The Interplay between the Host Receptor and Influenza Virus Hemagglutinin and Neuraminidase

The hemagglutinin (HA) and neuraminidase (NA) glycoproteins of influenza A virus are responsible for the surface interactions of the virion with the host. Entry of the virus is mediated by functions of the HA: binding to cellular receptors and facilitating fusion of the virion membrane with the endosomal membrane. The HA structure contains receptor binding sites in the globular membrane distal head domains of the trimer, and the fusion machinery resides in the stem region. These sites have specific characteristics associated with subtype and host, and the differences often define species barriers. For example, avian viruses preferentially recognize α2,3-Sialic acid terminating glycans as receptors and mammalian viruses recognize α2,6-Sialic acid. The neuraminidase, or the receptor-destroying protein, cleaves the sialic acid from cellular membrane constituents and viral glycoproteins allowing for egress of nascent virions. A functional balance of activity has been demonstrated between the two glycoproteins, resulting in an optimum level of HA affinity and NA enzymatic cleavage to allow for productive infection. As more is understood about both HA and NA, the relevance for functional balance between HA and NA continues to expand, with potential implications for interspecies transmission, host adaptation, and pathogenicity

Extensions of group retractions

In this paper a condition, which is necessary and sufficient, is determined when a retraction of a subgroup H of a torsion-free group G can be extended to a retraction of G. It is also shown that each retraction of a torsion-free abelian group can be uniquely extended to a retraction of its divisible closure

Src kinase participates in LPS-induced activation of NADPH oxidase

The production of superoxide from NADPH oxidase by macrophages in response to endotoxin (LPS) is an important innate immune response, yet it is not clear how LPS signals the activation of NADPH oxidase. The hypothesis is that LPS-induced src kinase and PI3 kinase (PI3K) facilitates the activation of p47phox, the regulatory subunit of NADPH oxidase. In mouse macrophage RAW264.7 cells, inhibition of src tyrosine family kinases inhibited LPS-induced activation of NADPH oxidase, phosphorylation of p47phox, activation of PI3K and phosphorylation of the TLR4. Moreover, inhibition of LPS-induced increases in intracellular calcium blunted src kinase activation, PI3K association with TLR4, as well as PI3 kinase activation. These data suggest that both src kinase and PI3 kinase are involved in LPS-induced NADPH oxidase activation. Importantly, these data suggest that LPS-induced src kinase activation is critical for PI3 kinase activation as well as TLR4 phosphorylation and is dependent upon LPS-induced increase in intracellular calcium. These signaling events fill critical gaps in our understanding of LPS-induced free radical production as well as may potentially responsible for the mechanism of innate immune tolerance or desensitization caused by steroids or ethanol

Improving Depression Among HIV-Infected Adults: Transporting the Effect of a Depression Treatment Intervention to Routine Care

Depression affects 20-30% of people with HIV. Randomized controlled trials (RCTs) have demonstrated the effectiveness of interventions to improve depression among HIV-infected adults, but typically have highly selected populations which may limit generalizability. Inverse probability of sampling weights (IPSW) are a recently proposed method to transport (or standardize) findings from RCTs to a specific external target population

HIV primary care providers—Screening, knowledge, attitudes and behaviors related to alcohol interventions

Alcohol has particularly harmful health effects in HIV-infected patients; therefore, HIV clinics are an important setting for integration of brief alcohol intervention and alcohol pharmacotherapy to improve patient outcomes. Current practices of alcohol screening, counseling, and prescription of pharmacotherapy by HIV providers are unknown

Phylogenomics reveals the history of host use in mosquitoes

Mosquitoes have profoundly affected human history and continue to threaten human health through the transmission of a diverse array of pathogens. The phylogeny of mosquitoes has remained poorly characterized due to difficulty in taxonomic sampling and limited availability of genomic data beyond the most important vector species. Here, we used phylogenomic analysis of 709 single copy ortholog groups from 256 mosquito species to produce a strongly supported phylogeny that resolves the position of the major disease vector species and the major mosquito lineages. Our analyses support an origin of mosquitoes in the early Triassic (217 MYA [highest posterior density region: 188–250 MYA]), considerably older than previous estimates. Moreover, we utilize an extensive database of host associations for mosquitoes to show that mosquitoes have shifted to feeding upon the blood of mammals numerous times, and that mosquito diversification and host-use patterns within major lineages appear to coincide in earth history both with major continental drift events and with the diversification of vertebrate classes. © 2023, Springer Nature Limited

Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans

INTRODUCTION: African Americans' (AAs) late-onset Alzheimer's disease (LOAD) genetic risk profile is incompletely understood. Including clinical covariates in genetic analyses using informed conditioning might improve study power. METHODS: We conducted a genome-wide association study (GWAS) in AAs employing informed conditioning in 1825 LOAD cases and 3784 cognitively normal controls. We derived a posterior liability conditioned on age, sex, diabetes status, current smoking status, educational attainment, and affection status, with parameters informed by external prevalence information. We assessed association between the posterior liability and a genome-wide set of single-nucleotide polymorphisms (SNPs), controlling for APOE and ABCA7, identified previously in a LOAD GWAS of AAs. RESULTS: Two SNPs at novel loci, rs112404845 (P = 3.8 × 10-8), upstream of COBL, and rs16961023 (P = 4.6 × 10-8), downstream of SLC10A2, obtained genome-wide significant evidence of association with the posterior liability. DISCUSSION: An informed conditioning approach can detect LOAD genetic associations in AAs not identified by traditional GWAS

The oral microbiome and breast cancer and nonmalignant breast disease, and its relationship with the fecal microbiome in the Ghana Breast Health Study

The oral microbiome, like the fecal microbiome, may be related to breast cancer risk. Therefore, we investigated whether the oral microbiome was associated with breast cancer and nonmalignant breast disease, and its relationship with the fecal microbiome in a case-control study in Ghana. A total of 881 women were included (369 breast cancers, 93 nonmalignant cases and 419 population-based controls). The V4 region of the 16S rRNA gene was sequenced from oral and fecal samples. Alpha-diversity (observed amplicon sequence variants [ASVs], Shannon index and Faiths Phylogenetic Diversity) and beta-diversity (Bray-Curtis, Jaccard and weighted and unweighted UniFrac) metrics were computed. MiRKAT and logistic regression models were used to investigate the case-control associations. Oral sample alpha-diversity was inversely associated with breast cancer and nonmalignant breast disease with odds ratios (95% CIs) per every 10 observed ASVs of 0.86 (0.83-0.89) and 0.79 (0.73-0.85), respectively, compared to controls. Beta-diversity was also associated with breast cancer and nonmalignant breast disease compared to controls (P ≤ .001). The relative abundances of Porphyromonas and Fusobacterium were lower for breast cancer cases compared to controls. Alpha-diversity and presence/relative abundance of specific genera from the oral and fecal microbiome were strongly correlated among breast cancer cases, but weakly correlated among controls. Particularly, the relative abundance of oral Porphyromonas was strongly, inversely correlated with fecal Bacteroides among breast cancer cases (r = -.37, P ≤ .001). Many oral microbial metrics were strongly associated with breast cancer and nonmalignant breast disease, and strongly correlated with fecal microbiome among breast cancer cases, but not controls