Clathrin mediates both internalization and vesicular release of triggered T cell receptor at the immunological synapse

Ligation of T cell receptor (TCR) to peptide-MHC (pMHC) complexes initiates signaling leading to T cell activation and TCR ubiquitination. Ubiquitinated TCR is then either internalized by the T cell or released toward the antigen-presenting cell (APC) in extracellular vesicles. How these distinct fates are orchestrated is unknown. Here, we show that clathrin is first recruited to TCR microclusters by HRS and STAM2 to initiate release of TCR in extracellular vesicles through clathrin- and ESCRT-mediated ectocytosis directly from the plasma membrane. Subsequently, EPN1 recruits clathrin to remaining TCR microclusters to enable trans-endocytosis of pMHC-TCR conjugates from the APC. With these results, we demonstrate how clathrin governs bidirectional membrane exchange at the immunological synapse through two topologically opposite processes coordinated by the sequential recruitment of ecto- and endocytic adaptors. This provides a scaffold for direct two-way communication between T cells and APCs

Tyrosol, at the concentration found in Maltese extra virgin olive oil, induces HL-60 differentiation towards the monocyte lineage

Tyrosol is a phenolic found in extra virgin olive oil (EVOO). In a Maltese monocultivar EVOO, it was present at a concentration of 9.23 ppm. The HL-60 acute myeloid leukaemia cell line, which can be differentiated to both monocytes and neutrophils, was exposed to tyrosol at this concentration and analysed for evidence of differentiation and effects of cytotoxicity. The polyphenol induced a 1.93-fold increase in cellular oxidative activity (p-value 0.044) and enhanced surface expression of CD11b and CD14. This indicates that tyrosol induces monocytic-like differentiation. An RNA-seq analysis confirmed the upregulation of monocyte genes and the loss of neutrophil genes concomitant with the bi-potential promyelocyte precursor moving down the monocytic pathway. A cell cycle analysis showed an accumulation of cells in the Sub G0/G1 phase following tyrosol exposure for 5 days, which coincided with an increase in apoptotic and necrotic markers. This indicates differentiation followed by cell death, unlike the positive monocyte differentiation control PMA. This selective cytotoxic effect following differentiation indicates therapeutic potential against leukaemia.peer-reviewe

Formative evaluation of the telecare fall prevention project for older veterans

<p>Abstract</p> <p>Background</p> <p>Fall prevention interventions for community-dwelling older adults have been found to reduce falls in some research studies. However, wider implementation of fall prevention activities in routine care has yielded mixed results. We implemented a theory-driven program to improve care for falls at our Veterans Affairs healthcare facility. The first project arising from this program used a nurse advice telephone line to identify patients' risk factors for falls and to triage patients to appropriate services. Here we report the formative evaluation of this project.</p> <p>Methods</p> <p>To evaluate the intervention we: 1) interviewed patient and employee stakeholders, 2) reviewed participating patients' electronic health record data and 3) abstracted information from meeting minutes. We describe the implementation process, including whether the project was implemented according to plan; identify barriers and facilitators to implementation; and assess the incremental benefit to the quality of health care for fall prevention received by patients in the project. We also estimate the cost of developing the pilot project.</p> <p>Results</p> <p>The project underwent multiple changes over its life span, including the addition of an option to mail patients educational materials about falls. During the project's lifespan, 113 patients were considered for inclusion and 35 participated. Patient and employee interviews suggested support for the project, but revealed that transportation to medical care was a major barrier in following up on fall risks identified by nurse telephone triage. Medical record review showed that the project enhanced usual medical care with respect to home safety counseling. We discontinued the program after 18 months due to staffing limitations and competing priorities. We estimated a cost of $9194 for meeting time to develop the project.</p> <p>Conclusions</p> <p>The project appeared feasible at its outset but could not be sustained past the first cycle of evaluation due to insufficient resources and a waning of local leadership support due to competing national priorities. Future projects will need both front-level staff commitment and prolonged high-level leadership involvement to thrive.</p

Design of a continuous quality improvement program to prevent falls among community-dwelling older adults in an integrated healthcare system

<p>Abstract</p> <p>Background</p> <p>Implementing quality improvement programs that require behavior change on the part of health care professionals and patients has proven difficult in routine care. Significant randomized trial evidence supports creating fall prevention programs for community-dwelling older adults, but adoption in routine care has been limited. Nationally-collected data indicated that our local facility could improve its performance on fall prevention in community-dwelling older people. We sought to develop a sustainable local fall prevention program, using theory to guide program development.</p> <p>Methods</p> <p>We planned program development to include important stakeholders within our organization. The theory-derived plan consisted of 1) an initial leadership meeting to agree on whether creating a fall prevention program was a priority for the organization, 2) focus groups with patients and health care professionals to develop ideas for the program, 3) monthly workgroup meetings with representatives from key departments to develop a blueprint for the program, 4) a second leadership meeting to confirm that the blueprint developed by the workgroup was satisfactory, and also to solicit feedback on ideas for program refinement.</p> <p>Results</p> <p>The leadership and workgroup meetings occurred as planned and led to the development of a functional program. The focus groups did not occur as planned, mainly due to the complexity of obtaining research approval for focus groups. The fall prevention program uses an existing telephonic nurse advice line to 1) place outgoing calls to patients at high fall risk, 2) assess these patients' risk factors for falls, and 3) triage these patients to the appropriate services. The workgroup continues to meet monthly to monitor the progress of the program and improve it.</p> <p>Conclusion</p> <p>A theory-driven program development process has resulted in the successful initial implementation of a fall prevention program.</p

Effect of Neutralizing Monoclonal Antibody Treatment on Early Trajectories of Virologic and Immunologic Biomarkers in Patients Hospitalized With COVID-19

BACKGROUND: Neutralizing monoclonal antibodies (nmAbs) failed to show clear benefit for hospitalized patients with coronavirus disease 2019 (COVID-19). Dynamics of virologic and immunologic biomarkers remain poorly understood. METHODS: Participants enrolled in the Therapeutics for Inpatients with COVID-19 trials were randomized to nmAb versus placebo. Longitudinal differences between treatment and placebo groups in levels of plasma nucleocapsid antigen (N-Ag), anti-nucleocapsid antibody, C-reactive protein, interleukin-6, and D-dimer at enrollment, day 1, 3, and 5 were estimated using linear mixed models. A 7-point pulmonary ordinal scale assessed at day 5 was compared using proportional odds models. RESULTS: Analysis included 2149 participants enrolled between August 2020 and September 2021. Treatment resulted in 20% lower levels of plasma N-Ag compared with placebo (95% confidence interval, 12%-27%; P \u3c .001), and a steeper rate of decline through the first 5 days (P \u3c .001). The treatment difference did not vary between subgroups, and no difference was observed in trajectories of other biomarkers or the day 5 pulmonary ordinal scale. CONCLUSIONS: Our study suggests that nmAb has an antiviral effect assessed by plasma N-Ag among hospitalized patients with COVID-19, with no blunting of the endogenous anti-nucleocapsid antibody response. No effect on systemic inflammation or day 5 clinical status was observed. CLINICAL TRIALS REGISTRATION: NCT04501978

Alcohol consumption and lung cancer risk: A pooled analysis from the International Lung Cancer Consortium and the SYNERGY study

Background: There is inadequate evidence to determine whether there is an effect of alcohol consumption on lung cancer risk. We conducted a pooled analysis of data from the International Lung Cancer Consortium and the SYNERGY study to investigate this possible association by type of beverage with adjustment for other potential confounders. Methods: Twenty one case-control studies and one cohort study with alcohol-intake data obtained from questionnaires were included in this pooled analysis (19,149 cases and 362,340 controls). Adjusted odds ratios (OR) or hazard ratios (HR) with corresponding 95% confidence intervals (CI) were estimated for each measure of alcohol consumption. Effect estimates were combined using random or fixed-effects models where appropriate. Associations were examined for overall lung cancer and by histological type. Results: We observed an inverse association between overall risk of lung cancer and consumption of alcoholic beverages compared to non-drinkers, but the association was not monotonic. The lowest risk was observed for persons who consumed 10-19.9 g/day ethanol (OR vs. non-drinkers = 0.78; 95% CI: 0.67, 0.91), where 1 drink is approximately 12-15 g. This J-shaped association was most prominent for squamous cell carcinoma (SCC). The association with all lung cancer varied little by type of alcoholic beverage, but there were notable differences for SCC. We observed an association with beer intake (OR for >= 20 g/day vs nondrinker = 1.42; 95% CI: 1.06, 1.90). Conclusions: Whether the non-monotonic associations we observed or the positive association between beer drinking and squamous cell carcinoma reflect real effects await future analyses and insights about possible biological mechanisms

Acute graft versus host disease

Acute graft-versus-host disease (GVHD) occurs after allogeneic hematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues. Activated donor T cells damage host epithelial cells after an inflammatory cascade that begins with the preparative regimen. About 35%–50% of hematopoietic stem cell transplant (HSCT) recipients will develop acute GVHD. The exact risk is dependent on the stem cell source, age of the patient, conditioning, and GVHD prophylaxis used. Given the number of transplants performed, we can expect about 5500 patients/year to develop acute GVHD. Patients can have involvement of three organs: skin (rash/dermatitis), liver (hepatitis/jaundice), and gastrointestinal tract (abdominal pain/diarrhea). One or more organs may be involved. GVHD is a clinical diagnosis that may be supported with appropriate biopsies. The reason to pursue a tissue biopsy is to help differentiate from other diagnoses which may mimic GVHD, such as viral infection (hepatitis, colitis) or drug reaction (causing skin rash). Acute GVHD is staged and graded (grade 0-IV) by the number and extent of organ involvement. Patients with grade III/IV acute GVHD tend to have a poor outcome. Generally the patient is treated by optimizing their immunosuppression and adding methylprednisolone. About 50% of patients will have a solid response to methylprednisolone. If patients progress after 3 days or are not improved after 7 days, they will get salvage (second-line) immunosuppressive therapy for which there is currently no standard-of-care. Well-organized clinical trials are imperative to better define second-line therapies for this disease. Additional management issues are attention to wound infections in skin GVHD and fluid/nutrition management in gastrointestinal GVHD. About 50% of patients with acute GVHD will eventually have manifestations of chronic GVHD

Characterizing Emerging Canine H3 Influenza Viruses.

The continual emergence of novel influenza A strains from non-human hosts requires constant vigilance and the need for ongoing research to identify strains that may pose a human public health risk. Since 1999, canine H3 influenza A viruses (CIVs) have caused many thousands or millions of respiratory infections in dogs in the United States. While no human infections with CIVs have been reported to date, these viruses could pose a zoonotic risk. In these studies, the National Institutes of Allergy and Infectious Diseases (NIAID) Centers of Excellence for Influenza Research and Surveillance (CEIRS) network collaboratively demonstrated that CIVs replicated in some primary human cells and transmitted effectively in mammalian models. While people born after 1970 had little or no pre-existing humoral immunity against CIVs, the viruses were sensitive to existing antivirals and we identified a panel of H3 cross-reactive human monoclonal antibodies (hmAbs) that could have prophylactic and/or therapeutic value. Our data predict these CIVs posed a low risk to humans. Importantly, we showed that the CEIRS network could work together to provide basic research information important for characterizing emerging influenza viruses, although there were valuable lessons learned

Nikteb...

Ġabra ta’ poeżiji u proża li tinkludi: L-iben il-ħali ta’ David Agius Muscat – Kaptan ta’ Kit Azzopardi – Il-lanterna ta’ Charles Bezzina – Li kelli mmur lura ta’ Ġorġ Borg – Firda ta’ Ġorġ Borg – Garden fairy ta’ Charles Briffa – Sejf jinfidlek ruħek ta’ Charles Briffa – Waqt ta’ Joseph Buttigieg – Vjaġġ ta’ John Caruana – Ċaqlembuta ta’ Antoine Cassar – Ħaġa tqila ta’ Carmel G. Cauchi – F’tarf il-blat ta’ Leanne Ellul – Int ta’ Victor Fenech – Pippin u l-bojja ta’ Charles Flores – L-arloġġ ta’ Joe Friggieri – Il-fjur tal-ġakaranda ta’ Joe Friggieri – Fjur tal-kaktus ta’ Joel Galea – Biss is-skiet ta’ Joel Galea – Għalissa ta’ Maria Grech Ganado – Ilsna ta’ Maria Grech Ganado – Is-sried ixoqqna fin fin ta’ Adrian Grima – Ħsieb ħalliel... ta’ Patrick Sammut – Lament lil ommi ta’ Salv Sammut – Hekk kif tinħass ġol-arja x-xitwa ta’ Lillian Sciberras – F’għajnejha, il-ħarsa siekta ta’ Clare Azzopardi – Għad jagħdab l-irdum ta’ Paul P. Borg – Forsi...xi darba ta’ Charles Casha – Faxxa ngħas ta’ Sergio Grech – Il-mejda tal-mogħdija ta’ Pierre J. Mejlak – Min jaf bi Stojan Kurepa? ta’ Immanuel Mifsud – L-eħrex jum tal-gwerra ta’ Maurice Mifsud Bonnici – Il-vażett tal-bewsiet ta’ Rita Saliba – Pjanu ta’ Trevor Żahra – Il-ħalliel ta’ Guy de Maupassant, traduzzjoni ta’ Toni Aquilina – Salvu tal-pasturi ta’ Francis Ebejer, traduzzjoni ta’ Steve Borg – Sunetti ta’ William Shakespeare, traduzzjoni ta’ Oliver Friggieri – Nikteb... ta’ Nizar Qabbani, traduzzjoni ta’ Kevin Saliba.peer-reviewe

An open-access database and analysis tool for perovskite solar cells based on the FAIR data principles

Large datasets are now ubiquitous as technology enables higher-throughput experiments, but rarely can a research field truly benefit from the research data generated due to inconsistent formatting, undocumented storage or improper dissemination. Here we extract all the meaningful device data from peer-reviewed papers on metal-halide perovskite solar cells published so far and make them available in a database. We collect data from over 42,400 photovoltaic devices with up to 100 parameters per device. We then develop open-source and accessible procedures to analyse the data, providing examples of insights that can be gleaned from the analysis of a large dataset. The database, graphics and analysis tools are made available to the community and will continue to evolve as an open-source initiative. This approach of extensively capturing the progress of an entire field, including sorting, interactive exploration and graphical representation of the data, will be applicable to many fields in materials science, engineering and biosciences