Autophagy: A Forty-Year Search for a Missing Membrane Source

Autophagy is central to diverse biological processes in eukaryotes including animal development and cellular survival, and also to neurodegenerative diseases, but the origin of the membranes that make up autophagic vesicles is unknown

The biological function of some human transcription factor binding motifs varies with position relative to the transcription start site

A number of previous studies have predicted transcription factor binding sites (TFBSs) by exploiting the position of genomic landmarks like the transcriptional start site (TSS). The studies’ methods are generally too computationally intensive for genome-scale investigation, so the full potential of ‘positional regulomics’ to discover TFBSs and determine their function remains unknown. Because databases often annotate the genomic landmarks in DNA sequences, the methodical exploitation of positional regulomics has become increasingly urgent. Accordingly, we examined a set of 7914 human putative promoter regions (PPRs) with a known TSS. Our methods identified 1226 eight-letter DNA words with significant positional preferences with respect to the TSS, of which only 608 of the 1226 words matched known TFBSs. Many groups of genes whose PPRs contained a common word displayed similar expression profiles and related biological functions, however. Most interestingly, our results included 78 words, each of which clustered significantly in two or three different positions relative to the TSS. Often, the gene groups corresponding to different positional clusters of the same word corresponded to diverse functions, e.g. activation or repression in different tissues. Thus, different clusters of the same word likely reflect the phenomenon of ‘positional regulation’, i.e. a word's regulatory function can vary with its position relative to a genomic landmark, a conclusion inaccessible to methods based purely on sequence. Further integrative analysis of words co-occurring in PPRs also yielded 24 different groups of genes, likely identifying cis-regulatory modules de novo. Whereas comparative genomics requires precise sequence alignments, positional regulomics exploits genomic landmarks to provide a ‘poor man's alignment’. By exploiting the phenomenon of positional regulation, it uses position to differentiate the biological functions of subsets of TFBSs sharing a common sequence motif

A rightward shift in the visuospatial attention vector with healthy aging

The study of lateralised visuospatial attention bias in non-clinical samples has revealed a systematic group-level leftward bias (pseudoneglect), possibly as a consequence of right hemisphere dominance for visuospatial attention. Pseudoneglect appears to be modulated by age, with a reduced or even reversed bias typically present in elderly participants. It has been suggested that this shift in bias may arise due to disproportionate aging of the right hemisphere and/or an increase in complementary functional recruitment of the left hemisphere for visuospatial processing. In this study, we report rightward shifts in subjective midpoint judgement relative to healthy young participants whilst elderly participants performed a computerized version of the landmark task (in which they had to judge whether a transection mark appeared closer to the right or left end of a line) on three different line lengths. This manipulation of stimulus properties led to a similar behavioural pattern in both the young and the elderly: a rightward shift in subjective midpoint with decreasing line length, which even resulted in a systematic rightward bias in elderly participants for the shortest line length (1.98° of visual angle). Overall performance precision for the task was lower in the elderly participants regardless of line length, suggesting reduced landmark task discrimination sensitivity with healthy aging. This rightward shift in the attentional vector with healthy aging is likely to result from a reduction in right hemisphere resources/dominance for attentional processing in elderly participants. The significant rightward bias in the elderly for short lines may even suggest a reversal of hemisphere dominance in favour of the left hemisphere/right visual field under specific conditions

Beneficial autoimmunity at body surfaces – immune surveillance and rapid type 2 immunity regulate tissue homeostasis and cancer

Epithelial cells line body surface tissues and provide a physicochemical barrier to the external environment. Frequent microbial and non-microbial challenges such as those imposed by mechanical disruption, injury or exposure to noxious environmental substances including chemicals, carcinogens, ultraviolet-irradiation or toxins cause activation of epithelial cells with release of cytokines and chemokines as well as alterations in the expression of cell surface ligands. Such display of epithelial stress is rapidly sensed by tissue resident immunocytes, which can directly interact with self-moieties on epithelial cells and initiate both local and systemic immune responses. Epithelial cells are thus key drivers of immune surveillance at body surface tissues. However, epithelial cells have a propensity to drive type 2 immunity (rather than type 1) upon non-invasive challenge or stress – a type of immunity whose regulation and function still remain enigmatic. Here we review the induction and possible role of type 2 immunity in epithelial tissues and propose that rapid immune surveillance and type 2 immunity are key regulators of tissue homeostasis and carcinogenesis

Discriminating Between the Physical Processes that Drive Spheroid Size Evolution

Massive galaxies at high-z have smaller effective radii than those today, but similar central densities. Their size growth therefore relates primarily to the evolving abundance of low-density material. Various models have been proposed to explain this evolution, which have different implications for galaxy, star, and BH formation. We compile observations of spheroid properties as a function of redshift and use them to test proposed models. Evolution in progenitor gas-richness with redshift gives rise to initial formation of smaller spheroids at high-z. These systems can then evolve in apparent or physical size via several channels: (1) equal-density 'dry' mergers, (2) later major or minor 'dry' mergers with less-dense galaxies, (3) adiabatic expansion, (4) evolution in stellar populations & mass-to-light-ratio gradients, (5) age-dependent bias in stellar mass estimators, (6) observational fitting/selection effects. If any one of these is tuned to explain observed size evolution, they make distinct predictions for evolution in other galaxy properties. Only model (2) is consistent with observations as a dominant effect. It is the only model which allows for an increase in M_BH/M_bulge with redshift. Still, the amount of merging needed is larger than that observed or predicted. We therefore compare cosmologically motivated simulations, in which all these effects occur, & show they are consistent with all the observational constraints. Effect (2), which builds up an extended low-density envelope, does dominate the evolution, but effects 1,3,4, & 6 each contribute ~20% to the size evolution (a net factor ~2). This naturally also predicts evolution in M_BH-sigma similar to that observed.Comment: 19 pages, 7 figures. accepted to MNRAS (matches accepted version

Influence of viral genes on the cell-to-cell spread of RNA silencing

The turnip crinkle virus-based vector TCV–GFPΔCP had been devised previously to study cell-to-cell and long-distance spread of virus-induced RNA silencing. TCV–GFPΔCP, which had been constructed by replacing the coat protein (CP) gene with a green fluorescent protein (GFP) coding sequence, was able to induce RNA silencing in single epidermal cells, from which RNA silencing spread from cell-to-cell. Using this unique local silencing assay together with mutagenesis analysis, two TCV genes, p8 and p9, which were involved in the intercellular spread of virus-induced RNA silencing, were identified. TCV–GFPΔCP and its p8- or p9-mutated derivatives, TCVmp8–GFPΔCP and TCVmp9–GFPΔCP, replicated efficiently but were restricted to single Nicotiana benthamiana epidermal cells. TCV–GFPΔCP, TCVmp8–GFPΔCP, or TCVmp9–GFPΔCP was able to initiate RNA silencing that targeted and degraded recombinant viral RNAs in inoculated leaves of the GFP-expressing N. benthamiana line 16c. However, cell-to-cell spread of silencing to form silencing foci was triggered only by TCV–GFPΔCP. Non-replicating TCVmp88–GFPΔCP and TCVmp28mp88–GFPΔCP with dysfunctional replicase genes, and single-stranded gfp RNA did not induce RNA silencing. Transient expression of the TCV p9 protein could effectively complement TCVmp9–GFPΔCP to facilitate intercellular spread of silencing. These data suggest that the plant cellular trafficking machinery could hijack functional viral proteins to permit cell-to-cell movement of RNA silencing

Bringing the "self" into focus: conceptualising the role of self-experience for understanding and working with distressing voices

A primary goal of cognitive behavior therapy for psychosis (CBTp) is to reduce distress and disability, not to change the positive symptoms of psychosis, such as hearing voices. Despite demonstrated associations between beliefs about voices and distress, the effects of CBTp on reducing voice distress are disappointing. Research has begun to explore the role that the psychological construct of “self” (which includes numerous facets such as self-reflection, self-schema and self-concept) might play in causing and maintaining distress and disability in voice hearers. However, attempts to clarify and integrate these different perspectives within the voice hearing literature, or to explore their clinical implications, are still in their infancy. This paper outlines how the self has been conceptualised in the psychosis and CBT literatures, followed by a review of the evidence regarding the proposed role of this construct in the etiology of and adaptation to voice hearing experiences. We go on to discuss some of the specific intervention methods that aim to target these aspects of self-experience and end by identifying key research questions in this area. Notably, we suggest that interventions specifically targeting aspects of self-experience, including self-affection, self-reflection, self-schema and self-concept, may be sufficient to reduce distress and disruption in the context of hearing voices, a suggestion that now requires further empirical investigation

Patents and Industrialisation. An Historical Overview of the British Case, 1624-1907

A Report to the Strategic Advisory Board on Intellectual Property Policy (SABIP), U

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.

Funder: laura and john arnold foundationBACKGROUND: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX ). METHODS: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. RESULTS: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. CONCLUSIONS: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care