Miracle-dz/UniFAR-FTUs huggingface dataset:
Serum proteomic profiles of UK Biobank participants with Multiple Sclerosis

Discovery of serum protein biomarkers for Multiple Sclerosis risk and severity could shed light on pathophysiological mechanisms, suggest new drug targets, enhance the speed of diagnosis, and improve risk stratification algorithms for use in clinical practice or in the identification of high-risk participants for prevention trials. Prior proteome-wide studies of Multiple Sclerosis have yielded inconsistent results due to small sample sizes. We aimed to describe serum protein biomarkers of Multiple Sclerosis risk and to explore protein biomarkers of disease severity using radiological outcome measures. Multiple Sclerosis cases and controls were identified in UK Biobank, a longitudinal cohort study of ~500,000 British adults. Serum proteins were assayed in ~50,000 UK Biobank participants using the Olink proximity extension assay. We performed case-control association testing to examine the association between ~1300 proteins and Multiple Sclerosis, using linear models adjusted for confounding covariates. We performed a range of sensitivity analyses and validated our findings in a semi-independent testing set. We then compared results across a range of other autoimmune and neurodegenerative diseases within UK Biobank to evaluate disease specificity. Finally, associations with radiological lesion burden and brain volume were determined using a subset with available magnetic resonance imaging, using normalised T2-hyperintensity volume or whole brain volume as the outcome measure. 380 prevalent Multiple Sclerosis cases and 38,263 healthy controls were included. Cases and controls were reasonably well-matched for age, sex, ethnicity, and deprivation status. We discovered 100 proteins associated with Multiple Sclerosis at a Bonferroni-adjusted p-value of 0.05. The only proteins elevated in Multiple Sclerosis at this significance level were interleukin-15 and neurofilament light chain. 98 proteins were decreased in Multiple Sclerosis, including several integrin proteins and cystatin D. Suggestive (False Discovery Rate < 1%) positive associations were found for an additional 13 proteins, including Glial Fibrillary Acidic Protein, interleukin-17 receptor beta, and the interleukin-1 receptor accessory protein. A substantial minority of these proteins, including cystatin D, were not associated with other autoimmune or neurodegenerative disorders and so could be considered MS-specific. We found evidence (P < 0.05) for an association between higher serum Neurofilament Light Chain and T2 lesion load. We report the largest serum proteomic screen of Multiple Sclerosis, replicating important known associations and strengthening the evidence for the role of serum interleukin-15. While these findings require external validation, they demonstrate the power of biobank-scale datasets for discovering new biomarkers for Multiple Sclerosis.
Age- and sex-specific differences in immune responses to BNT162b2 COVID-19 and live-attenuated influenza vaccines in UK adolescents

Key to understanding COVID-19 correlates of protection is assessing vaccine-induced immunity in different demographic groups. Sex- and age-specific immune differences have a wide impact on outcomes from infections and immunisations. Typically, adult females make stronger immune responses and have better disease outcomes but suffer more adverse events following vaccination and are more prone to autoimmune disease. To understand better the mechanisms underlying these differences in vaccine responses, we studied immune responses to two doses of BNT162b2 Pfizer COVID-19 vaccine in an adolescent cohort (n=34, ages 12-16), an age group previously shown to make significantly greater immune responses to the same vaccine compared to young adults. At the same time, we were able to evaluate immune responses to the co-administered live attenuated influenza vaccine, which has been shown to induce stronger immune responses in adult females. Blood samples from 34 adolescents taken pre- and post-vaccination with COVID-19 and influenza vaccines were assayed for SARS-CoV-2-specific IgG and neutralising antibodies, and cellular immunity specific for SARS-CoV-2 and endemic betacoronaviruses. IgG targeting influenza lineages contained in the influenza vaccine was also assessed. As previously demonstrated, total IgG responses to SARS-CoV-2 Spike antigens were significantly higher among vaccinated adolescents compared to adults (aged 32-52) who received the BNT162b2 vaccine (comparing infection-naive, 49,696 vs 33,339; p=0.03; comparing SARS-CoV-2 previously-infected, 743,691 vs 269,985; p<0.0001) by MSD v-plex assay. However, unexpectedly, antibody responses to BNT162b2 and the live-attenuated influenza vaccine were not higher among female adolescents compared to males; among infection-naive adolescents, antibody responses to BNT162b2 were higher in males than females (62,270 vs 36,951 p=0.008). No sex difference was identified in vaccinated adults. These unexpected findings may result from the introduction of novel mRNA vaccination platforms, generating patterns of immunity divergent from established trends, and providing new insights into what might be protective following COVID-19 vaccination.
WEIRD or not: A Cross-Cultural Behavioral Economic Assessment of Demand for HIV and COVID-19 Vaccines

Background: Despite empirical evidence supporting vaccine effectiveness, vaccine hesitancy continues to thrive. Demand as a behavioral economic process provides useful indices for evaluating vaccine acceptance likelihood in individuals and groups. Using this framework, our study investigates the dynamics governing vaccine acceptance in two culturally dissimilar countries. Methods: Hypothetical purchase tasks (HPTs) assessed how Nigerian and US participants varied vaccine acceptance as a function of hospitalization risks due to vaccination (N = 109). Aggregate and individual demand indices (Q0 and Pmax) were computed with nonlinear regressions. Secondary analyses were conducted using repeated measures ANOVAs with vaccine type (COVID-19 and HIV) as the within-subject factor; country, age, and socioeconomic status as between-subjects factors; demand indices served as dependent variables. Results: Demand indices varied significantly as a function of vaccine type (F(1, 57) = 17.609, p < . 001, {eta}p2 = . 236). Demand for HIV vaccines was higher relative to COVID-19 vaccines. Interactions between vaccine type and country of origin (F(1, 56) = 4.001, p = . 05, {eta}p2 = . 067) were also significant with demand for HIV vaccines among Nigerian respondents higher than that of COVID-19 vaccines. This was reversed for US participants. Interactions between vaccine type, country of origin and age were also significant (F(2, 51) = 3.506, p < . 05, {eta}p2 = . 121). Conclusions: These findings provide evidence that vaccine type can influence demand. The relationship between demand and vaccine type also varies as a function of country of origin and age. Significance, limitations, and future directions are also discussed.
On the total variation regularized estimator over the branched path graph

We generalize to tree graphs obtained by connecting path graphs an oracle result obtained for the Fused Lasso over the path graph. Moreover we show that it is possible to substitute in the oracle inequality the minimum distance between jumps by the harmonic mean of the distances between jumps. In doing so we prove a lower bound on the compatibility constant for the total variation penalty. Our analysis leverages insights obtained for the path graph with one branch to understand the case of more general tree graphs. As a side result, we get insights into the irrepresentable condition for the branched path graph.
Flexibility of brain dynamics is increased and predicts clinical impairment in Relapsing-Remitting but not in Secondary Progressive Multiple Sclerosis

Background: Large-scale brain activity has long been investigated under the erroneous assumption of stationarity. Nowadays, we know that resting state functional connectivity is characterised by aperiodic, scale-free bursts of activity (i.e. neuronal avalanches) that intermittently recruit different brain regions. These different patterns of activity represent a measure of brain flexibility, whose reduction has been found to predict clinical impairment in multiple neurodegenerative diseases such as Parkinson s disease, Amyotrophic Lateral Sclerosis, and Alzheimer s disease. Brain flexibility has been recently found increased in Multiple Sclerosis (MS) but its relationship with clinical disability remains elusive. Also, potential differences in brain dynamics according to the MS clinical phenotypes remain unexplored so far. Methods: We studied brain flexibility through source-reconstruction of magnetoencephalography (MEG) signals in a cohort of 25 MS patients (10 RRMS and 15 SPMS) and 25 healthy controls (HC). Results: RRMS patients showed greater brain flexibility than HC. On the contrary, no differences in brain dynamics were found in SPMS patients as compared to HC. Finally, brain dynamics showed a different predictive power on clinical disability according to the MS type. Conclusion: For the first time, we investigated brain dynamics in MS patients through high temporal resolution techniques, unveiling differences in brain flexibility according to the MS phenotype and its relationship with clinical disability.
Assessment of the transmission blocking activity of antimalarial compounds by membrane feeding assays using natural Plasmodium falciparum gametocyte isolates from West-Africa

Antimalarial drugs that can block the transmission of Plasmodium gametocytes to mosquito vectors would be highly beneficial for malaria elimination efforts. Identifying transmission-blocking drugs currently relies on evaluation of their activity against gametocyte-producing laboratory parasite strains and would benefit from a testing pipeline with genetically diverse field isolates. The aims of this study were to develop a pipeline to test drugs against P. falciparum gametocyte field isolates and to evaluate the transmission-blocking activity of a set of novel compounds. Two assays were designed so they could identify both the overall transmission-blocking activity of a number of marketed and experimental drugs by direct membrane feeding assays (DMFA), and then also discriminate between those that are active against the gametocytes (gametocyte killing or sterilizing) or those that block development in the mosquito (sporontocidal). These DMFA assays used venous blood samples from naturally infected Plasmodium falciparum gametocyte carriers and locally reared Anopheles gambiae s.s. mosquitoes. Overall transmission-blocking activity was assessed following a 24 hour incubation of compound with gametocyte infected blood (TB-DMFA). Sporontocidal activity was evaluated following addition of compound directly prior to feeding, without incubation (SPORO-DMFA); Gametocyte viability was retained during 24-hour incubation at 37°C when gametocyte infected red blood cells were reconstituted in RPMI/serum. Methylene-blue, MMV693183, DDD107498, atovaquone and P218 showed potent transmission-blocking activity in the TB-DMFA, and both atovaquone and the novel antifolate P218 were potent inhibitors of sporogonic development in the SPORO-DMA. This work establishes a pipeline for the integral use of field isolates to assess the transmission-blocking capacity of antimalarial drugs to block transmission that should be validated in future studies.
Potent pan huACE2-dependent sarbecovirus neutralizing monoclonal antibodies isolated from a BNT162b2-vaccinated SARS survivor

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern such as Omicron hampered efforts in controlling the ongoing coronavirus disease 2019 pandemic due to their ability to escape neutralizing antibodies induced by vaccination or prior infection, highlighting the need to develop broad-spectrum vaccines and therapeutics. Most human monoclonal antibodies (mAbs) reported to date have not demonstrated true pan-sarbecovirus neutralizing breadth especially against animal sarbecoviruses. Here, we report the isolation and characterization of highly potent mAbs targeting the receptor binding domain (RBD) of huACE2-dependent sarbecovirus from a SARS-CoV survivor vaccinated with BNT162b2. Among the six mAbs identified, one (E7) showed better huACE2-dependent sarbecovirus neutralizing potency and breadth than any other mAbs reported to date. Mutagenesis and cryo–electron microscopy studies indicate that these mAbs have a unique RBD contact footprint and that E7 binds to a quaternary structure–dependent epitope.
Transparency of COVID-19-related research: A meta-research study

Background We aimed to assess the adherence to five transparency practices (data availability, code availability, protocol registration and conflicts of interest (COI), and funding disclosures) from open access Coronavirus disease 2019 (COVID-19) related articles. Methods We searched and exported all open access COVID-19-related articles from PubMed-indexed journals in the Europe PubMed Central database published from January 2020 to June 9, 2022. With a validated and automated tool, we detected transparent practices of three paper types: research articles, randomized controlled trials (RCTs), and reviews. Basic journal- and article-related information were retrieved from the database. We used R for the descriptive analyses. Results The total number of articles was 258,678, of which we were able to retrieve full texts of 186,157 (72%) articles from the database Over half of the papers (55.7%, n = 103,732) were research articles, 10.9% (n = 20,229) were review articles, and less than one percent (n = 1,202) were RCTs. Approximately nine-tenths of articles (in all three paper types) had a statement to disclose COI. Funding disclosure (83.9%, confidence interval (CI): 81.7–85.8 95%) and protocol registration (53.5%, 95% CI: 50.7–56.3) were more frequent in RCTs than in reviews or research articles. Reviews shared data (2.5%, 95% CI: 2.3–2.8) and code (0.4%, 95% CI: 0.4–0.5) less frequently than RCTs or research articles. Articles published in 2022 had the highest adherence to all five transparency practices. Most of the reviews (62%) and research articles (58%) adhered to two transparency practices, whereas almost half of the RCTs (47%) adhered to three practices. There were journal- and publisher-related differences in all five practices, and articles that did not adhere to transparency practices were more likely published in lowest impact journals and were less likely cited. Conclusion While most articles were freely available and had a COI disclosure, adherence to other transparent practices was far from acceptable. A much stronger commitment to open science practices, particularly to protocol registration, data and code sharing, is needed from all stakeholders.
Johansen’s Reduced Rank Estimator Is GMM

The generalized method of moments (GMM) estimator of the reduced-rank regression model is derived under the assumption of conditional homoscedasticity. It is shown that this GMM estimator is algebraically identical to the maximum likelihood estimator under normality developed by Johansen (1988). This includes the vector error correction model (VECM) of Engle and Granger. It is also shown that GMM tests for reduced rank (cointegration) are algebraically similar to the Gaussian likelihood ratio tests. This shows that normality is not necessary to motivate these estimators and tests.
Ophthalmic Education: The Top 100 Cited Articles in Ophthalmology Journals

Abstract Purpose To identify the top 100 (T100) cited articles on ophthalmic education and examine trends and areas of focus in ophthalmic education. Methods A literature search was conducted for articles published between 2011 and 2021 related to ophthalmic education within ophthalmology journals using the ISI Web of Science Core Collection database. The search was performed in June 2022 and was conducted using the search phrase ([educat* OR teach* OR instruct* OR train* OR “medical student*” OR residen* OR fellow* OR undergrad* OR postgrad* OR “faculty” OR “attending”] AND *ophthalm*). Results were analyzed using VOSviewer v.1. 6.18 and statistical analysis was performed using Microsoft Excel. Results The majority of articles were published in the Journal of Cataract & Refractive Surgery (19%), followed by Ophthalmology (12%), and Eye (12%). Articles were most often published in the year 2013 (15%), followed by 2014 (12%) and 2012 (12%). Articles most commonly originated from English-speaking countries, including the United States (43%), England (14%), Canada (8%), and India (8%). Topics most often examined in ophthalmic education were resident education (51%), medical school education (21%), and surgical training (21%). The most common study types were cohort studies (22%), case series (21%), and prospective trials (16%). There were 16 institutions that produced more than one article in the T100 articles list. Conclusion The T100 articles on ophthalmic education were primarily U.S. based and focused on resident education, surgical training, and medical school ophthalmic curriculum. Further research into ophthalmic education is warranted to establish evidence-based curricula guidelines.
Habitat isolation interacts with top-down and bottom-up processes in a seagrass ecosystem

Habitat loss is accelerating at unprecedented rates, leading to the emergence of smaller, more isolated habitat remnants. Habitat isolation adversely affects many ecological processes independently, but little is known about how habitat isolation may interact with ecosystem processes such as top-down (consumer-driven) and bottom-up (resource-driven) effects. To investigate the interactive influence of habitat isolation, resource availability and consumer distribution and impact on community structure, we tested two hypotheses using invertebrate and algal epibionts on temperate seagrasses, an ecosystem of ecological and conservation importance. First, we hypothesized that habitat isolation will change the structure of the seagrass epibiont community, and isolated patches of seagrass will have lower epibiont biomass and different epibiont community composition than contiguous meadows. Second, we hypothesized that habitat isolation would mediate top-down (i.e., herbivory) and bottom-up (i.e., nutrient enrichment) control for algal epibionts. We used observational studies in natural seagrass patches and experimental artificial seagrass to examine three levels of habitat isolation. We further manipulated top-down and bottom-up processes in artificial seagrass through consumer reductions and nutrient additions, respectively. We indeed found that habitat isolation of seagrass patches decreased epibiont biomass and modified epibiont community composition. This pattern was largely due to dispersal limitation of invertebrate epibionts that resulted in a decline in their abundance and richness in isolated patches. Further, habitat isolation reduced consumer abundances, weakening top-down control of algal epibionts in isolated seagrass patches. Nutrient additions, however, reversed this pattern, and allowed a top-down effect on algal richness to emerge in isolated habitats, demonstrating a complex interaction between patch isolation and top-down and bottom-up processes. Habitat isolation may therefore shape the relative importance of central processes in ecosystems, leading to changes in community composition and food web structure in marine habitats.
A multidisciplinary study on the social customs of the Tang Empire in the Medieval Ages

Multidisciplinary research on human remains can provide important information about population dynamics, culture diffusion, as well as social organization and customs in history. In this study, multidisciplinary analyses were undertaken on a joint burial (M56) in the Shuangzhao cemetery of the Tang Dynasty (618–907 AD), one of the most prosperous dynasties in Chinese history, to shed light on the genetic profile and sociocultural aspects of this dynasty. The archaeological investigation suggested that this burial belonged to the Mid-Tang period and was used by common civilians. The osteological analysis identified the sex, age, and health status of the three individuals excavated from M56, who shared a similar diet inferred from the stable isotopic data. Genomic evidence revealed that these co-buried individuals had no genetic kinship but all belonged to the gene pool of the ancient populations in the Central Plains, represented by Yangshao and Longshan individuals, etc. Multiple lines of evidence, including archaeology, historic records, as well as chemical and genetic analyses, have indicated a very probable familial joint burial of husband and wives. Our study provides insights into the burial customs and social organization of the Tang Dynasty and reconstructs a scenario of civilian life in historic China.
Genomic insights into the genetic basis of eagle‐beak jaw, large head, and long tail in the big‐headed turtle

Abstract The big‐headed turtle (Platysternon megacephalum) is an endemic chelonian species in Asia. Unlike most other turtles in the world, P. megacephalum is characterized with eagle‐beak jaw, large head, and long tail. Although these unique characteristics are well recognized, the underlying genetic basis remains largely elusive. Here, we performed comparative genomic analysis between P. megacephalum and other representative species, aiming to reveal the genetic basis of the unique morphological features. Our results revealed that the eagle‐beak jaw is most likely enabled by combined effects of expansion of SFRP5, extraction of FGF11, and mutation of both ZFYVE16 and PAX6. Large head is supported by mutations of SETD2 and FGRF2 and copy number variations of six head circumference modulation‐related genes (TGFBR2, Twist2, Rdh10, Gas1, Chst11, and SNAP25). The long tail is probably involved in a genetic network comprising Gdf11, Lin 28, and HoxC12, two of which showed a consistent expression pattern with a model organism (mice). These findings suggest that expansion, extraction, and mutation of those genes may have profound effects on unique phenotypes of P. megacephalum.
XBP1-mediated transcriptional regulation of SLC5A1 in human epithelial cells in disease conditions

Background: sodium-dependent glucose cotransporter 1 and 2 (SGLT1/2) belong to the family of glucose transporters, encoded by SLC5A1 and SLC5A2, respectively. SGLT-2 is almost exclusively expressed in the renal proximal convoluted tubule cells. SGLT-1 is expressed in the kidneys but also in other organs throughout the body. Many SGLT inhibitor drugs have been developed based on the mechanism of blocking glucose (re)absorption mediated by SGLT1/2, and several have gained major regulatory agencies’ approval for treating diabetes. Intriguingly these drugs are also effective in treating diseases beyond diabetes, for example heart failure and chronic kidney disease. We recently discovered that SGLT-1 is upregulated in the airway epithelial cells derived from patients of cystic fibrosis (CF), a devastating genetic disease affecting greater than 70,000 worldwide. Results: in the present work, we show that the SGLT-1 upregulation is coupled with elevated endoplasmic reticulum (ER) stress response, indicated by activation of the primary ER stress senor inositol-requiring protein 1a (IRE1a) and the ER stress-induced transcription factor X-box binding protein 1 (XBP1), in CF epithelial cells, and in epithelial cells of other stress conditions. Through biochemistry experiments, we demonstrated that XBP1 acts as a transcription factor for SLC5A1 by directly binding to its promoter region. Targeting this ER stress → SLC5A1 axis by either the ER stress inhibitor Rapamycin or the SGLT-1 inhibitor Sotagliflozin was effective in attenuating the ER stress response and reducing the SGLT-1 levels in these cellular model systems. Conclusions: the present work establishes a causal relationship between ER stress and SGLT-1 upregulation and provides a mechanistic explanation why SGLT inhibitor drugs benefit diseases beyond diabetes.