A Protective Monoclonal Antibody Targets a Site of Vulnerability on the Surface of Rift Valley Fever Virus

Summary: The Gn subcomponent of the Gn-Gc assembly that envelopes the human and animal pathogen, Rift Valley fever virus (RVFV), is a primary target of the neutralizing antibody response. To better understand the molecular basis for immune recognition, we raised a class of neutralizing monoclonal antibodies (nAbs) against RVFV Gn, which exhibited protective efficacy in a mouse infection model. Structural characterization revealed that these nAbs were directed to the membrane-distal domain of RVFV Gn and likely prevented virus entry into a host cell by blocking fusogenic rearrangements of the Gn-Gc lattice. Genome sequence analysis confirmed that this region of the RVFV Gn-Gc assembly was under selective pressure and constituted a site of vulnerability on the virion surface. These data provide a blueprint for the rational design of immunotherapeutics and vaccines capable of preventing RVFV infection and a model for understanding Ab-mediated neutralization of bunyaviruses more generally. : Allen et al. reveal a molecular basis of antibody-mediated neutralization of Rift Valley fever virus, an important human and animal pathogen. They isolate and demonstrate the protective efficacy of a monoclonal antibody in a murine model of virus infection, providing a blueprint for rational therapeutic and vaccine design. Keywords: phlebovirus, Rift Valley fever virus, antibody, structure, bunyavirus, virus-host interactions, immune response, vaccine, antiviral, neutralizatio

The re-identification risk of Canadians from longitudinal demographics

<p>Abstract</p> <p>Background</p> <p>The public is less willing to allow their personal health information to be disclosed for research purposes if they do not trust researchers and how researchers manage their data. However, the public is more comfortable with their data being used for research if the risk of re-identification is low. There are few studies on the risk of re-identification of Canadians from their basic demographics, and no studies on their risk from their longitudinal data. Our objective was to estimate the risk of re-identification from the basic cross-sectional and longitudinal demographics of Canadians.</p> <p>Methods</p> <p>Uniqueness is a common measure of re-identification risk. Demographic data on a 25% random sample of the population of Montreal were analyzed to estimate population uniqueness on postal code, date of birth, and gender as well as their generalizations, for periods ranging from 1 year to 11 years.</p> <p>Results</p> <p>Almost 98% of the population was unique on full postal code, date of birth and gender: these three variables are effectively a unique identifier for Montrealers. Uniqueness increased for longitudinal data. Considerable generalization was required to reach acceptably low uniqueness levels, especially for longitudinal data. Detailed guidelines and disclosure policies on how to ensure that the re-identification risk is low are provided.</p> <p>Conclusions</p> <p>A large percentage of Montreal residents are unique on basic demographics. For non-longitudinal data sets, the three character postal code, gender, and month/year of birth represent sufficiently low re-identification risk. Data custodians need to generalize their demographic information further for longitudinal data sets.</p

The First Post-Kepler Brightness Dips of KIC 8462852

We present a photometric detection of the first brightness dips of the unique variable star KIC 8462852 since the end of the Kepler space mission in 2013 May. Our regular photometric surveillance started in October 2015, and a sequence of dipping began in 2017 May continuing on through the end of 2017, when the star was no longer visible from Earth. We distinguish four main 1-2.5% dips, named "Elsie," "Celeste," "Skara Brae," and "Angkor", which persist on timescales from several days to weeks. Our main results so far are: (i) there are no apparent changes of the stellar spectrum or polarization during the dips; (ii) the multiband photometry of the dips shows differential reddening favoring non-grey extinction. Therefore, our data are inconsistent with dip models that invoke optically thick material, but rather they are in-line with predictions for an occulter consisting primarily of ordinary dust, where much of the material must be optically thin with a size scale <<1um, and may also be consistent with models invoking variations intrinsic to the stellar photosphere. Notably, our data do not place constraints on the color of the longer-term "secular" dimming, which may be caused by independent processes, or probe different regimes of a single process

De novo and biallelic DEAF1 variants cause a phenotypic spectrum.

PURPOSE: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. METHODS: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. RESULTS: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). CONCLUSION: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients

Loss Of Erα Partially Reverses The Effects Of Maternal High-Fat Diet On Energy Homeostasis In Female Mice

Maternal high-fat diet (HFD) alters hypothalamic developmental programming and disrupts offspring energy homeostasis in rodents. 17β-estradiol (E2) also influences hypothalamic programming through estrogen receptor (ER) α. Therefore, we hypothesized that females lacking ERα would be more susceptible to maternal HFD. To address this question, heterozygous ERα knockout (WT/KO) dams were fed a control breeder chow diet (25% fat) or a semi-purified HFD (45% fat) 4 weeks prior to mating with WT/KO males or heterozygous males with an ERα DNA-binding domain mutation knocked in (WT/KI) to produce WT, ERα KO, or ERα KIKO females lacking ERE-dependent ERα signaling. Maternal HFD increased body weight in WT and KIKO, in part, due to increased adiposity and daytime carbohydrate utilization in WT and KIKO, while increasing nighttime fat utilization in KO. Maternal HFD also increased plasma leptin, IL-6, and MCP-1 in WT and increased arcuate expression of Kiss1 and Esr1 (ERα) and liver expression of G6pc and Pepck in WT and KIKO. Contrary to our hypothesis, these data suggest that loss of ERα signaling blocks the influence of maternal HFD on energy homeostasis, inflammation, and hypothalamic and liver gene expression and that restoration of ERE-independent ERα signaling partially reestablishes susceptibility to maternal HFD

EXT418, a novel long‐acting ghrelin, mitigates Lewis lung carcinoma induced cachexia in mice

Abstract Background Ghrelin is a potential therapy for cachexia due to its orexigenic properties and anabolic effects on muscle and fat. However, its clinical use is limited by the short half‐life of active (acylated) ghrelin (~11 min in humans). EXT418 is a novel long‐acting, constitutively active ghrelin analog created by covalently linking it to a vitamin D derivative. Here, we evaluated the effects and mechanisms of action of EXT418 on Lewis lung carcinoma (LLC)‐induced cachexia in mice. Methods Male C57BL/6J mice (5‐ to 7‐month‐old) were implanted with 1 × 106 heat‐killed (HK) or live LLC cells. When the tumour was palpable, mice were injected with vehicle (T + V) or EXT418 daily (T + 418 Daily, 0.25 mg/kg/day) or every other day (T + 418 EOD, 0.5 mg/kg/EOD) for up to 14 days, whereas HK‐treated mice were given vehicle (HK + V). Subsets of T + 418 Daily or EOD‐treated mice were pair‐fed to the T + V group. Body composition and grip strength were evaluated before tumour implantation and at the end of the experiment. Molecular markers were probed in muscles upon termination. Results In tumour‐bearing mice, administration of EXT418 daily or EOD partially prevented weight loss (T + V vs. T + 418 Daily, P = 0.030; and vs. T + 418 EOD, P = 0.020). Similar effects were observed in whole body fat and lean body mass. Grip strength in tumour‐bearing mice was improved by EXT418 daily (P = 0.010) or EOD (P = 0.008) administration compared with vehicle‐treated mice. These effects of EXT418 on weight and grip strength were partially independent of food intake. EXT418 daily administration also improved type IIA (P = 0.015), IIB (P = 0.037) and IIX (P = 0.050) fibre cross‐sectional area (CSA) in tibialis anterior (TA) and EXT418 EOD improved CSA of IIB fibres in red gastrocnemius (GAS; P = 0.005). In skeletal muscles, tumour‐induced increases in atrogenes Fbxo32 and Trim63 were ameliorated by EXT418 treatments (TA and GAS/plantaris, PL), which were independent of food intake. EXT418 administration decreased expression of the mitophagy marker Bnip3 (GAS/PL; P ≤ 0.010). Similar effects of EXT418 EOD were observed in p62 (GAS/PL; P = 0.039). In addition, EXT418 treatments ameliorated the tumour‐induced elevation in muscle Il6 transcript levels (TA and GAS/PL), independently of food intake. Il‐6 transcript levels in adipose tissue and circulating IL‐10 were elevated in response to the tumour but these increases were not significant with EXT418 administration. Tumour mass was not altered by EXT418. Conclusions EXT418 mitigates LLC‐induced cachexia by attenuating skeletal muscle inflammation, proteolysis, and mitophagy, without affecting tumour mass and partially independent of food intake