GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Book Review: The Word Rides Again: Rereading the Frontier in American Fiction

The method of The Word Rides Again is straightforward. J. David Stevens first constructs a model of the popular Western novel or frontier narrative, complete with standard genealogy and a concise review of fifty years of critical response, and then uses that template to demonstrate that some mainstream novels (Hobomok, A Connecticut Yankee in King Arthur\u27s Court, Death Comes for the Archbishop) are actually frontier fiction in disguise, while some frontier fiction (by Bret Harte, Owen Wister, and Frank Waters) is actually more complex or problematic than the stereotype would suggest

Here Comes the Sun—Methylene Blue in Combination with Sunlight Sanitises Surgical Masks Contaminated with a Coronavirus and a Tenacious Small Non-Enveloped Virus

In the context of the SARS-CoV-2 pandemic, the reuse of personal protective equipment, specifically face coverings, has been recommended. Reuse of such items necessitates procedures to inactivate contaminating human respiratory and gastrointestinal pathogens. We previously demonstrated decontamination of face coverings contaminated with either infectious SARS-CoV-2 and animal coronaviruses or a highly resistant, non-enveloped norovirus via a novel photochemical treatment. Contaminated materials were coated with photosensitive methylene blue dye and were subsequently exposed to a visible bright light source (LED-equipped light boxes) to trigger the generation of virucidal singlet oxygen. A possible factor restricting the widespread use of such photochemical decontamination is its reliance on the availability of electricity to power light sources. Here, we show that natural sunlight can be used in lieu of artificial light. We demonstrate efficient inactivation of a SARS-CoV-2 surrogate, porcine respiratory coronavirus, via 10 µM dye coating in conjunction with short outdoor exposures of 5–30 min (blue sky to cloudy day; mean 46,578 lx). A tenacious human norovirus surrogate, murine norovirus, is inactivated via methylene blue solar decontamination involving 100 µM dye concentrations and 30 min of high-illuminance sunlight (blue sky; mean 93,445 lx) or 2 h of mid- to low-illuminance (cloudy day; mean 28,558 lx). The protocol developed here thus solidifies the position of methylene blue solar decontamination as an important equitable tool in the package of practical pandemic preparedness

Foraging economies and population in the Middle Holocene highlands of southern Yemen

International audienc

The long-acting C5 inhibitor, Ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment.

Ravulizumab is a long-acting C5 inhibitor engineered from eculizumab with increased elimination half-life, allowing an extended dosing interval from two to eight weeks. Here we evaluate the efficacy and safety of ravulizumab in adults with atypical hemolytic uremic syndrome presenting with thrombotic microangiopathy. In this global, phase 3, single arm study in complement inhibitor-naïve adults (18 years and older) who fulfilled diagnostic criteria for atypical hemolytic uremic syndrome, enrolled patients received ravulizumab through a 26-week initial evaluation period. The primary endpoint was complete thrombotic microangiopathy response defined as normalization of platelet count and lactate dehydrogenase and 25% or more improvement in serum creatinine. Secondary endpoints included changes in hematologic variables and renal function. Safety was also evaluated. Ravulizumab treatment resulted in an immediate, complete, and sustained C5 inhibition in all patients. Complete thrombotic microangiopathy response was achieved in 53.6% of patients. Normalization of platelet count, lactate dehydrogenase and 25% or more improvement in serum creatinine was achieved in 83.9%, 76.8% and 58.9% of patients, respectively. Improvement in estimated glomerular filtration rate by one or more stage was achieved in 68.1% of patients by day 183. No unexpected adverse events were reported across a safety analysis set of 58 patients. Four deaths occurred (three within one month of study initiation, including one in a patient excluded based on eligibility criteria after the first dose) with none considered treatment-related by the study investigator. Thus, treatment with ravulizumab once every eight weeks resulted in rapidly improved hematologic and renal endpoints with no unexpected adverse events in adults with atypical hemolytic uremic syndrome

Activation of a GPCR leads to eIF4G phosphorylation at the 5' cap and to IRES-dependent translation

The control of mRNA translation has been mainly explored in response to activated tyrosine kinase receptors. In contrast, mechanistic details on the translational machinery are far less available in the case of ligand-bound G protein-coupled receptors. Here, using the follicle-stimulating hormone receptor as a model receptor, we demonstrate that part of the translational regulations occurs by phosphorylation of the translation pre-initiation complex scaffold protein, eukaryotic initiation factor 4G, in HEK293 cells stably expressing the follicle-stimulating hormone receptor. This phosphorylation event occurred when eukaryotic initiation factor 4G was bound to the mRNA 5'cap, and likely involves mammalian target of rapamycin. This regulation might contribute to cap-dependent translation in response to follicle-stimulating hormone. The cap-binding protein eukaryotic initiation factor 4E also had its phosphorylation level enhanced upon follicle-stimulating hormone stimulation. In addition, we also show that follicle-stimulating hormone-induced signaling not only led to cap-dependent translation but also to internal ribosome entry site-dependent translation of some mRNA. These data add detailed information on the molecular bases underlying the regulation of selective mRNA translation by a G protein-coupled receptor, and a topological model recapitulating these mechanisms is proposed

Of masks and methylene blue - the use of methylene blue photochemical treatment to decontaminate surgical masks contaminated with a tenacious small non-enveloped norovirus

BACKGROUND: In the context of the SARS-CoV-2 pandemic, reuse of personal protective equipment, specifically that of medical face coverings, has been recommended. The reuse of these typically single-use only items necessitates procedures to inactivate contaminating human respiratory and gastrointestinal pathogens. We previously demonstrated decontamination of surgical masks and respirators contaminated with infectious SARS-CoV-2 and various animal coronaviruses via low concentration- and short exposure methylene blue photochemical treatment (10 µM methylene blue, 30 minutes of 12,500-lux red light or 50,000 lux white light exposure). METHODS: Here, we describe the adaptation of this protocol to the decontamination of a more resistant, non-enveloped gastrointestinal virus and demonstrate efficient photodynamic inactivation of murine norovirus, a human norovirus surrogate. RESULTS: Methylene blue photochemical treatment (100 µM methylene blue, 30 minutes of 12,500-lux red light exposure) of murine norovirus-contaminated masks reduced infectious viral titers by over four orders of magnitude on surgical mask surfaces. DISCUSSION AND CONCLUSIONS: Inactivation of a norovirus, the most difficult to inactivate of the respiratory and gastrointestinal human viruses, can predict the inactivation of any less resistant viral mask contaminant. The protocol developed here thus solidifies the position of methylene blue photochemical decontamination as an important tool in the package of practical pandemic preparedness