Belclare and Cambridge are prolific sheep breeds, the origins of which involved selecting ewes with exceptionally high litter size records from commercial flocks. The variation in ovulation rate in both breeds is consistent with segregation of a gene (or genes) with a large effect on this trait. Sterile ewes, due to a failure of normal ovarian follicle development, occur in both breeds. New naturally occurring mutations in genes for the oocyte-derived growth factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are described. These mutations are associated with increased ovulation rate in heterozygous carriers and sterility in homozygous carriers in both breeds. This is the first time that a mutation in the gene for GDF9 has been found that causes increased ovulation rate and infertility in a manner similar to inactivating mutations in BMP15, and shows that GDF9 is essential for normal folliculogenesis in sheep. Furthermore, it is shown, for the first time in any species, that individuals with mutations in both GDF9 and BMP15 have a greater ovulation rate than sheep with either of the mutations separately.

Background There have been limited data regarding the clinical impact of COVID-19 disease on people with HIV (PWH). In this study we compared outcomes for PWH with COVID-19 disease to a matched comparison group. Design We identified 88 PWH hospitalized with laboratory confirmed COVID-19 in our hospital system in New York between March 12 and April 23, 2020. We collected data on baseline clinical characteristics, laboratory values, HIV infection status, COVID-19 treatment, and outcomes from this group and matched comparators (one PWH to up to five patients by age, sex, race/ethnicity and calendar week of infection). We compared baseline clinical characteristics and outcomes (death, mechanical ventilation, hospital discharge) for these two groups, as well as cumulative incidence of death by HIV status. Results Patients did not differ significantly by HIV status by age, sex or race/ethnicity due to the matching algorithm. PWH hospitalized with COVID-19 had high proportions of HIV virologic control on antiretroviral therapy. PWH had greater proportions of smoking (p<0.001) and comorbid illness than demographically similar uninfected comparators. There was no difference in COVID-19 severity on admission by HIV status (p=0.15). Poor outcomes for hospitalized PWH were frequent but similar to proportions in comparators; 18% required mechanical ventilation and ultimately 21% died during follow-up (compared with 23% and 20% respectively). There was similar cumulative incidence of death over time by HIV status (p=0.94). Interpretation We found no differences in adverse outcomes associated with HIV infection for hospitalized COVID-19 patients compared to a demographically similar patient group.

We have used exons 2 and 3 of the rat a-tropomyosin gene to analyze the basis of mutually exclusive exon selection. The basis of the strict mutually exclusive behavior of this exon pair is enforced by the proximity of the exon 3 branchpoint to the 5' splice site of exon 2. With the exception of smooth muscle cells, exon 3 rather than exon 2 is incorporated into mRNA in all cell types. We show here, using both in vivo and in vitro cell-free systems, that this alternative exon selection is a consequence of general principles that govern 3' splice site selection. In the absence of exon 3, exon 2 is utilized efficiently in all cells. Selection of exon 3 is therefore the default result of a competition between exons 2 and 3 for the flanking constitutive splice sites. The basis of this competition is the relative strength of the polypyrimidine tract/branchpoint elements of the two exons. The major determinant of this splice site strength is the pyrimidine content adjacent to the branchpoint, and this involves no other sequence specificity. The branchpoint elements play an important but secondary role. The functional strengths of the different polypyrimidine tract/branchpoint combinations, as determined in cis competition assays, showed a perfect correlation with their binding affinities to a spliceosome component that interacts with the pre-mRNA in an ATP-independent manner. Selection of exon 3 in most cell types therefore reflects the preferential interaction of these splice site elements with constitutive splicing factors early in spliceosome assembly. The aspects of splice site selection analyzed here are likely to be of general applicability to constitutive and alternative pre-mRNA splicing.[Key Words: Rat c~-tropomyosin gene; exon selection; branchpoint polypyrimidine tracts; splice site selection] Received December 10, 1990; revised version accepted February 1, 1991.One of the major unresolved issues conceming premRNA splicing is the problem of splice site selection. Most eukaryotic genes possess multiple intervening sequences, or introns, each bounded by a pair of functional 5' and 3' splice sites. The open reading frame of the mature mRNA is preserved by the accurate excision of these introns from the primary transcript. Potentially, splice sites could pair in many different combinations disruptive to message integrity. That this does not occur to any great extent is testimony to the high fidelity of the splicing process. The role of limited consensus sequences at the ends of introns in specifying splice sites has long been recognized [Mount 1982). These elements include the practically invariant GU and AG dinucleotides at the 5' and 3' splice sites, respectively, the 5' splice site consensus sequence that base-pairs with U1 snRNA [Zhuang and Weiner 1986), the branchpoint consensus sequence that base-pairs with U2 snRNA {Parker et al. 1987; Wu and Manley 1989;, and the polypyrimidine tract between the branchpoint and the 3' splice site AG. However, comparisons of primary sequences have yet to produce a set of ...

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We performed a retrospective study of Covid-19 in people with HIV (PWH). PWH with Covid-19 demonstrated severe lymphopenia and decreased CD4+ T cell counts. Levels of inflammatory markers, including C-reactive protein, fibrinogen, D-dimer, interleukin-6, interleukin-8, and TNF-alpha were commonly elevated. In all, 19/72 hospitalized individuals (26.4%) died and 53 (73.6%) recovered. PWH who died had higher levels of inflammatory markers and more severe lymphopenia than those who recovered. These findings suggest that PWH remain at risk for severe manifestations of Covid-19 despite ART and that those with increased markers of inflammation and immune dysregulation are at risk for worse outcomes.

We describe 2 cases in which the prolonged use of linezolid to treat complicated methicillin-resistant Staphylococcus aureus infections was followed by acutely developed blurred vision and progressive loss of vision and color perception during the ensuing few weeks. Both patients received a diagnosis of toxic optic neuropathy, and linezolid therapy was stopped. The patients experienced an initial rapid partial improvement and a subsequent gradual, almost complete, recovery over many months.

Uterine secretions, or histotroph, are a critical component for early embryo survival, functioning as the sole supply of vitamins, minerals, enzymes, and other myriad of nutrients required by the developing conceptus before implantation. Histotroph is therefore a promising source for biomarkers of uterine function and for enhancing our understanding of the environment supporting early embryo development and survival. Utilizing label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) shotgun proteomics, we characterized the uterine proteome at two key preimplantation stages of the estrous cycle in high fertility cattle. We identified 300 proteins on Day 7 and 510 proteins on Day 13 including 281 proteins shared between days. Five proteins were more abundant (P < 0.05) on Day 7 compared with Day 13 and included novel histotroph proteins cytokeratin 10 and stathmin. Twenty-nine proteins were more abundant (P < 0.05) including 13 unique on Day 13 compared with Day 7 and included previously identified legumain, metalloprotease inhibitor-2, and novel histotroph proteins chromogranin A and pyridoxal kinase. Functional analysis of the 34 differentially expressed proteins (including 14 novel to histotroph) revealed distinct biological roles putatively involved in early pregnancy, including remodelling of the uterine environment in preparation for implantation; nutrient metabolism; embryo growth, development and protection; maintenance of uterine health; and maternal immune modulation. This study is the first reported LC-MS/MS based global proteomic characterization of the uterine environment in any domesticated species before implantation and provides novel information on the temporal alterations in histotroph composition during critical stages for early embryo development and uterine function during the early establishment of pregnancy.

Outbreaks of acute hepatitis C virus (HCV) infection are occurring in HIV-infected men who have sex with men. We evaluated risk factors and liver histopathology in 11 consecutively enrolled men with newly acquired HCV infection that was diagnosed on the basis of antibody seroconversion, new elevations in alanine aminotransferase level, and wide fluctuations in HCV RNA level. Ten patients reported unprotected anal intercourse, and 7 reported “club-drug” use, including methamphetamine. Liver biopsy showed moderately advanced fibrosis (Scheuer stage 2) in 9 patients (82%). No cause of liver damage other than acute HCV infection was identified. The specific pathways leading to periportal fibrosis in HIV-infected men with newly acquired HCV infection require investigation.