Like-minded sources on Facebook are prevalent but not polarizing.

Many critics raise concerns about the prevalence of 'echo chambers' on social media and their potential role in increasing political polarization. However, the lack of available data and the challenges of conducting large-scale field experiments have made it difficult to assess the scope of the problem1,2. Here we present data from 2020 for the entire population of active adult Facebook users in the USA showing that content from 'like-minded' sources constitutes the majority of what people see on the platform, although political information and news represent only a small fraction of these exposures. To evaluate a potential response to concerns about the effects of echo chambers, we conducted a multi-wave field experiment on Facebook among 23,377 users for whom we reduced exposure to content from like-minded sources during the 2020 US presidential election by about one-third. We found that the intervention increased their exposure to content from cross-cutting sources and decreased exposure to uncivil language, but had no measurable effects on eight preregistered attitudinal measures such as affective polarization, ideological extremity, candidate evaluations and belief in false claims. These precisely estimated results suggest that although exposure to content from like-minded sources on social media is common, reducing its prevalence during the 2020 US presidential election did not correspondingly reduce polarization in beliefs or attitudes.

IDH-mutant myeloid neoplasms are associated with seronegative rheumatoid arthritis and innate immune activation.

ABSTRACT: High prevalence of IDH mutations in seronegative rheumatoid arthritis (RA) with myeloid neoplasm, elevated 2-hydroxyglutarate, dysregulated innate immunity, and proinflammatory microenvironment suggests causative association between IDH mutations and seronegative RA. Our findings merit investigation of IDH inhibitors as therapeutics for seronegative IDH-mutated RA.

Mitochondrial translocation of TFEB regulates complex I and inflammation.

TFEB is a master regulator of autophagy, lysosome biogenesis, mitochondrial metabolism, and immunity that works primarily through transcription controlled by cytosol-to-nuclear translocation. Emerging data indicate additional regulatory interactions at the surface of organelles such as lysosomes. Here we show that TFEB has a non-transcriptional role in mitochondria, regulating the electron transport chain complex I to down-modulate inflammation. Proteomics analysis reveals extensive TFEB co-immunoprecipitation with several mitochondrial proteins, whose interactions are disrupted upon infection with S. Typhimurium. High resolution confocal microscopy and biochemistry confirms TFEB localization in the mitochondrial matrix. TFEB translocation depends on a conserved N-terminal TOMM20-binding motif and is enhanced by mTOR inhibition. Within the mitochondria, TFEB and protease LONP1 antagonistically co-regulate complex I, reactive oxygen species and the inflammatory response. Consequently, during infection, lack of TFEB specifically in the mitochondria exacerbates the expression of pro-inflammatory cytokines, contributing to innate immune pathogenesis.

Disrupting hate: The effect of deplatforming hate organizations on their online audience.

How does removing the leadership of online hate organizations from online platforms change behavior in their target audience? We study the effects of six network disruptions of designated and banned hate-based organizations on Facebook, in which known members of the organizations were removed from the platform, by examining the online engagements of the audience of the organization. Using a differences-in-differences approach, we show that on average the network disruptions reduced the consumption and production of hateful content, along with engagement within the network among periphery members. Members of the audience closest to the core members exhibit signs of backlash in the short term, but reduce their engagement within the network and with hateful content over time. The results suggest that strategies of targeted removals, such as leadership removal and network degradation efforts, can reduce the ability of hate organizations to successfully operate online.

Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia.

Inducing cell death by the sphingolipid ceramide is a potential anticancer strategy, but the underlying mechanisms remain poorly defined. In this study, triggering an accumulation of ceramide in acute myeloid leukemia (AML) cells by inhibition of sphingosine kinase induced an apoptotic integrated stress response (ISR) through protein kinase R-mediated activation of the master transcription factor ATF4. This effect led to transcription of the BH3-only protein Noxa and degradation of the prosurvival Mcl-1 protein on which AML cells are highly dependent for survival. Targeting this novel ISR pathway, in combination with the Bcl-2 inhibitor venetoclax, synergistically killed primary AML blasts, including those with venetoclax-resistant mutations, as well as immunophenotypic leukemic stem cells, and reduced leukemic engraftment in patient-derived AML xenografts. Collectively, these findings provide mechanistic insight into the anticancer effects of ceramide and preclinical evidence for new approaches to augment Bcl-2 inhibition in the therapy of AML and other cancers with high Mcl-1 dependency.

Interband cascade lasers grown simultaneously on GaSb, GaAs and Si substrates.

We report on Sb-based interband cascade lasers simultaneously grown on GaSb, GaAs and Si substrates. 8 µm x 2 mm devices exhibited similar threshold currents around 40 mA at 20°C and achieved continuous-wave (CW) operation up to 65°C on GaSb, GaAs and Si substrates despite a dislocation density of ∼ 4.108 cm-2 for both mismatched substrates. In the CW regime the output power of the devices emitting at 3.3 µm exceeded 30 mW/facet at 20°C. ICLs on GaAs and Si were subsequently aged at 50°C with an injection current of 200 mA, i.e. five times the laser-threshold current. No degradation was observed after 500 h of CW operation, demonstrating the high performance of ICLs and their tolerance to dislocations.

Targeting human CALR-mutated MPN progenitors with a neoepitope-directed monoclonal antibody.

Calreticulin (CALR) is recurrently mutated in myelofibrosis via a frameshift that removes an endoplasmic reticulum retention signal, creating a neoepitope potentially targetable by immunotherapeutic approaches. We developed a specific rat monoclonal IgG2α antibody, 4D7, directed against the common sequence encoded by both insertion and deletion mutations. 4D7 selectively bound to cells co-expressing mutant CALR and thrombopoietin receptor (TpoR) and blocked JAK-STAT signalling, TPO-independent proliferation and megakaryocyte differentiation of mutant CALR myelofibrosis progenitors by disrupting the binding of CALR dimers to TpoR. Importantly, 4D7 inhibited proliferation of patient samples with both insertion and deletion CALR mutations but not JAK2 V617F and prolonged survival in xenografted bone marrow models of mutant CALR-dependent myeloproliferation. Together, our data demonstrate a novel therapeutic approach to target a problematic disease driven by a recurrent somatic mutation that would normally be considered undruggable.

A genetically related cluster of Salmonella Typhimurium cases in humans associated with ruminant livestock and related food chains, United Kingdom, August 2021-December 2022.

Following an outbreak of Salmonella Typhimurium in Wales in July 2021 associated with sheep meat and offal, further genetically related cases were detected across the UK. Cases were UK residents with laboratory-confirmed Salmonella Typhimurium in the same 5-single-nucleotide polymorphism (SNP) single-linkage cluster with specimen date between 01/08/2021-2031/12/2022. We described cases using routine (UK) and enhanced (Wales only) surveillance data. Exposures in cases in Wales were compared with non-Typhimurium Salmonella case-controls. Environmental Health Practitioners and the Food Standards Agency investigated supply chains of food premises reported by ≥2 cases. Animal, carcass, and environmental samples taken for diagnostic or monitoring purposes for gastrointestinal pathogens were included in microbiological investigations. We identified 142 cases: 75% in England, 23% in Wales and 3% in Scotland. Median age was 32 years, and 59% were male. Direct contact with sheep was associated with becoming a case (aOR: 14, 95%CI: 1.4-145) but reported by few (6/32 cases). No single food item, premises, or supplier linked all cases. Multi-agency collaboration enabled the identification of isolates in the same 5-SNP single-linkage cluster from a sheep carcass at an English abattoir and in ruminant, wildlife, poultry, and environmental samples, suggesting multiple vehicles and pathways of infection.

Evolutionary divergence of enzymatic mechanisms for posttranslational polyglycylation.

Polyglycylation is a posttranslational modification that generates glycine side chains on proteins. Here we identify a family of evolutionarily conserved glycine ligases that modify tubulin using different enzymatic mechanisms. In mammals, two distinct enzyme types catalyze the initiation and elongation steps of polyglycylation, whereas Drosophila glycylases are bifunctional. We further show that the human elongating glycylase has lost enzymatic activity due to two amino acid changes, suggesting that the functions of protein glycylation could be sufficiently fulfilled by monoglycylation. Depletion of a glycylase in Drosophila using RNA interference results in adult flies with strongly decreased total glycylation levels and male sterility associated with defects in sperm individualization and axonemal maintenance. A more severe RNAi depletion is lethal at early developmental stages, indicating that protein glycylation is essential. Together with the observation that multiple proteins are glycylated, our functional data point towards a general role of glycylation in protein functions.

Developing a best-practice agenda for music therapy research to support informal carers of terminally ill patients pre- and post-death bereavement: a world café approach.

BACKGROUND: Informal carers of terminally ill patients play a vital role in providing palliative care at home, which impacts on their pre- and post-death bereavement experience and presents an up to 50% greater risk for mental-health problems. However, developing and implementing effective bereavement support remains challenging. There is a need to build the evidence base for music therapy as a potentially promising bereavement support for this vulnerable population. This study aimed to co-design an international best practice agenda for research into music therapy for informal carers of patients pre- and post-death bereavement. METHODS: Online half day workshop using a World Café approach; an innovative method for harnessing group intelligence within a group of international expert stakeholders (music therapy clinicians and academics with experience of music therapy with informal carers at end-of-life). Demographics, experience, key priorities and methodological challenges were gathered during a pre-workshop survey to inform workshop discussions. The online workshop involved four rounds of rotating, 25-minute, small group parallel discussions using Padlet. One final large group discussion involved a consensus building activity. All data were analysed thematically to identify patterns to inform priorities and recommendations. RESULTS: Twenty-two consented and completed the pre-event survey (response rate 44%), from countries representing 10 different time zones. Sixteen participated in the workshop and developed the following best practice agenda. The effectiveness of music therapy in supporting informal carers across the bereavement continuum should be prioritised. This should be done using a mixed methods design to draw on the strengths of different methodological approaches to building the evidence base. It should involve service users throughout and should use a core outcome set to guide the choice of clinically important bereavement outcome measures in efficacy/effectiveness research. CONCLUSIONS: Findings should inform future pre- and post-death bereavement support research for informal caregivers of terminally ill patients. This is an important step in building the evidence base for commissioners and service providers on how to incorporate more innovative approaches in palliative care bereavement services.

Is heated tobacco a harm reduction tool? / Le tabac chauffé est-il un outil de réduction des risques ?

Heated tobacco (HT), a new tobacco product, is presented by the tobacco industry as an effective and safe alternative to cigarettes. Even if the quantities of harmful compounds emitted by HT are lower than those found in cigarette smoke, this reduction in exposure cannot be equated with a reduction in risk. No study has provided evidence that switching from cigarettes to HT reduces the risk of tobacco-related diseases. HT cannot be considered as a cigarette cessation product and was even designed as a product to initiate or return to tobacco consumption. To promote this product, the tobacco industry essentially exploits the concept of harm reduction and, as such, tries in its commercial communication to create confusion between HT and electronic cigarettes, despite these two products having nothing in common. This promotion is based, on the one hand, on the data of internal studies in contradiction with those of independent studies, and, on the other, illegally, on social networks and communication in contradiction with the statements of regulation authorities. HT is a new lure offered by the tobacco industry, intended to maintain its profits in a world that is moving away from "traditional" cigarettes. It should be strictly advised against for both non-smokers and smokers.

Le tabac chauffé (TC), nouveau produit du tabac, est présenté par l'industrie du tabac comme une alternative efficace et sûre à la cigarette. Même si les quantités de composés nocifs pour la santé émises par le TC sont inférieures à celles trouvées dans la fumée de cigarette, cette diminution d'exposition ne peut être assimilée à une réduction des risques. Aucune étude n'a apporté la preuve que le passage de la cigarette au TC réduisait le risque des maladies liées au tabac. Le TC ne peut pas être considéré comme un produit de sevrage de la cigarette et a même été conçu comme un produit pour entrer dans la consommation de tabac ou y revenir. Pour faire la promotion de ce produit, l'industrie du tabac exploite essentiellement le concept de réduction des risques et, à ce titre, essaie dans sa communication commerciale de créer la confusion entre le TC et la cigarette électronique alors que ces deux produits n'ont rien à voir. Cette promotion s'appuie, d'une part, sur les données d'études internes contradictoires avec celles d'études indépendantes, d'autre part, de façon illégale, sur les réseaux sociaux et une communication en contradiction avec les avis des autorités de régulation. Le TC est un nouveau leurre de l'industrie du tabac, destiné à assurer le maintien de ses profits dans un monde qui s'éloigne de la cigarette « traditionnelle ¼. Il doit être formellement déconseillé, tant aux non-fumeurs qu'aux fumeurs.

Determination of Indispensable Amino Acid Digestibility of the Red Kidney Bean in Humans Using a Dual Stable Isotope Tracer Method.

BACKGROUND: Protein quality of the red kidney bean (RKB), a common source of dietary protein, has been assessed using the protein digestibility-corrected amino acid score (PDCAAS) determined in animal models using mainly oro-fecal digestibility. More recently, the FAO recommended to use digestible indispensable amino acid score (DIAAS) instead of PDCAAS but highlighted insufficient data on true ileal indispensable amino acid (IAA) digestibility of proteins because amino acids are absorbed in the ileum. OBJECTIVES: Using a recently developed dual stable isotope tracer method, we aimed to measure each IAA digestibility as representation of true ileal digestibility of the RKB, Phaseolus vulgaris, in humans consuming a typical Jamaican meal. METHODS: RKB-IAAs were intrinsically labeled by adding 2H2O to the plants. Uniformly labeled-[13C]-spirulina (standard protein) was added to a meal prepared with the labeled RKB and fed to 10 healthy adults (5 males, 5 females) in a nonrandomized trial as primed/intermittent doses to achieve a steady state IAA enrichment in plasma. Enrichment of 2H- and 13C-labeled IAA in plasma and the bean was measured by mass spectrometry. Each IAA digestibility (except tryptophan and histidine) was calculated as the ratio of plasma 2H-IAA to meal 2H-IAA divided by the ratio of plasma 13C-IAA to meal 13C-IAA adjusted for loss of 2H-atom during transamination and digestibility of spirulina. RESULTS: Adequate IAA labeling (>1000 ppm 2H excess) and plasma plateau isotopic enrichment were achieved. Mean RKB-IAA digestibility (%) was 79.4 ± 0.5, ranging from 69.0 ± 1.2 (threonine) to 85.7 ± 1.7 (lysine). CONCLUSION: The dual stable isotope tracer digestibility data are similar to published oro-fecal digestibility supporting substantial nitrogen exchange in the colon. The individual IAA digestibility is useful to derive DIAAS to replace PDCAAS. Using published RKB-IAA composition, extrapolated DIAAS was 0.63 based on the lowest score for methionine. CLINICAL TRIAL REGISTRATION: https://register. CLINICALTRIALS: gov; ID: NCT-04118517.

Reflux of Endoplasmic Reticulum proteins to the cytosol inactivates tumor suppressors.

In the past decades, many studies reported the presence of endoplasmic reticulum (ER)-resident proteins in the cytosol. However, the mechanisms by which these proteins relocate and whether they exert cytosolic functions remain unknown. We find that a subset of ER luminal proteins accumulates in the cytosol of glioblastoma cells isolated from mouse and human tumors. In cultured cells, ER protein reflux to the cytosol occurs upon ER proteostasis perturbation. Using the ER luminal protein anterior gradient 2 (AGR2) as a proof of concept, we tested whether the refluxed proteins gain new functions in the cytosol. We find that refluxed, cytosolic AGR2 binds and inhibits the tumor suppressor p53. These data suggest that ER reflux constitutes an ER surveillance mechanism to relieve the ER from its contents upon stress, providing a selective advantage to tumor cells through gain-of-cytosolic functions-a phenomenon we name ER to Cytosol Signaling (ERCYS).

An outbreak of Salmonella Typhimurium associated with the consumption of raw liver at an Eid al-Adha celebration in Wales (UK), July 2021.

In July 2021, Public Health Wales received two notifications of salmonella gastroenteritis. Both cases has attended the same barbecue to celebrate Eid al-Adha, two days earlier. Additional cases attending the same barbecue were found and an outbreak investigation was initiated. The barbecue was attended by a North African community's social network. On same day, smaller lunches were held in three homes in the social network. Many people attended both a lunch and the barbecue. Cases were defined as someone with an epidemiological link to the barbecue and/or lunches with diarrhoea and/or vomiting with date of onset following these events. We undertook a cohort study of 36 people attending the barbecue and/or lunch, and a nested case-control study using Firth logistic regression. A communication campaign, sensitive towards different cultural practices, was developed in collaboration with the affected community. Consumption of a traditional raw liver dish, 'marrara', at the barbecue was the likely vehicle for infection (Firth logistic regression, aOR: 49.99, 95%CI 1.71-1461.54, p = 0.02). Meat and offal came from two local butchers (same supplier) and samples yielded identical whole genome sequences as cases. Future outbreak investigations should be relevant to the community affected by considering dishes beyond those found in routine questionnaires.

Infrared action spectroscopy of the deprotonated formic acid trimer, trapped in helium nanodroplets.

Hydrogen bonding interactions are essential in the structural stabilization and physicochemical properties of complex molecular systems, and carboxylic acid functional groups are common participants in these motifs. Consequently, the neutral formic acid (FA) dimer has been extensively investigated in the past, as it represents a useful model system to investigate proton donor-acceptor interactions. The analogous deprotonated dimers, in which two carboxylate groups are bound by a single proton, have also served as informative model systems. In these complexes, the position of the shared proton is mainly determined by the proton affinity of the carboxylate units. However, very little is known about the nature of the hydrogen bonding interactions in systems containing more than two carboxylate units. Here we report a study on the deprotonated (anionic) FA trimer. IR spectra are recorded in the 400-2000 cm-1 spectral range by means of vibrational action spectroscopy of FA trimer ions embedded in helium nanodroplets. Characterization of the gas-phase conformer and assignment of the vibrational features is achieved by comparing the experimental results with electronic structure calculations. To assist in the assignments, the 2H and 18O FA trimer anion isotopologues are also measured under the same experimental conditions. Comparison between the experimental and computed spectra, especially the observed shifts in spectral line positions upon isotopic substitution of the exchangeable protons, suggests that the prevalent conformer, under the experimental conditions, exhibits a planar structure that resembles the crystalline structure of formic acid.

Association between single-slice and whole heart measurements of epicardial and pericardial fat in cardiac MRI.

BACKGROUND: Epicardial (ECF) and pericardial fat (PCF) are important prognostic markers for various cardiac diseases. However, volumetry of the fat compartments is time-consuming. PURPOSE: To investigate whether total volume of ECF and PCF can be estimated by axial single-slice measurements and in a four-chamber view. MATERIAL AND METHODS: A total of 113 individuals (79 patients and 34 healthy) were included in this retrospective magnetic resonance imaging (MRI) study. The total volume of ECF and PCF was determined using a 3D-Dixon sequence. Additionally, the area of ECF and PCF was obtained in single axial layers at five anatomical landmarks (left coronary artery, right coronary artery, right pulmonary artery, mitral valve, coronary sinus) of the Dixon sequence and in a four-chamber view of a standard cine sequence. Pearson's correlation coefficient was calculated between the total volume and each single-slice measurement. RESULTS: Axial single-slice measurements of ECF and PCF correlated strongly with the total fat volumes at all landmarks (ECF: r = 0.85-0.94, P < 0.001; PCF: r = 0.89-0.94, P < 0.001). The best correlation was found at the level of the left coronary artery for ECF and PCF (r = 0.94, P < 0.001). Correlation between single-slice measurement in the four-chamber view and the total ECF and PCF volume was lower (r = 0.75 and r = 0.8, respectively, P < 0.001). CONCLUSION: Single-slice measurements allow an estimation of ECF and PCF volume. This time-efficient analysis allows studies of larger patient cohorts and the opportunistic determination of ECF/PCF from routine examinations.

Serosurveillance of SARS-CoV-2 in Welsh Blood Donors: Establishment of the surveillance system and results up to November 2022.

BackgroundIn 2020, Wales experienced some of the highest rates of confirmed COVID-19 cases in Europe. We set up a serosurveillance scheme using residual samples from blood donations to inform the pandemic response in Wales.AimTo identify changes in SARS-CoV-2 antibody seroprevalence in Wales by time, demography and location.MethodsResidual samples from blood donations made in Wales between 29 June 2020 and 20 November 2022 were tested for antibodies to the nucleocapsid antigen (anti-N) of SARS-CoV-2, resulting from natural infection. Donations made between 12 April 2021 and 20 November 2022 were also tested for antibodies to the spike antigen (anti-S) occurring as a result of natural infection and vaccination.ResultsAge-standardised seroprevalence of anti-N antibodies in donors remained stable (4.4-5.5%) until November 2020 before increasing to 16.7% by February 2021. Trends remained steady until November 2021 before increasing, peaking in November 2022 (80.2%). For anti-S, seroprevalence increased from 67.1% to 98.6% between May and September 2021, then remained above 99%. Anti-N seroprevalence was highest in younger donors and in donors living in urban South Wales. In contrast, seroprevalence of anti-S was highest in older donors and was similar across regions. No significant difference was observed by sex. Seroprevalence of anti-N antibodies was higher in Black, Asian and other minority ethnicities (self-reported) compared with White donors, with the converse observed for anti-S antibodies.ConclusionWe successfully set up long-term serological surveillance of SARS-CoV-2 using residual samples from blood donations, demonstrating variation based on age, ethnicity and location.

Le tabac chauffé est-il un outil de réduction des risques ?

Heated tobacco (HT), a new tobacco product, is presented by the tobacco industry as an effective and safe alternative to cigarettes. Even if the quantities of harmful compounds emitted by HT are lower than those found in cigarette smoke, this reduction in exposure cannot be equated with a reduction in risk. No study has provided evidence that switching from cigarettes to HT reduces the risk of tobacco-related diseases. HT cannot be considered as a cigarette cessation product and was even designed as a product to initiate or return to tobacco consumption. To promote this product, the tobacco industry essentially exploits the concept of harm reduction and, as such, tries in its commercial communication to create confusion between HT and electronic cigarettes, despite these two products having nothing in common. This promotion is based, on the one hand, on the data of internal studies in contradiction with those of independent studies, and, on the other, illegally, on social networks and communication in contradiction with the statements of regulation authorities. HT is a new lure offered by the tobacco industry, intended to maintain its profits in a world that is moving away from "traditional" cigarettes. It should be strictly advised against for both non-smokers and smokers.

Genomes shed light on the evolution of Begonia, a mega-diverse genus.

Clarifying the evolutionary processes underlying species diversification and adaptation is a key focus of evolutionary biology. Begonia (Begoniaceae) is one of the most species-rich angiosperm genera with c. 2000 species, most of which are shade-adapted. Here, we present chromosome-scale genome assemblies for four species of Begonia (B. loranthoides, B. masoniana, B. darthvaderiana and B. peltatifolia), and whole genome shotgun data for an additional 74 Begonia representatives to investigate lineage evolution and shade adaptation of the genus. The four genome assemblies range in size from 331.75 Mb (B. peltatifolia) to 799.83 Mb (B. masoniana), and harbor 22 059-23 444 protein-coding genes. Synteny analysis revealed a lineage-specific whole-genome duplication (WGD) that occurred just before the diversification of Begonia. Functional enrichment of gene families retained after WGD highlights the significance of modified carbohydrate metabolism and photosynthesis possibly linked to shade adaptation in the genus, which is further supported by expansions of gene families involved in light perception and harvesting. Phylogenomic reconstructions and genomics studies indicate that genomic introgression has also played a role in the evolution of Begonia. Overall, this study provides valuable genomic resources for Begonia and suggests potential drivers underlying the diversity and adaptive evolution of this mega-diverse clade.