Infrared light excites cells by changing their electrical capacitance

Optical stimulation has enabled important advances in the study of brain function and other biological processes, and holds promise for medical applications ranging from hearing restoration to cardiac pace making. In particular, pulsed laser stimulation using infrared wavelengths >1.5 μm has therapeutic potential based on its ability to directly stimulate nerves and muscles without any genetic or chemical pre-treatment. However, the mechanism of infrared stimulation has been a mystery, hindering its path to the clinic. Here we show that infrared light excites cells through a novel, highly general electrostatic mechanism. Infrared pulses are absorbed by water, producing a rapid local increase in temperature. This heating reversibly alters the electrical capacitance of the plasma membrane, depolarizing the target cell. This mechanism is fully reversible and requires only the most basic properties of cell membranes. Our findings underscore the generality of pulsed infrared stimulation and its medical potential

A small-molecule inhibitor of the BRCA2-RAD51 interaction modulates RAD51 assembly and potentiates DNA damage-induced cell death

Supplemental information: Document S1. Figures S1–S5, Tables S1–S3, and Methods S1 available at: https://www.cell.com/cms/10.1016/j.chembiol.2021.02.006/attachment/3e31e265-54fc-4337-ac40-861ecb85706e/mmc1.pdf (1.44 MB)Copyright © 2021 The Authors. BRCA2 controls RAD51 recombinase during homologous DNA recombination (HDR) through eight evolutionarily conserved BRC repeats, which individually engage RAD51 via the motif Phe-x-x-Ala. Using structure-guided molecular design, templated on a monomeric thermostable chimera between human RAD51 and archaeal RadA, we identify CAM833, a 529 Da orthosteric inhibitor of RAD51:BRC with a Kd of 366 nM. The quinoline of CAM833 occupies a hotspot, the Phe-binding pocket on RAD51 and the methyl of the substituted α-methylbenzyl group occupies the Ala-binding pocket. In cells, CAM833 diminishes formation of damage-induced RAD51 nuclear foci; inhibits RAD51 molecular clustering, suppressing extended RAD51 filament assembly; potentiates cytotoxicity by ionizing radiation, augmenting 4N cell-cycle arrest and apoptotic cell death and works with poly-ADP ribose polymerase (PARP)1 inhibitors to suppress growth in BRCA2-wildtype cells. Thus, chemical inhibition of the protein-protein interaction between BRCA2 and RAD51 disrupts HDR and potentiates DNA damage-induced cell death, with implications for cancer therapy.Wellcome Trust Translational Award ( 080083/Z/06/Z ); Seeding Drug Discovery Award ( 091058/Z/09/Z ); Medical Research Council (MRC) Program grants MC_UU_12022/1 and MC_UU_12022/8; Astex Pharmaceuticals

The complete sequence of the Acacia ligulata chloroplast genome reveals a highly divergent clpP1 gene

Legumes are a highly diverse angiosperm family that include many agriculturally important species. To date, 21 complete chloroplast genomes have been sequenced from legume crops confined to the Papilionoideae subfamily. Here we report the first chloroplast genome from the Mimosoideae, Acacia ligulata, and compare it to the previously sequenced legume genomes. The A. ligulata chloroplast genome is 158,724 bp in size, comprising inverted repeats of 25,925 bp and single-copy regions of 88,576 bp and 18,298 bp. Acacia ligulata lacks the inversion present in many of the Papilionoideae, but is not otherwise significantly different in terms of gene and repeat content. The key feature is its highly divergent clpP1 gene, normally considered essential in chloroplast genomes. In A. ligulata, although transcribed and spliced, it probably encodes a catalytically inactive protein. This study provides a significant resource for further genetic research into Acacia and the Mimosoideae. The divergent clpP1 gene suggests that Acacia will provide an interesting source of information on the evolution and functional diversity of the chloroplast Clp protease comple

Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.

Protein-protein interactions (PPIs) are of pivotal importance in the regulation of biological systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clinical development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.JS, DES and ARB thank the Wellcome Trust for funding.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nrd.2016.2

The MedConnect Program: Symptomatology, Return Visits, and Hospitalization of COVID-19 Outpatients Following Discharge from the Emergency Department

Background and objective Although hospitalization is required for only a minority of those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the high rates of morbidity and mortality among these patients have led researchers to focus on the predictors of admission and adverse outcomes in the inpatient population. However, there is scarce data on the clinical trajectory of individuals symptomatic enough to present for emergency care, but not sick enough to be admitted. In light of this, we aimed to examine the symptomatology, emergency department (ED) revisits, and hospitalization of coronavirus disease 2019 (COVID-19) outpatients after discharge from the ED. Methods Adult patients with COVID-19 infection were prospectively enrolled after discharge from the ED between May and December 2020. Patients were followed up longitudinally for 14 days via phone interviews designed to provide support and information and to track symptomatology, ED revisits, and hospitalization. Results A volunteer, medical student-run program enrolled 199 COVID-19 patients discharged from the ED during the first nine months of the pandemic. Of the 176 patients (88.4%) who completed the 14-day protocol, 29 (16.5%) had a second ED visit and 17 (9.6%) were admitted, 16 (9%) for worsening COVID-19 symptoms. Age, male sex, comorbid illnesses, and self-reported dyspnea, diarrhea, chills, and fever were associated with hospital admission for patients with a subsequent ED visit. For those who did not require admission, symptoms generally improved following ED discharge. Age >65 years and a history of cardiovascular disease (CVD) were associated with a longer duration of cough, but generally, patient characteristics and comorbidities did not significantly affect the overall number or duration of symptoms. Conclusions Nearly one in five patients discharged from the ED with COVID-19 infection had a second ED evaluation during a 14-day follow-up period, despite regular phone interactions aimed at providing support and information. More than half of them required admission for worsening COVID-19 symptoms. Established risk factors for severe disease and self-reported persistence of certain symptoms were associated with hospital admission, while those who did not require hospitalization had a steady improvement in symptoms over the 14-day period.http://deepblue.lib.umich.edu/bitstream/2027.42/174748/2/The MedConnect Program Symptomatology, Return Visits, and Hospitalization of COVID-19 Outpatients Following Discharge From t.pdfPublished versionDescription of The MedConnect Program Symptomatology, Return Visits, and Hospitalization of COVID-19 Outpatients Following Discharge From t.pdf : Published versio