We performed RNA-seq and high-resolution mass spectrometry on 128 blood samples from COVID-19-positive and COVID-19-negative patients with diverse disease severities and outcomes. Quantified ...transcripts, proteins, metabolites, and lipids were associated with clinical outcomes in a curated relational database, uniquely enabling systems analysis and cross-ome correlations to molecules and patient prognoses. We mapped 219 molecular features with high significance to COVID-19 status and severity, many of which were involved in complement activation, dysregulated lipid transport, and neutrophil activation. We identified sets of covarying molecules, e.g., protein gelsolin and metabolite citrate or plasmalogens and apolipoproteins, offering pathophysiological insights and therapeutic suggestions. The observed dysregulation of platelet function, blood coagulation, acute phase response, and endotheliopathy further illuminated the unique COVID-19 phenotype. We present a web-based tool (covid-omics.app) enabling interactive exploration of our compendium and illustrate its utility through a machine learning approach for prediction of COVID-19 severity.
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•We surveyed biomolecules in 102 COVID-19 and 26 non-COVID-19 patient blood samples•We found 219 biomolecules strongly associated with COVID-19 status and severity•We observed pronounced dysregulation of lipid transport and neutrophil degranulation•Our resource of measurements and patient data is located at https://covid-omics.app
Leukocyte mRNA expression and plasma protein, metabolite, and lipid levels were measured in 102 COVID-19 and 26 non-COVID-19 patient samples. 219 diverse biomolecules were strongly associated with COVID-19 status and severity and pointed to dysregulation of processes related to lipid transport, blood coagulation, acute phase response, endotheliopathy, and neutrophil degranulation in this disease.
ABSTRACT
MIGHTEE is a galaxy evolution survey using simultaneous radio continuum, spectropolarimetry, and spectral line observations from the South African MeerKAT telescope. When complete, the ...survey will image ∼20 deg2 over the COSMOS, E-CDFS, ELAIS-S1, and XMM-Newton Large Scale Structure field (XMM-LSS) extragalactic deep fields with a central frequency of 1284 MHz. These were selected based on the extensive multiwavelength data sets from numerous existing and forthcoming observational campaigns. Here, we describe and validate the data processing strategy for the total intensity continuum aspect of MIGHTEE, using a single deep pointing in COSMOS (1.6 deg2) and a three-pointing mosaic in XMM-LSS (3.5 deg2). The processing includes the correction of direction-dependent effects, and results in thermal noise levels below 2 $\mathrm{\mu }$Jy beam−1 in both fields, limited in the central regions by classical confusion at ∼8 arcsec angular resolution, and meeting the survey specifications. We also produce images at ∼5 arcsec resolution that are ∼3 times shallower. The resulting image products form the basis of the Early Science continuum data release for MIGHTEE. From these images we extract catalogues containing 9896 and 20 274 radio components in COSMOS and XMM-LSS, respectively. We also process a close-packed mosaic of 14 additional pointings in COSMOS and use these in conjunction with the Early Science pointing to investigate methods for primary beam correction of broad-band radio images, an analysis that is of relevance to all full-band MeerKAT continuum observations, and wide-field interferometric imaging in general. A public release of the MIGHTEE Early Science continuum data products accompanies this article.
The performance and stability of thin-film transistors with zinc oxide as the channel layer are investigated using gate bias stress. It is found that the effective channel mobility, ON/OFF ratio, and ...subthreshold slope of the devices that incorporate SiN are superior to those with SiO 2 as the dielectric. The application of positive and negative stress results in the device transfer characteristics shifting in positive and negative directions, respectively. The devices also demonstrate a logarithmic time-dependent threshold voltage shift suggestive of charge trapping within the band gap and the band tails responsible for the deterioration of device parameters. It is postulated that this device instability is partly a consequence of the lattice mismatch at the channel/insulator interface. All stressed devices recover to near-original characteristics after a short period at room temperature without the need for any thermal or bias annealing.
Kinks are a structural feature of alpha-helices and many are known to have functional roles. Kinks have previously tended to be defined in a binary fashion. In this paper we have deliberately moved ...towards defining them on a continuum, which given the unimodal distribution of kink angles is a better description. From this perspective, we examine the conservation of kinks in proteins. We find that kink angles are not generally a conserved property of homologs, pointing either to their not being functionally critical or to their function being related to conformational flexibility. In the latter case, the different structures of homologs are providing snapshots of different conformations. Sequence identity between homologous helices is informative in terms of kink conservation, but almost equally so is the sequence identity of residues in spatial proximity to the kink. In the specific case of proline, which is known to be prevalent in kinked helices, loss of a proline from a kinked helix often also results in the loss of a kink or reduction in its kink angle. We carried out a study of the seven transmembrane helices in the GPCR family and found that changes in kinks could be related both to subfamilies of GPCRs and also, in a particular subfamily, to the binding of agonists or antagonists. These results suggest conformational change upon receptor activation within the GPCR family. We also found correlation between kink angles in different helices, and the possibility of concerted motion could be investigated further by applying our method to molecular dynamics simulations. These observations reinforce the belief that helix kinks are key, functional, flexible points in structures.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Intrathecal synthesis of central nervous system (CNS)-reactive autoantibodies is observed across patients with autoimmune encephalitis (AE), who show multiple residual neurobehavioral deficits and ...relapses despite immunotherapies. We leveraged two common forms of AE, mediated by leucine-rich glioma inactivated-1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies, as human models to comprehensively reconstruct and profile cerebrospinal fluid (CSF) B cell receptor (BCR) characteristics. We hypothesized that the resultant observations would both inform the observed therapeutic gap and determine the contribution of intrathecal maturation to pathogenic B cell lineages. From the CSF of three patients, 381 cognate-paired IgG BCRs were isolated by cell sorting and scRNA-seq, and 166 expressed as monoclonal antibodies (mAbs). Sixty-two percent of mAbs from singleton BCRs reacted with either LGI1 or CASPR2 and, strikingly, this rose to 100% of cells in clonal groups with ≥4 members. These autoantigen-reactivities were more concentrated within antibody-secreting cells (ASCs) versus B cells (
< 0.0001), and both these cell types were more differentiated than LGI1- and CASPR2-unreactive counterparts. Despite greater differentiation, autoantigen-reactive cells had acquired few mutations intrathecally and showed minimal variation in autoantigen affinities within clonal expansions. Also, limited CSF T cell receptor clonality was observed. In contrast, a comparison of germline-encoded BCRs versus the founder intrathecal clone revealed marked gains in both affinity and mutational distances (
= 0.004 and
< 0.0001, respectively). Taken together, in patients with LGI1 and CASPR2 antibody encephalitis, our results identify CSF as a compartment with a remarkably high frequency of clonally expanded autoantigen-reactive ASCs whose BCR maturity appears dominantly acquired outside the CNS.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a childhood-onset neurological disease resulting from mutations in the SACS gene encoding sacsin, a 4,579-aa protein of unknown ...function. Originally identified as a founder disease in Québec, ARSACS is now recognized worldwide. Prominent features include pyramidal spasticity and cerebellar ataxia, but the underlying pathology and pathophysiological mechanisms are unknown. We have generated an animal model for ARSACS, sacsin knockout mice, that display agedependent neurodegeneration of cerebellar Purkinje cells. To explore the pathophysiological basis for this observation, we examined the cell biological properties of sacsin. We show that sacsin localizes to mitochondria in non-neuronal cells and primary neurons and that it interacts with dynamin-related protein 1, which participates in mitochondrial fission. Fibroblasto from ARSACS patients show a hyperfused mitochondrial network, consistent with defects in mitochondrial fission. Sacsin knockdown leads to an overly interconnected and functionally impaired mitochondrial network, and mitochondria accumulate in the soma and proximal dendrites of sacsin knockdown neurons. Disruption of mitochondrial transport into dendrites has been shown to lead to abnormal dendritic morphology, and we observe striking alterations in the organization of dendritic fields in the cerebellum of knockout mice that precedes Purkinje cell death. Our data identifies mitochondrial dysfunction/mislocalization as the likely cellular basis for ARSACS and indicates a role for sacsin in regulation of mitochondrial dynamics.
BACKGROUND: L-arginine is the precursor of endothelium derived nitric oxide (NO) and increasing the available substrate may increase the production of NO. This has been shown by local infusion in ...peripheral vascular beds but there are few studies of the effects during systemic infusion. Renal vasoconstriction is known to be important in the pathogenesis of cor pulmonale in patients with hypoxic chronic obstructive pulmonary disease (COPD). The effects of a systemic infusion of L-arginine on renal and aortic haemodynamics were therefore investigated in normal subjects and in patients with hypoxic COPD. METHODS: Ten normal volunteers were recruited from the research staff of King's College Hospital Six patients with COPD and hypoxia (arterial oxygen tension (PaO2) < 8.5 kPa) were recruited from the thoracic medicine outpatient clinic at King's College Hospital and five age and sex matched normal subjects were recruited from a group of normal subjects recruited from the database of the Department of Health Care for the Elderly as volunteers for medical research. There was no history of renal, cardiac, or hepatic disease. Baseline values of time averaged mean of the maximum instantaneous velocity (Tamx) and maximum velocity (Vmax) of blood flow in intrarenal arteries were obtained using colour flow Doppler ultrasound. Using the same technique, Vmax was obtained from the abdominal aorta just distal to the xiphisternum before and after infusion of L-arginine via a large peripheral vein (20 g in 100 ml sterile water over 30 minutes). RESULTS: In normal subjects L-arginine increased blood velocity in the intrarenal vessels from a mean of 0.22 m/s to 0.26 m/s, an increase of 19.8%. There was no effect on arterial blood pressure, heart rate, or aortic blood velocity. L-arginine had no effect on intrarenal or aortic blood velocity in patients with hypoxic COPD. In age matched controls L-arginine increased blood velocity in the intrarenal vessels from a mean of 0.20 m/s to 0.26 m/s, an increase of 36.8%. There was no effect on arterial blood pressure, heart rate, or aortic blood velocity. CONCLUSIONS: L-arginine, at the doses administered, increased renal blood flow, as assessed by renal arterial velocity. This effect was not seen in patients with hypoxic COPD but was present in age matched controls. This suggests that the abnormal renal vascular control seen in hypoxic patients with COPD may reflect a disturbance of the L-arginine/nitric oxide pathway.
ABSTRACT
We study the nature of the faint radio source population detected in the MeerKAT International GHz Tiered Extragalactic Exploration (MIGHTEE) Early Science data in the COSMOS field, focusing ...on the properties of the radio-loud active galactic nuclei (AGNs). Using the extensive multiwavelength data available in the field, we are able to classify 88 per cent of the 5223 radio sources in the field with host galaxy identifications as AGNs (35 per cent) or star-forming galaxies (54 per cent). We select a sample of radio-loud AGNs with redshifts out to z ∼ 6 and radio luminosities 1020 < L1.4 GHz/W Hz−1 < 1027 and classify them as high-excitation and low-excitation radio galaxies (HERGs and LERGs). The classification catalogue is released with this work. We find no significant difference in the host galaxy properties of the HERGs and LERGs in our sample. In contrast to previous work, we find that the HERGs and LERGs have very similar Eddington-scaled accretion rates; in particular we identify a population of very slowly accreting AGNs that are formally classified as HERGs at these low radio luminosities, where separating into HERGs and LERGs possibly becomes redundant. We investigate how black hole mass affects jet power, and find that a black hole mass ≳ 107.8 M⊙ is required to power a jet with mechanical power greater than the radiative luminosity of the AGN (Lmech/Lbol > 1). We discuss that both a high black hole mass and black hole spin may be necessary to launch and sustain a dominant radio jet.
Homo naledi is a previously-unknown species of extinct hominin discovered within the Dinaledi Chamber of the Rising Star cave system, Cradle of Humankind, South Africa. This species is characterized ...by body mass and stature similar to small-bodied human populations but a small endocranial volume similar to australopiths. Cranial morphology of H. naledi is unique, but most similar to early Homo species including Homo erectus, Homo habilis or Homo rudolfensis. While primitive, the dentition is generally small and simple in occlusal morphology. H. naledi has humanlike manipulatory adaptations of the hand and wrist. It also exhibits a humanlike foot and lower limb. These humanlike aspects are contrasted in the postcrania with a more primitive or australopith-like trunk, shoulder, pelvis and proximal femur. Representing at least 15 individuals with most skeletal elements repeated multiple times, this is the largest assemblage of a single species of hominins yet discovered in Africa.
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