Genetic loci regulate Sarbecovirus pathogenesis: A comparison across mice and humans

Coronavirus (CoV) cause considerable morbidity and mortality in humans and other mammals, as evidenced by the emergence of Severe Acute Respiratory CoV (SARS-CoV) in 2003, Middle East Respiratory CoV (MERS-CoV) in 2012, and SARS-CoV-2 in 2019. Although poorly characterized, natural genetic variation in human and other mammals modulate virus pathogenesis, as reflected by the spectrum of clinical outcomes ranging from asymptomatic infections to lethal disease. Using multiple human epidemic and zoonotic Sarbecoviruses, coupled with murine Collaborative Cross genetic reference populations, we identify several dozen quantitative trait loci that regulate SARS-like group-2B CoV pathogenesis and replication. Under a Chr4 QTL, we deleted a candidate interferon stimulated gene, Trim14 which resulted in enhanced SARS-CoV titers and clinical disease, suggesting an antiviral role during infection. Importantly, about 60 % of the murine QTL encode susceptibility genes identified as priority candidates from human genome-wide association studies (GWAS) studies after SARS-CoV-2 infection, suggesting that similar selective forces have targeted analogous genes and pathways to regulate Sarbecovirus disease across diverse mammalian hosts. These studies provide an experimental platform in rodents to investigate the molecular-genetic mechanisms by which potential cross mammalian susceptibility loci and genes regulate type-specific and cross-SARS-like group 2B CoV replication, immunity, and pathogenesis in rodent models. Our study also provides a paradigm for identifying susceptibility loci for other highly heterogeneous and virulent viruses that sporadically emerge from zoonotic reservoirs to plague human and animal populations

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Yield of irrigated cool-season grasses in southwestern Kansas

Nine varieties and a commercial mix of perennial cool-season grasses were planted in four replicated plots in two counties in southwestern Kansas to evaluate yield and adaptability when produced under irrigation. The varieties were smooth bromegrass, ‘Slate’ intermediate and ‘Hycrest’ crested wheatgrass, ‘Kentucky 31’ and ‘Max-Q®’ tall fescue, ‘Profile’ orchardgrass, ‘Hykor’ festulolium, and ‘Dixon®’ and ‘Lakota®’ matua grass. The mix was Sharp Brothers’ ‘Pasture Mix #6®’, a blend of smooth bromegrass, ‘Regar’ meadow bromegrass, Slate, Profile, and ‘Garrison’ creeping foxtail. Grasses were planted in September 2002. Forage samples were collected in the spring and fall of 2003 and 2004 to measure dry matter content and yield. Fall 2003 samples were not collected at Stevens County because calves grazed them. The greatest grazing preference was for orchardgrass. The least preferred was crested wheatgrass. Spring cuttings yielded less forage than expected in Ford County in 2004 and in Stevens in both years due to dry winters and higher than normal spring temperatures in 2004. Annual dry matter yields ranged from 10,565 to 13,694 lb per acre in Ford County during 2003, 5661 to 9032 lb per acre in Ford in 2004, and 6189 to 14,552 lb per acre in Stevens County in 2004. The consistently highest-producing grasses for both years were the fescues, intermediate wheatgrass, orchardgrass, and the pasture mix. The matuas had high yields in Ford County during 2003, but winter kill reduced the other spring yields. However, new grass plants from a high 2003 and 2004 seed production improved fall 2004 matua yields. The overall lowest-producing grass was crested wheatgrass

AbiEi binds cooperatively to the Type IV abiE toxin-antitoxin operator via a positively-charged surface and causes DNA bending and negative autoregulation

Bacteria resist phage infection using multiple strategies, including CRISPR-Cas and abortive infection (Abi) systems. Abi systems provide population-level protection from phage predation, via “altruistic” cell suicide. It has recently been shown that some Abi systems function via a toxin-antitoxin (TA) mechanism, such as the widespread AbiE family. The Streptococcus agalactiae AbiE system consists of a bicistronic operon encoding the AbiEi antitoxin and AbiEii toxin, which function as a Type IV TA system. Here we examine the AbiEi antitoxin, which belongs to a large family of transcriptional regulators with a conserved N-terminal winged-helix-turn-helix (wHTH) domain. This wHTH is essential for transcriptional repression of the abiE operon. The function of the AbiEi C-terminal domain (CTD) is poorly characterised, but it contributes to transcriptional repression and is sufficient for toxin neutralization. We demonstrate that a conserved charged surface on one face of the CTD assists sequence-specific DNA binding and negative autoregulation, without influencing antitoxicity. Furthermore, AbiEi binds cooperatively to two inverted repeats within the abiE promoter and bends the DNA by 72°. These findings demonstrate the mechanism of DNA binding by the widespread family of AbiEi antitoxins and transcriptional regulators can contribute to negative autoregulation

Intimate partner violence among HIV-positive persons in an urban clinic

While the intersection of HIV/AIDS and intimate partner violence (IPV) has gained increased attention, little focus has been given to the relationship among minority men and men who have sex with men (MSM). This pilot study, conducted at an urban clinic, explores the IPV experiences of HIV-positive persons involved in both heterosexual and homosexual relationships. Fifty-six HIV-positive individuals were interviewed to assess for verbal, physical, and sexual IPV, and for HIV-related abuse and attitudes regarding routine IPV screening. Approximately three quarters (73%) of the sample reported lifetime IPV and 20% reported current abuse. Physical IPV (85%) was cited the most by abused participants. IPV rates were highest among African-Americans and MSM. More than one-fourth (29%) of those abused felt the abuse was related to their HIV status. A majority of participants favored IPV screening by providers, but felt it might increase risk of IPV. IPV and its association to HIV are significant issues among this sample. Findings support the need for developing new programs that address these epidemics simultaneously. © 2010 Taylor & Francis