h Griffithsin (GRFT) is a red-alga-derived lectin that binds the terminal mannose residues of N-linked glycans found on the surface of human immunodeficiency virus type 1 (HIV-1), HIV-2, and other enveloped viruses, including hepatitis C virus (HCV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Ebola virus. GRFT displays no human T-cell mitogenic activity and does not induce production of proinflammatory cytokines in treated human cell lines. However, despite the growing evidence showing the broad-spectrum nanomolar or better antiviral activity of GRFT, no study has reported a comprehensive assessment of GRFT safety as a potential systemic antiviral treatment. The results presented in this work show that minimal toxicity was induced by a range of single and repeated daily subcutaneous doses of GRFT in two rodent species, although we noted treatment-associated increases in spleen and liver mass suggestive of an antidrug immune response. The drug is systemically distributed, accumulating to high levels in the serum and plasma after subcutaneous delivery. Further, we showed that serum from GRFT-treated animals retained antiviral activity against HIV-1-enveloped pseudoviruses in a cell-based neutralization assay. Overall, our data presented here show that GRFT accumulates to relevant therapeutic concentrations which are tolerated with minimal toxicity. These studies support further development of GRFT as a systemic antiviral therapeutic agent against enveloped viruses, although deimmunizing the molecule may be necessary if it is to be used in long-term treatment of chronic viral infections.

Intracellular proteins with a carboxy-terminal transmembrane domain and the amino-terminus oriented toward the cytosol are known as 'tail-anchored' proteins. Tailanchored proteins have been of considerable interest because several important classes of proteins, including the vesicle-targeting/fusion proteins known as SNAREs and the apoptosis-related proteins of the Bcl-2 family, among others, utilize this unique membrane-anchoring motif. Here, we use a bioinformatic technique to develop a comprehensive list of potentially tail-anchored proteins in the human genome. Our final list contains 411 entries derived from 325 unique genes. We also analyzed both known and predicted tail-anchored proteins with respect to the amino acid composition of the transmembrane segments. This analysis revealed a distinctive composition of the membrane anchor in SNARE proteins.

Potentially modifiable factors to improve employment are earlier referral and better education regarding Medicare eligibility.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory condition. Primary HLH occurs early in life due to monogenic biallelic mutations affecting lymphocyte cytotoxicity. Secondary HLH occurs mostly in adults secondary to infections, lymphoma or rheumatic diseases. In this latter setting, lymphocyte cytotoxicity status is not known. We conducted a systematic evaluation of NK cell cytotoxicity in adult patients with secondary HLH. Adult patients with secondary HLH were prospectively studied ex vivo for total lymphocyte count and subtypes, NK cell phenotype, perforin expression and degranulation, natural or ADCC cytotoxicity, in comparison with patients affected by the same underlying diseases without HLH (disease controls, DC) and with healthy controls (HC). Screening for variants of cytotoxity genes was systematically performed. 68 patients were included in the HLH group, 34 in the DC and HC groups, respectively. In HLH patients, a severe and transient lymphopenia, an activated NK cell phenotype (increased CD69, ICAM-1, HLADR, CCR5 expression) and a decreased capacity of interferon gamma production were observed. Mean perforin expression was normal, degranulation tests and NK cell cytotoxicity were not different from DC. A monoallelic variant of uncertain significance affecting one of the lymphocyte cytotoxicity genes, or the perforin variant A91V, was observed in almost 50% of the patients. We detected no major intrinsic cytotoxicity dysfunction in secondary HLH compared to DC and no predicted pathogenic gene variant. The activated NK phenotype profile associated with decreased interferon gamma production appear similar to other hyperinflammatory diseases such as sepsis or systemic juvenile idiopathic arthritis.

Background The cause of progressive supranuclear palsy (PSP) is largely unknown. Based on evidence for impaired mitochondrial activity in PSP, we hypothesized that the disease may be related to exposure to environmental toxins, some of which are mitochondrial inhibitors. Methods This multicenter case-control study included 284 incident PSP cases out of 350 cases and 284 age-, sex- and race-matched controls primarily from the same geographical areas. All subjects were administered standardized interviews to obtain data on demographics, residential history and lifetime occupational history. An industrial hygienist and a toxicologist unaware of case status assessed occupational histories to estimate past exposure to metals, pesticides, organic solvents and other chemicals. Findings Cases and controls were similar on demographic factors. In unadjusted analyses, PSP was associated with lower education, lower income, more smoking pack-years, more years of drinking well water, more years living on a farm, more years living one mile from an agricultural region, more transportation jobs, and more jobs with exposure to metals in general. However, in adjusted models, only more years of drinking well water was significantly associated with PSP. There was an inverse association with having a college degree. Interpretation We did not find evidence for a specific causative chemical exposure; higher number of years of drinking well water is a risk factor for PSP. This result remained significant after adjusting for income, smoking, education and occupational exposures. This is the first case-control study to demonstrate PSP is associated with environmental factors. Funding US National Institutes of Health 5R01AG024040.