Phosphoinositide 3–kinase γ participates in T cell receptor–induced T cell activation

Class I phosphoinositide 3–kinases (PI3Ks) constitute a family of enzymes that generates 3-phosphorylated polyphosphoinositides at the cell membrane after stimulation of protein tyrosine (Tyr) kinase–associated receptors or G protein–coupled receptors (GPCRs). The class I PI3Ks are divided into two types: class IA p85/p110 heterodimers, which are activated by Tyr kinases, and the class IB p110γ isoform, which is activated by GPCR. Although the T cell receptor (TCR) is a protein Tyr kinase–associated receptor, p110γ deletion affects TCR-induced T cell stimulation. We examined whether the TCR activates p110γ, as well as the consequences of interfering with p110γ expression or function for T cell activation. We found that after TCR ligation, p110γ interacts with Gαq/11, lymphocyte-specific Tyr kinase, and ζ-associated protein. TCR stimulation activates p110γ, which affects 3-phosphorylated polyphosphoinositide levels at the immunological synapse. We show that TCR-stimulated p110γ controls RAS-related C3 botulinum substrate 1 activity, F-actin polarization, and the interaction between T cells and antigen-presenting cells, illustrating a crucial role for p110γ in TCR-induced T cell activation

Incubation period of COVID-19: a rapid systematic review and meta-analysis of observational research

Objectives: The aim of this study was to conduct a rapid systematic review and meta-analysis of estimates of the incubation period of COVID-19.Design: Rapid systematic review and meta-analysis of observational research.Setting: International studies on incubation period of COVID-19.Participants: Searches were carried out in PubMed, Google Scholar, Embase, Cochrane Library as well as the preprint servers MedRxiv and BioRxiv. Studies were selected for meta-analysis if they reported either the parameters and CIs of the distributions fit to the data, or sufficient information to facilitate calculation of those values. After initial eligibility screening, 24 studies were selected for initial review, nine of these were shortlisted for meta-analysis. Final estimates are from meta-analysis of eight studies.Primary outcome measures: Parameters of a lognormal distribution of incubation periods.Results: The incubation period distribution may be modelled with a lognormal distribution with pooled mu and sigma parameters (95% CIs) of 1.63 (95% CI 1.51 to 1.75) and 0.50 (95% CI 0.46 to 0.55), respectively. The corresponding mean (95% CIs) was 5.8 (95% CI 5.0 to 6.7) days. It should be noted that uncertainty increases towards the tail of the distribution: the pooled parameter estimates (95% CIs) resulted in a median incubation period of 5.1 (95% CI 4.5 to 5.8) days, whereas the 95th percentile was 11.7 (95% CI 9.7 to 14.2) days.Conclusions: The choice of which parameter values are adopted will depend on how the information is used, the associated risks and the perceived consequences of decisions to be taken. These recommendations will need to be revisited once further relevant information becomes available. Accordingly, we present an R Shiny app that facilitates updating these estimates as new data become available

Metal worker’s lung: spatial association with Mycobacterium avium

Background Outbreaks of hypersensitivity pneumonitis (HP) are not uncommon in workplaces where metal working fluid (MWF) is used to facilitate metal turning. Inhalation of microbe-contaminated MWF has been assumed to be the cause, but previous investigations have failed to establish a spatial relationship between a contaminated source and an outbreak. Objectives After an outbreak of five cases of HP in a UK factory, we carried out blinded, molecular-based microbiological investigation of MWF samples in order to identify potential links between specific microbial taxa and machines in the outbreak zone. Methods Custom-quantitative PCR assays, microscopy and phylogenetic analyses were performed on blinded MWF samples to quantify microbial burden and identify potential aetiological agents of HP in metal workers. Measurements and main results MWF from machines fed by a central sump, but not those with an isolated supply, was contaminated by mycobacteria. The factory sump and a single linked machine at the centre of the outbreak zone, known to be the workstation of the index cases, had very high levels of detectable organisms. Phylogenetic placement of mycobacterial taxonomic marker genes generated from these samples indicated that the contaminating organisms were closely related to Mycobacterium avium. Conclusions We describe, for the first time, a close spatial relationship between the abundance of a mycobacterium-like organism, most probably M. avium, and a localised outbreak of MWF-associated HP. The further development of sequence-based analytic techniques should assist in the prevention of this important occupational disease

Alineamiento de competencias, actividades y evaluación continuada en grupos grandes. Una propuesta desde el Derecho penal

El presente estudio expone la reflexión realizada por la Unidad de Derecho penal y Criminología de la UAB frente a la exigencia normativa de incrementar hasta el 50% de la nota final con la evaluación continuada. El reto era visto como una oportunidad para desarrollar resultados de aprendizaje mucho más prácticos; para diseñar e implementar un modelo de evaluación continuada sin que, en contextos de grupos grandes, necesariamente desbordara la capacidad de corrección de los profesores y de retorno de los resultados al alumnado; y, finalmente, para implementar una propuesta colectiva de alineamiento constructivo entre competencias, actividades propuestas a los alumnos dentro y fuera del aula y las actividades de evaluación continuada y final. La propuesta docente fue sometida a una encuesta de los alumnos y un grupo de discusión con los profesores dando como resultado una valoración positiva de los objetivos propuestos, así como de la necesidad de limitar el número de actividades evaluables para mejorar el rendimiento académico de los alumnos

Development and evaluation of the Galleria mellonella (greater wax moth) infection model to study Brucella host-pathogen interaction

Brucellosis is a zoonotic disease caused by Gram-negative bacteria of the genus Brucella. These pathogens cause long-lasting infections, a process in which Brucella modifications in the lipopolysaccharide (LPS) and envelope lipids reduce pathogen-associated molecular pattern (PAMP) recognition, thus hampering innate immunity activation. In vivo models are essential to investigate bacterial virulence, mice being the most used model. However, ethical and practical considerations impede their use in high-throughput screening studies. Although lacking the complexity of the mammalian immune system, insects share key-aspects of innate immunity with mammals, and Galleria mellonella has been used increasingly as a model. G. mellonella larvae have been shown useful in virulence analyses, including Gram-negative pathogens like Klebsiella pneumoniae and Legionella pneumophila. To assess its potential to study Brucella virulence, we first evaluated larva survival upon infection with representative Brucella species (i.e.B. abortus 2308W, B. microti CCM4915 and B. suis biovar 2) and mutants in the VirB type-IV secretion system (T4SS) or in the LPS-O-polysaccharide (O-PS). As compared to K.pneumoniae, the Brucella spp. tested induced a delayed and less severe mortality profile consistent with an escape of innate immunity detection. Brucella replication within larvae was affected by the lack of O-PS, which is reminiscent of their attenuation in natural hosts. On the contrary, replication was not affected by T4SS dysfunction and the mutant induced only slightly less mortality (not statistically significant) than its parental strain. We also evaluated G. mellonella to efficiently recognise Brucella and their LPS by quantification of the pro-phenoloxidase system and melanisation activation, using Pseudomonas LPS as a positive control. Among the brucellae, only B. microti LPS triggered an early-melanisation response consistent with the slightly increased endotoxicity of this species in mice. Therefore, G. mellonella represents a tool to screen for potential Brucella factors modulating innate immunity, but its usefulness to investigate other mechanisms relevant in Brucella intracellular life is limited

Determinants of R-loop formation at convergent bidirectionally transcribed trinucleotide repeats

R-loops have been described at immunoglobulin class switch sequences, prokaryotic and mitochondrial replication origins, and disease-associated (CAG)n and (GAA)n trinucleotide repeats. The determinants of trinucleotide R-loop formation are unclear. Trinucleotide repeat expansions cause diseases including DM1 (CTG)n, SCA1 (CAG)n, FRAXA (CGG)n, FRAXE (CCG)n and FRDA (GAA)n. Bidirectional convergent transcription across these disease repeats can occur. We find R-loops formed when CTG or CGG and their complementary strands CAG or CCG were transcribed; GAA transcription, but not TTC, yielded R-loops. R-loop formation was sensitive to DNA supercoiling, repeat length, insensitive to repeat interruptions, and formed by extension of RNA:DNA hybrids in the RNA polymerase. R-loops arose by transcription in one direction followed by transcription in the opposite direction, and during simultaneous convergent bidirectional transcription of the same repeat forming double R-loop structures. Since each transcribed disease repeat formed R-loops suggests they may have biological functions

Computer- or web-based interventions for perinatal mental health: A systematic review

Background: Treating prenatal mental health issues is of great importance, but access to treatment is often poor. One way of accessing treatment is through computer- or web-based interventions. Reviews have shown that these interventions can be effective for a variety of mental health disorder across different populations. However, their effectiveness for women in the perinatal period has not been reviewed. This review therefore aimed to provide a first overview of computer- or web-based interventions for women's perinatal mental health issues by systematically identifying and reviewing their characteristics and efficacy. Methods: Twelve electronic databases were searched for published and unpublished literature using keywords, supplemented by hand searches. Data were extracted for characteristics of the intervention and the study, study findings and the methodological quality was assessed. Results: The majority of the eleven eligible studies were randomized controlled trials. Interventions were targeted at depression, stress, and complicated grief during the antenatal or postpartum period or the time after pregnancy loss. Findings suggest that computer- or web-based interventions targeted at improving mental health, especially depression and complicated grief, may be effective. Limitations: Findings and their generalizability is limited by the heterogeneity of reviewed interventions and study designs, as well as methodological limitations. Conclusions: This systematic review constitutes the first synthesis of research on computer- or web-based interventions for perinatal mental health issues and provides preliminary support that this could be a promising form of treatment during this period. However, there are significant gaps in the current evidence-base so further research is needed

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy