Specific Rab GTPase-activating proteins define the Shiga toxin and epidermal growth factor uptake pathways

Rab family guanosine triphosphatases (GTPases) together with their regulators define specific pathways of membrane traffic within eukaryotic cells. In this study, we have investigated which Rab GTPase-activating proteins (GAPs) can interfere with the trafficking of Shiga toxin from the cell surface to the Golgi apparatus and studied transport of the epidermal growth factor (EGF) from the cell surface to endosomes. This screen identifies 6 (EVI5, RN-tre/USP6NL, TBC1D10A–C, and TBC1D17) of 39 predicted human Rab GAPs as specific regulators of Shiga toxin but not EGF uptake. We show that Rab43 is the target of RN-tre and is required for Shiga toxin uptake. In contrast, RabGAP-5, a Rab5 GAP, was unique among the GAPs tested and reduced the uptake of EGF but not Shiga toxin. These results suggest that Shiga toxin trafficking to the Golgi is a multistep process controlled by several Rab GAPs and their target Rabs and that this process is discrete from ligand-induced EGF receptor trafficking

The Computational Complexity of Knot and Link Problems

We consider the problem of deciding whether a polygonal knot in 3-dimensional Euclidean space is unknotted, capable of being continuously deformed without self-intersection so that it lies in a plane. We show that this problem, {\sc unknotting problem} is in {\bf NP}. We also consider the problem, {\sc unknotting problem} of determining whether two or more such polygons can be split, or continuously deformed without self-intersection so that they occupy both sides of a plane without intersecting it. We show that it also is in NP. Finally, we show that the problem of determining the genus of a polygonal knot (a generalization of the problem of determining whether it is unknotted) is in {\bf PSPACE}. We also give exponential worst-case running time bounds for deterministic algorithms to solve each of these problems. These algorithms are based on the use of normal surfaces and decision procedures due to W. Haken, with recent extensions by W. Jaco and J. L. Tollefson.Comment: 32 pages, 1 figur

Luminescence spectra and kinetics of disordered solid solutions

We have studied both theoretically and experimentally the luminescence spectra and kinetics of crystalline, disordered solid solutions after pulsed excitation. First, we present the model calculations of the steady-state luminescence band shape caused by recombination of excitons localized in the wells of random potential induced by disorder. Classification of optically active tail states of the main exciton band into two groups is proposed. The majority of the states responsible for the optical absorption corresponds to the group of extended states belonging to the percolation cluster, whereas only a relatively small group of “radiative” states forms the steady-state luminescence band. The continuum percolation theory is applied to distinguish the “radiative” localized states, which are isolated in space and have no ways for nonradiative transitions along the tail states. It is found that the analysis of the exciton-phonon interaction gives the information about the character of the localization of excitons. We have shown that the model used describes quite well the experimental cw spectra of CdS(1−c)Sec and ZnSe(1−c)Tec solid solutions. Further, the experimental results are presented for the temporal evolution of the luminescence band. It is shown that the changes of band shape with time come from the interplay of population dynamics of extended states and spatially isolated “radiative” states. Finally, the measurements of the decay of the spectrally integrated luminescence intensity at long delay times are presented. It is shown that the observed temporal behavior can be described in terms of relaxation of separated pairs followed by subsequent exciton formation and radiative recombination. Electron tunneling processes are supposed to be responsible for the luminescence in the long-time limit at excitation below the exciton mobility edge. At excitation by photons with higher energies the diffusion of electrons can account for the observed behavior of the luminescence

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth

Probing Flexibility in Porphyrin-Based Molecular Wires Using Double Electron Electron Resonance

A series of butadiyne-linked zinc porphyrin oligomers, with one, two, three, and four porphyrin units and lengths of up to 75 angstrom, have been spin-labeled at both ends with stable nitroxide TEMPO radicals. The pulsed EPR technique of double electron electron resonance (DEER) was used to probe the distribution of intramolecular end-to-end distances, under a range of conditions. DEER measurements were carried out at 50 K in two types of dilute solution glasses: deutero-toluene (with 10% deutero-pyridine) and deutero-o-terphenyl (with 5% 4-benzyl pyridine). The complexes of the porphyrin oligomers with monodentate ligands (pyridine or 4-benzyl pyridine) principally adopt linear conformations. Nonlinear conformations are less populated in the lower glass-transition temperature solvent. When the oligomers bind star-shaped multidentate ligands, they are forced to bend into nonlinear geometries, and the experimental end-to-end distances for these complexes match those from molecular mechanics calculations. Our results show that porphyrin-based molecular wires are shape-persistent, and yet that their shapes can deformed by binding to multivalent ligands. Self-assembled ladder-shaped 2:2 complexes were also investigated to illustrate the scope of DEER measurements for providing structural information on synthetic noncovalent nanostructures

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease