of 13 TeV. The data were recorded with the CMS detector at the CERN LHC in 2016 and correspond to an integrated luminosity of 35.9 fb(-1). The number of signal events is found to agree with the expected background yields from standard model processes. The results are interpreted in the context of simplified models of SUSY that assume the production of gluino or squark pairs and their prompt decay to quarks and the lightest neutralino. The masses of bottom, top, and mass-degenerate light-flavour squarks are probed up to 1050, 1000, and 1325 GeV, respectively. The gluino mass is probed up to 1900, 1650, and 1650 GeV when the gluino decays via virtual states of the aforementioned squarks. The strongest mass bounds on the neutralinos from gluino and squark decays are 1150 and 575 GeV, respectively. The search also provides sensitivity to simplified models inspired by split SUSY that involve the production and decay of long-lived gluinos. Values of the proper decay length CT0 from 10(-3) to 10(5) mm are considered, as well as a metastable gluino scenario. Gluino masses up to 1750 and 900 GeV are probed for CT0 = 1mm and for the metastable state, respectively. The sensitivity is moderately dependent on model assumptions for CT0 greater than or similar to 1 m. The search provides coverage of the CT0 parameter space for models involving long-lived gluinos that is complementary to existing techniques at the LHC.

A search for the standard model (SM) Higgs boson (H) decaying to b(b)over-bar when produced in association with an electroweak vector boson is reported for the following processes: Z(vv)H, W(mu v)H, W(ev)H, Z(mu mu)H, and Z(ee)H. The search is performed in data samples corresponding to an integrated luminosity of 35.9 f( -1) at root s = 13 TeV recorded by the CMS experiment at the LHC during Run 2 in 2016. An excess of events is observed in data compared to the expectation in the absence of a H -> b(b)over-bar, signal. The significance of this excess is 3.3 standard deviations, where the expectation from SM Higgs boson production is 2.8. The signal strength corresponding to this excess, relative to that of the SM Higgs boson production, is 1.2 +/- 0.4. When combined with the Run 1 measurement of the same processes, the signal significance is 3.8 standard deviations with 3.8 expected. The corresponding signal strength, relative to that of the SM Higgs boson, is 1.06(-0.29)(+0.31). (C) 2018 The Author(s). Published by Elsevier B.V.

Most broadly neutralizing antibodies to HIV-1 have in common an extreme degree of somatic hypermutation (SHM), which correlates with their ability to neutralize multiple viral strains. However, achieving such extreme SHM by immunization remains a challenge. Here, we discuss how antigenic variation during HIV-1 infection may work to exacerbate SHM by permitting multiple iterative cycles of affinity maturation in germinal centers, and speculate on how this could be recapitulated through vaccination.

Proteasome inhibitors are used as research tools and to treat multiple myeloma, and proteasome activity is diminished in several neurodegenerative diseases. We therefore studied how cells compensate for proteasome inhibition. In 4 h, proteasome inhibitor treatment caused dramatic and selective induction of GARA PL1 (but not other autophagy genes) and p62, which binds ubiquitinated proteins and GARA PL1 on autophagosomes. Knockdown of p62 or GARA PL1 reduced cell survival upon proteasome inhibition. p62 induction requires the transcription factor nuclear factor (erythroid-derived 2)-like 1 (Nrf1), which simultaneously induces proteasome genes. After 20-h exposure to proteasome inhibitors, cells activated autophagy and expression of most autophagy genes by an Nrf1-independent mechanism. Although p62 facilitates the association of ubiquitinated proteins with autophagosomes, its knockdown in neuroblastoma cells blocked the buildup of ubiquitin conjugates in perinuclear aggresomes and of sumoylated proteins in nuclear inclusions but did not reduce the degradation of ubiquitinated proteins. Thus, upon proteasome inhibition, cells rapidly induce p62 expression, which enhances survival primarily by sequestering ubiquitinated proteins in inclusions.