Miracle-dz/UniFAR-FTUs huggingface dataset:
Comparative population genomic analyses of transporters within the Asgard archaeal superphylum

Upon discovery of the first archaeal species in the 1970s, life has been subdivided into three domains: Eukarya, Archaea, and Bacteria. However, the organization of the three-domain tree of life has been challenged following the discovery of archaeal lineages such as the TACK and Asgard superphyla. The Asgard Superphylum has emerged as the closest archaeal ancestor to eukaryotes, potentially improving our understanding of the evolution of life forms. We characterized the transportomes and their substrates within four metagenome-assembled genomes (MAGs), that is, Odin-, Thor-, Heimdall- and Loki-archaeota as well as the fully sequenced genome of Candidatus Prometheoarchaeum syntrophicum strain MK-D1 that belongs to the Loki phylum. Using the Transporter Classification Database (TCDB) as reference, candidate transporters encoded within the proteomes were identified based on sequence similarity, alignment coverage, compatibility of hydropathy profiles, TMS topologies and shared domains. Identified transport systems were compared within the Asgard superphylum as well as within dissimilar eukaryotic, archaeal and bacterial organisms. From these analyses, we infer that Asgard organisms rely mostly on the transport of substrates driven by the proton motive force (pmf), the proton electrochemical gradient which then can be used for ATP production and to drive the activities of secondary carriers. The results indicate that Asgard archaea depend heavily on the uptake of organic molecules such as lipid precursors, amino acids and their derivatives, and sugars and their derivatives. Overall, the majority of the transporters identified are more similar to prokaryotic transporters than eukaryotic systems although several instances of the reverse were documented. Taken together, the results support the previous suggestions that the Asgard superphylum includes organisms that are largely mixotrophic and anaerobic but more clearly define their metabolic potential while providing evidence regarding their relatedness to eukaryotes.
Evolution and insights into the structure and function of the DedA superfamily containing TMEM41B and VMP1

TMEM41B and VMP1 are endoplasmic reticulum (ER)-localizing multi-spanning membrane proteins required for ER-related cellular processes such as autophagosome formation, lipid droplet homeostasis, and lipoprotein secretion in eukaryotes. Both proteins have a VTT domain, which is similar to the DedA domain found in bacterial DedA family proteins. However, the molecular function and structure of the DedA and VTT domains (collectively referred to as DedA domains) and the evolutionary relationships among the DedA domain-containing proteins are largely unknown. Here, we conduct remote homology search and identify a new clade consisting mainly of bacterial PF06695 proteins of unknown function. Phylogenetic analysis reveals that the TMEM41, VMP1, DedA, and PF06695 families form a superfamily with a common origin, which we term the DedA superfamily. Coevolution-based structural prediction suggests that the DedA domain contains two reentrant loops that face each other in the membrane. This topology is biochemically verified by the substituted cysteine accessibility method. The predicted structure is topologically similar to that of the substrate-binding region of Na+-coupled glutamate transporter solute carrier 1. A potential ion-coupled transport function of the DedA superfamily proteins is discussed.
Addressing the elephant in the room: COVID-19 vaccine hesitancy in Black and Asian communities.

minority ethnic groups in the UK have experienced poorer outcomes in relation to the COVID-19 pandemic. People of Black and Asian ethnicity have faced higher diagnostic rates, higher intensive care admission rates, and ultimately higher death rates compared to the White population.1–3 Despite comprising the minority of the workforce, Black and Asian healthcare staff make up approximately two-thirds of the deaths observed in this setting.4
Clinical Staging, Angioarchitecture Type, and Surgical Treatment of Arteriovenous Malformations in the Head and Neck: A Single-Center Retrospective Analysis

Supplemental Digital Content is available in the text Objective: Head and neck are the predilection sites of arteriovenous malformations (AVMs). Although embolization is the first-line treatment for AVMs, complete surgical removal of the lesion still has its value due to the best outcome with low recurrence rate. Here, the authors made a retrospective analysis on the surgical treatment of AVMs in the head and neck. Methods: From January 2006 to December 2019, a total of 18 patients with AVMs in the head and neck were enrolled in this study, including 10 males. The Schobinger clinical staging, Yakes’ angioarchitecture type, and surgical treatment were analyzed. The follow-up data were collected. Then, individual treatment strategies were summarized. Results: According to Schobinger clinical classification system, 6 patients were at stage I, 7 patients at stage II, and 5 patients at stage III. According to Yakes’ AVM classification system, 3 Type I, 4 Type II, 5 Type III, and 3 Type IV were confirmed. 3 patients cannot be confirmed due to lacking of arteriographic data. Surgical treatments included simple surgical excision (8 patients), dilator therapy (6 patients), and skin grafting after surgical excision (4 patients). In the follow-up period, 2 patients had recurrence and accepted operation again. All patients were satisfied with the appearance. Conclusions: Individual surgical treatment based on the clinical stage and angioarchitecture type can achieve satisfactory results in AVMs in the head and neck.
Posterior lamellar keratoplasty: techniques, outcomes, and recent advances

This review on PLK discusses the evolution of PLK, including current surgical techniques, management of complications, and the direction of future treatment for corneal endothelial disease. Over the past 2 decades, posterior lamellar keratoplasty (PLK) has emerged as an alternative to penetrating keratoplasty in the treatment of corneal endothelial disorders. The reasons for this trend include the search for a safer procedure to replace diseased endothelium that provides faster and better visual rehabilitation and reduces the need for postoperative care. Different surgical techniques, surgical instruments, devices, and lasers have been introduced to overcome technical difficulties, thus improving clinical outcomes. Yet, surgeons and eye banks must address the complications and limitations that arise during the transition to these new techniques. This review discusses the most significant aspects of the evolution of PLK, including a detailed description of current techniques and the direction of future treatment for corneal endothelial disease with the use of laser-assisted surgery, bioengineered corneas, cell therapy, and new pharmacologic therapy.
Association of APOE Genotype With Heterogeneity of Cognitive Decline Rate in Alzheimer Disease

Objective To test the hypothesis that the APOE genotype is a significant driver of heterogeneity in Alzheimer disease (AD) clinical progression, which could have important implications for clinical trial design and interpretation. Methods We applied novel reverse-time longitudinal models to analyze the trajectories of Clinical Dementia Rating Sum of Boxes (CDR-SOB) and Mini-Mental State Examination (MMSE) scores—2 common outcome measures in AD clinical trials—in 1,102 autopsy-proven AD cases (moderate/frequent neuritic plaques and Braak tangle stage III or greater) from the National Alzheimer's Coordinating Center Neuropathology database resembling participants with mild to moderate AD in therapeutic clinical trials. Results APOE ε4 carriers exhibited ≈1.5 times faster CDR-SOB increase than APOE ε3/ε3 carriers (2.12 points per year vs 1.44 points per year) and ≈1.3 times faster increase than APOE ε2 carriers (1.65 points per year), whereas APOE ε2 vs APOE ε3/ε3 difference was not statistically significant. APOE ε4 carriers had ≈1.1 times faster MMSE decline than APOE ε3/ε3 carriers (−3.45 vs −3.03 points per year) and ≈1.4 times faster decline than APOE ε2 carriers (−2.43 points per year), whereas APOE ε2 carriers had ≈1.2 times slower decline than APOE ε3/ε3 carriers (−2.43 vs −3.03 points per year). These findings remained largely unchanged after controlling for the effect of AD neuropathologic changes on the rate of cognitive decline and for the presence and severity of comorbid pathologies. Conclusion Compared to the APOE ε3/ε3 reference genotype, the APOE ε2 and ε4 alleles have opposite (slowing and accelerating, respectively) effects on the rate of cognitive decline, which are clinically relevant and largely independent of the differential APOE allele effects on AD and comorbid pathologies. Thus, APOE genotype contributes to the heterogeneity in rate of clinical progression in AD.
Risk Factors for Enterococcal Intra-Abdominal Infections and Outcomes in Intensive Care Unit Patients.

Background: To investigate the risk factors for enterococcal intra-abdominal infections (EIAIs) and the association between EIAIs and outcomes in intensive care unit (ICU) patients. Methods: We reviewed retrospectively the records of patients with intra-abdominal infections admitted to the Department of Critical Care Medicine at Nanfang Hospital, Southern Medical University, China, from January 2011 to December 2018. Patients with intra-abdominal infections were divided into enterococcal and non-enterococcal groups based on whether enterococci were isolated from intra-abdominal specimens. Results: A total of 431 patients with intra-abdominal infections were included, of whom 119 were infected with enterococci and 312 were infected with non-enterococci. Enterococci were isolated in 27.6% of patients, accounting for 24.5% (129/527) of all clinical bacterial isolates. Post-operative abdominal infection (adjusted odds ratio [OR], 2.361; p = 0.004), intestinal infection (adjusted OR, 2.703; p < 0.001), Mannheim Peritonitis Index score (MPI; adjusted OR, 1.052; p = 0.015), and use of antibiotic agents within the previous 90 days (adjusted OR, 1.880; p = 0.025) were associated with an increased risk of EIAIs. Compared with patients without enterococcal infection, ICU patients with enterococcal infection had a higher risk of failure of initial clinical therapy (49.6% vs. 24.2%; p < 0.001) and longer hospital stays (33 days [19, 48] vs. 18 days [12, 29]; p < 0.001). Enterococcal infection was associated with increased 28-day mortality, in-hospital mortality, and ICU mortality. However, no difference was found in length of ICU stay between the two groups. Additionally, there was no difference in ICU mortality, hospital mortality, or 28-day mortality in patients infected with enterococcus who did or did not receive empirical anti-enterococcal therapy. Conclusion: Post-operative abdominal infection, intestinal infection, MPI score, and use of antibiotic agents within the previous 90 days were independent risk factors for enterococcal infection. Enterococcal infection was associated with reduced short-term survival in ICU patients.
Integrating concentration gradient generator and single-cell trapper array for high-throughput screening bioeffects of nanomaterials.

The need of generating nanomaterial gradients is increasing. However, the previously reported gradient generators may lead to the aggregation or uneven dilution of nanomaterials, which will inevitably hinder their applications. To address this issue, we herein develop a concentration gradient generator (CGG) on a microfluidic chip for diluting different nanoparticles. Specifically designed compact disk (CD)-shaped microchannels in the CGG module could thoroughly mix the flowing solutions and generate linear concentration gradient of nanoparticles without aggregation. We combine the CGG with a single-cell trapper array (SCA) on microfluidics to evaluate the concentration-dependent bioeffects of the nanoparticles. The precise control of the spatiotemporal generation of nanoparticle concentration on the CGG module and the single-cell-level monitoring of the cell behaviors on the SCA module by a high-content system in real-time, render the CGG-SCA system a highly precise platform, which can exclude the average effect of cell population and reflect the response of individual cells to the gradient concentrations accurately. In addition, the CGG-SCA system provides an automated platform for high-throughput screening of nanomedicines with high precision and low sample consumption.
Inferring the Deep Past from Molecular Data

Abstract There is an expectation that analyses of molecular sequences might be able to distinguish between alternative hypotheses for ancient relationships, but the phylogenetic methods used and types of data analyzed are of critical importance in any attempt to recover historical signal. Here, we discuss some common issues that can influence the topology of trees obtained when using overly simple models to analyze molecular data that often display complicated patterns of sequence heterogeneity. To illustrate our discussion, we have used three examples of inferred relationships which have changed radically as models and methods of analysis have improved. In two of these examples, the sister-group relationship between thermophilic Thermus and mesophilic Deinococcus, and the position of long-branch Microsporidia among eukaryotes, we show that recovering what is now generally considered to be the correct tree is critically dependent on the fit between model and data. In the third example, the position of eukaryotes in the tree of life, the hypothesis that is currently supported by the best available methods is fundamentally different from the classical view of relationships between major cellular domains. Since heterogeneity appears to be pervasive and varied among all molecular sequence data, and even the best available models can still struggle to deal with some problems, the issues we discuss are generally relevant to phylogenetic analyses. It remains essential to maintain a critical attitude to all trees as hypotheses of relationship that may change with more data and better methods.
Circulating NT-proANP level is a predictor of mortality for systemic sclerosis: a retrospective study of an Italian cohort

ABSTRACT Objectives: The authors aimed to evaluate the role of N-terminal proANP (NT-proANP) and of NT-proBNP circulating levels as predictive markers of death due to systemic sclerosis (SSc). Methods: The authors retrospectively enrolled 51 SSc patients. At baseline, NT-proBNP and NT-proANP circulating levels and clinical features were collected. Date and causes of death were extracted during a 6-year follow-up. Results: 13 SSc patients (23.2%) died for SSc complications (9 for interstitial lung disease and 4 for pulmonary arterial hypertension). The median NT-proBNP plasma level did not significantly differ (p > 0.05) in SSc patients died or alive [645 (448–1026) fmol/ml vs 592 (409–789) fmol/ml]. The median NT-proANP plasma level was significantly (p < 0.01) higher in SSc died than in SSc patients alive [4000 (2100–6722) fmol/ml vs 1640 (1381–2721) fmol/ml]. The Kaplan–Meier analysis revealed that SSc patients with increased NT-proANP level had increased mortality (p < 0.05). In the multivariate analysis, DLco [HR 0.966 (0.934–0.999), p < 0.05] and NT-proANP level [HR 1 (1–1), p < 0.05] were predictive markers of death due to SSc. Conclusions: NT-proANP plasma level is a predictive marker of death due to SSc.
Anti-inflammatory effect of resveratrol attenuates the severity of diabetic neuropathy by activating the Nrf2 pathway

The mechanisms underlying the development of neuropathy associated with diabetes mellitus are not fully understood. Resveratrol, as a nonflavonoid polyphenol, plays a variety of beneficial roles in the treatment of chronic diseases such as Alzheimer's disease, coronary heart disease and obesity. In our study, the role of nuclear erythroid 2-related factor 2 (Nrf2) in resveratrol-mediated protection against streptozotocin-induced diabetic peripheral neuropathy (DPN) was investigated, and the antioxidant effect of resveratrol in diabetic peripheral nerves was studied. The STZ-treated model mice were divided into two groups. The resveratrol group was intragastrically administered 10 ml/kg 10% resveratrol once a day until the 12th week after STZ injection. The vehicle-treated mice were injected with the same volume of DMSO. Analysis of the effects of resveratrol in DPN revealed the following novel findings: (i) the pain and temperature sensitivities of diabetic mice were improved after treatment with resveratrol; (ii) Nrf2 expression was increased in the diabetic peripheral nerves of resveratrol-treated mice, and NF-KB pathway inhibition protected nerves upon resveratrol treatment in peripheral neuropathy; and (iii) resveratrol modulated the anti-inflammatory microenvironment of peripheral nerves by increasing Nrf2 activation and the expression of p-p65, and these changes may have been responsible for the neuroprotective effect of resveratrol in DPN, which was confirmed by Nrf2 knockout in diabetic mice. Overall, this study demonstrates that resveratrol may attenuate the severity of DPN by protecting peripheral nerves from apoptosis by inhibiting the NF-KB pathway and increasing Nrf2 expression.
Co-translational folding of the first transmembrane domain of ABC-transporter CFTR is supported by assembly with the first cytosolic domain

ABC-transporters transport a wealth of molecules across membranes and consist of transmembrane and cytosolic domains. Their activity cycle involves a tightly regulated and concerted domain choreography. Regulation is driven by the cytosolic domains and function by the transmembrane domains. Folding of these polytopic multidomain proteins to their functional state is a challenge for cells, which is mitigated by co-translational and sequential events. We here reveal the first stages of co-translational domain folding and assembly of CFTR, the ABC-transporter defective in the most abundant rare inherited disease cystic fibrosis. We have combined biosynthetic radiolabeling with protease-susceptibility assays and domain-specific antibodies. The most N-terminal domain, TMD1 (transmembrane domain 1), folds both its hydrophobic and soluble helices during translation: the transmembrane helices pack tightly and the cytosolic N- and C-termini assemble with the first cytosolic helical loop ICL1, leaving only ICL2 exposed. This N-C-ICL1 assembly is strengthened by two independent events: i) assembly of ICL1 with the N-terminal subdomain of the next domain, cytosolic NBD1 (nucleotide-binding domain 1); and ii) in the presence of corrector drug VX-809, which rescues cell-surface expression of a range of disease-causing CFTR mutants. Both lead to increased shielding of the CFTR N-terminus, and their additivity implies different modes of action. Early assembly of NBD1 and TMD1 is essential for CFTR folding and positions both domains for the required assembly with TMD2. Altogether, we have gained insights into this first, nucleating, VX-809-enhanced domain-assembly event during and immediately after CFTR translation, involving structures conserved in type-I ABC exporters.
The Shared Genetic Architectures Between Lung Cancer and Multiple Polygenic Phenotypes in Genome-Wide Association Studies

Background: Prior genome-wide association studies have identified numerous lung cancer risk loci and reveal substantial etiologic heterogeneity across histologic subtypes. Analyzing the shared genetic architecture underlying variation in complex traits can elucidate common genetic etiologies across phenotypes. Exploring pairwise genetic correlations between lung cancer and other polygenic traits can reveal the common genetic etiology of correlated phenotypes. Methods: Using cross-trait linkage disequilibrium score regression, we estimated the pairwise genetic correlation and heritability between lung cancer and multiple traits using publicly available summary statistics. Identified genetic relationships were also examined after excluding genomic regions known to be associated with smoking behaviors, a major risk factor for lung cancer. Results: We observed several traits showing moderate single nucleotide polymorphism–based heritability and significant genetic correlations with lung cancer. We observed highly significant correlations between the genetic architectures of lung cancer and emphysema/chronic bronchitis across all histologic subtypes, as well as among lung cancer occurring among smokers. Our analyses revealed highly significant positive correlations between lung cancer and paternal history of lung cancer. We also observed a strong negative correlation with parental longevity. We observed consistent directions in genetic patterns after excluding genomic regions associated with smoking behaviors. Conclusions: This study identifies numerous phenotypic traits that share genomic architecture with lung carcinogenesis and are not fully accounted for by known smoking-associated genomic loci. Impact: These findings provide new insights into the etiology of lung cancer by identifying traits that are genetically correlated with increased risk of lung cancer.
Short-term forecasts of expected deaths

Significance We introduce a simple but powerful method for analyzing mortality after a major shock. We apply the method to show, more conclusively than up to now, that Denmark, which imposed a lockdown during the first wave of the coronavirus pandemic, suffered considerably lower risks of death than Sweden, which did not impose a lockdown. Our method makes short-term forecasts of the number of deaths that would have occurred if the coronavirus pandemic or other health catastrophe had not occurred. By subtracting the forecast counts from actual death counts, excess mortality can be estimated. This can be done by age, sex, and other characteristics. The method can also be used for other kinds of short-term forecasting. We introduce a method for making short-term mortality forecasts of a few months, illustrating it by estimating how many deaths might have happened if some major shock had not occurred. We apply the method to assess excess mortality from March to June 2020 in Denmark and Sweden as a result of the first wave of the coronavirus pandemic; associated policy interventions; and behavioral, healthcare, social, and economic changes. We chose to compare Denmark and Sweden because reliable data were available and because the two countries are similar but chose different responses to COVID-19: Denmark imposed a rather severe lockdown; Sweden did not. We make forecasts by age and sex to predict expected deaths if COVID-19 had not struck. Subtracting these forecasts from observed deaths gives the excess death count. Excess deaths were lower in Denmark than Sweden during the first wave of the pandemic. The later/earlier ratio we propose for shortcasting is easy to understand, requires less data than more elaborate approaches, and may be useful in many countries in making both predictions about the future and the past to study the impact on mortality of coronavirus and other epidemics. In the application to Denmark and Sweden, prediction intervals are narrower and bias is less than when forecasts are based on averages of the last 5 y, as is often done. More generally, later/earlier ratios may prove useful in short-term forecasting of illnesses and births as well as economic and other activity that varies seasonally or periodically.