Miracle-dz/UniFAR-FTUs huggingface dataset:
Deep learning of immune cell differentiation

Significance Applying artificial intelligence tools to a highly complex question of immunology, we show that a deep neural network can learn to predict the patterns of chromatin opening across 81 stem and differentiated cells across the immune system, solely from the DNA sequence of regulatory regions. It does so by discovering ab initio the binding motifs for known master regulators, along with some unknown ones, and their combinatorial operation. These predictions validated biochemically, and a mouse-trained neural network predicts human enhancer/promoter activity much better than sequence comparisons would. Beyond serving as a trove of testable functional frameworks, this work is important in showing how massively complex integrated questions of immunology can be handled with such tools. Although we know many sequence-specific transcription factors (TFs), how the DNA sequence of cis-regulatory elements is decoded and orchestrated on the genome scale to determine immune cell differentiation is beyond our grasp. Leveraging a granular atlas of chromatin accessibility across 81 immune cell types, we asked if a convolutional neural network (CNN) could learn to infer cell type-specific chromatin accessibility solely from regulatory DNA sequences. With a tailored architecture and an ensemble approach to CNN parameter interpretation, we show that our trained network (“AI-TAC”) does so by rediscovering ab initio the binding motifs for known regulators and some unknown ones. Motifs whose importance is learned virtually as functionally important overlap strikingly well with positions determined by chromatin immunoprecipitation for several TFs. AI-TAC establishes a hierarchy of TFs and their interactions that drives lineage specification and also identifies stage-specific interactions, like Pax5/Ebf1 vs. Pax5/Prdm1, or the role of different NF-κB dimers in different cell types. AI-TAC assigns Spi1/Cebp and Pax5/Ebf1 as the drivers necessary for myeloid and B lineage fates, respectively, but no factors seemed as dominantly required for T cell differentiation, which may represent a fall-back pathway. Mouse-trained AI-TAC can parse human DNA, revealing a strikingly similar ranking of influential TFs and providing additional support that AI-TAC is a generalizable regulatory sequence decoder. Thus, deep learning can reveal the regulatory syntax predictive of the full differentiative complexity of the immune system.
Role of a Ketogenic Diet on Body Composition, Physical Health, Psychosocial Well-Being and Sports Performance in Athletes: A Scoping Review

Background: Recently, a focus has been placed on investigating the potential benefits of adherence to a ketogenic diet in enhancing body composition, physical health, psychological well-being, and performance of athletes from various sporting disciplines. As the available research is yet to be collated and analyzed in a single review, this scoping review aims to analyze and draw conclusions from the available literature that exists on the efficacy of a ketogenic diet among athletic populations. Methods: Several primary research databases and any relevant citation lists were searched to locate appropriate studies for inclusion in this scoping review. Studies that investigated the effects of adherence to a ketogenic diet (KD), defined by a carbohydrate intake of less than 5% of total energy intake, on body composition, physical health, psychological well-being, and performance among an athletic population were included in the review. From 814 articles screened, 12 were identified as meeting the inclusion criteria and were included in the final scoping review. Results: Adherence to a KD has beneficial effects on body weight and fat mass. Varying effects were identified on physical health with the diet, eliciting positive effects on fat oxidation but potentially deleterious effects on stool microbiota and iron metabolism. Conflicting results were reported regarding the effects of a KD on sporting performance. Benefits were reported regarding athlete well-being following commencement of a KD, but only after week two. Conclusions: The results of this scoping review demonstrate that there are both beneficial and detrimental effects associated with adherence to a KD among athletic populations. It is understood that further research is required to make any concrete recommendations regarding a KD to athletes.
On the accuracy of official Chinese crop production data: Evidence from biophysical indexes of net primary production

Significance With rapid economic growth and urbanization, there has been an increasing debate on food security and crop supplies in China. Grains have become central to China’s agriculture policy of ensuring food security mostly through domestic supply. Accurate production statistics are essential for research, monitoring, and planning. Recent increases in crop production reported by national statistics have come under increasing scrutiny. This paper provides an approach to validate Chinese official grain data, based on integrated socioecological indicators of terrestrial net primary production. This approach, grounded on agriculture’s biophysical spatially explicit constraints, provides a powerful means to check the plausibility of China’s grain production statistics at different administrative levels, generates insights about their discrepancies, and can contribute to improved crop production measurements. With rapid economic growth and urbanization, self-sufficiency in crop production has become central to China’s agriculture policy. Accurate crop production statistics are essential for research, monitoring, and planning. Although researchers agree that China’s statistical authority has considerably modernized over time, China’s economic statistics have still been viewed as unreliable and often overstated to meet growth targets at different administrative levels. Recent increases in crop production reported by national statistics have also come under increasing scrutiny. This paper investigates crop production data quality from a planetary boundary perspective—comparing net primary production (NPP) harvested obtained from national statistics with satellite-driven NPP estimates that are supported by detailed observation of land cover, combined with observations on physical factors that limit plant growth. This approach provides a powerful means to check the plausibility of China’s grain production statistics at different administrative levels that can generate insights about their discrepancies and can contribute to improved crop production measurements. We find some evidence of potential misreporting problems from the lower administration level where the risk of manipulation of statistics is higher. We also find problems from provincial-level major grain producers. These values can also affect the national totals. Although the numbers are affected by large uncertainties, we find that improving the spatial resolution of key agricultural parameters can greatly improve the reliability of the indicator that in turn can help improve data quality. More reliable production data will be vital for relevant research and provide better insights into food security problems, the carbon cycle, and sustainable development.
Identification of Modulators of HIV-1 Proviral Transcription from a Library of FDA-Approved Pharmaceuticals

Human immunodeficiency virus 1 (HIV-1) is the most prevalent human retrovirus. Recent data show that 34 million people are living with HIV-1 worldwide. HIV-1 infections can lead to AIDS which still causes nearly 20,000 deaths annually in the USA alone. As this retrovirus leads to high morbidity and mortality conditions, more effective therapeutic regimens must be developed to treat these viral infections. A key target for intervention for which there are no current FDA-approved modulators is at the point of proviral transcription. One successful method for identifying novel therapeutics for treating infectious diseases is the repurposing of pharmaceuticals that are approved by the FDA for alternate indications. Major benefits of using FDA-approved drugs include the fact that the compounds have well established toxicity profiles, approved manufacturing processes, and immediate commercial availability to the patients. Here, we demonstrate that pharmaceuticals previously approved for other indications can be utilized to either activate or inhibit HIV-1 proviral transcription. Specifically, we found febuxostat, eltrombopag, and resveratrol to be activators of HIV-1 transcription, while mycophenolate was our lead inhibitor of HIV-1 transcription. Additionally, we observed that the infected cells of lymphoid and myeloid lineage responded differently to our lead transcriptional modulators. Finally, we demonstrated that the use of a multi-dose regimen allowed for enhanced activation with our transcriptional activators.
Specific suppression of D-RNA G-quadruplex–protein interaction with an L-RNA aptamer

Abstract G-quadruplexes (G4s) are nucleic acid structure motifs that are of significance in chemistry and biology. The function of G4s is often governed by their interaction with G4-binding proteins. Few categories of G4-specific tools have been developed to inhibit G4–protein interactions; however, until now there is no aptamer tool being developed to do so. Herein, we present a novel L-RNA aptamer that can generally bind to D-RNA G-quadruplex (rG4) structure, and interfere with rG4–protein interaction. Using hTERC rG4 as the target for in vitro selection, we report the shortest L-aptamer being developed so far, with only 25 nucleotides. Notably, this new aptamer, L-Apt.4-1c, adopts a stem–loop structure with the loop folding into an rG4 motif with two G-quartet, demonstrates preferential binding toward rG4s over non-G4s and DNA G-quadruplexes (dG4s), and suppresses hTERC rG4–nucleolin interactions. We also show that inhibition of rG4–protein interaction using L-RNA aptamer L-Apt.4-1c is comparable to or better than G4-specific ligands such as carboxypyridostatin and QUMA-1 respectively, highlighting that our approach and findings expand the current G4 toolbox, and open a new avenue for diverse applications.
The influence of dietary patterns on arterial stiffness, lipid metabolism, and liver and renal function in the population of Greater Poland.

BACKGROUND The consumption of breakfast, salty meals, red meat, whole grain products, and dark chocolate are dietary habits that influence health, but the effects on arterial stiffness have not been well-investigated. Aim. To assess the effects of selected dietary patterns on arterial stiffness, liver and renal function, inflammation, and glucose and lipid biochemical parameters. METHODS 829 patients completed health and food frequency questionnaires, and underwent anthropometric, arterial stiffness, and blood pressure measurements. Serum concentrations of lipids, glucose, alanine and aspartate aminotransferases, creatinine, uric acid, and C-reactive protein were determined. RESULTS The aspartate aminotransferase serum concentration was lower in the breakfast-consuming group (25.88 ±7.05 U/L) compared to non-consumers (27.75 ±10.67 U/L). A lower concentration of creatinine and alanine aminotransferase and a higher concentration of C-reactive protein was found in whole grain product consumers. Individuals consuming more red meat had higher alanine aminotransferase and low-density lipoprotein serum concentrations. Individuals with greater dark chocolate consumption had higher serum concentrations of uric acid (5.20 ±1.46 vs. 4.72 ±1.18) and more intensified arterial stiffness (peak-to-peak time 213.86 ±54.98 ms vs. 238.70 ±60.83 ms). CONCLUSIONS The investigated dietary patterns had a significant impact on serum lipid concentrations, biochemical markers of liver and renal function and inflammation, and arterial stiffness. High consumption of red meat and dark chocolate intensified cardiovascular risk, contrary to the intake of whole grain products.
Older People’s Non-Physical Contacts and Depression During the COVID-19 Lockdown

Abstract Background and Objectives With the goal of slowing down the spread of the Sars-CoV-2 virus, restrictions to physical contacts have been taken in many countries. We examine to what extent intergenerational and other types of non-physical contacts have reduced the risk of increased perceived depressive feelings during the lockdown for people aged 50+. Research Design and Methods We implemented an on-line panel survey based on quota sampling in France, Italy, and Spain in April 2020, about one month after the start of the lockdown. Our analyses are based on logistic regression models and use post-stratification weights. Results About 50% of individuals aged 50+ felt sad or depressed more often than usual during the lockdown in the three considered countries. Older people who increased or maintained unchanged non-physical contacts with non-coresident individuals during the lockdown were at a lower risk of increased perceived depressive feelings compared to those who experienced a reduction in non-physical contacts. The beneficial effect of non-physical contacts was stronger for intergenerational relationships. The effects were similar by gender and stronger among individuals aged 70+, living in Spain and not living alone before the start of the lockdown. Discussion and Implications In the next phases of the COVID-19 pandemic, or during future similar pandemic, policy makers may implement measures that balance the need to reduce the spread of the virus with the necessity of allowing for limited physical contacts. Social contacts at a distance may be encouraged as a means to keep social closeness, while being physically distant.
Exploring the Role of Gut Bacteria in Health and Disease in Preterm Neonates

The mortality rate of very preterm infants with birth weight <1500 g is as high as 15%. The survivors till discharge have a high incidence of significant morbidity, which includes necrotising enterocolitis (NEC), early-onset neonatal sepsis (EONS) and late-onset neonatal sepsis (LONS). More than 25% of preterm births are associated with microbial invasion of amniotic cavity. The preterm gut microbiome subsequently undergoes an early disruption before achieving bacterial maturation. It is postulated that bacterial gut colonisation at birth and postnatal intestinal dysbacteriosis precede the development of NEC and LONS in very preterm infants. In fact, bacterial colonization patterns in preterm infants greatly differ from term infants due to maternal chorioamnionitis, gestational age, delivery method, feeding type, antibiotic exposure and the environment factor in neonatal intensive care unit (NICU). In this regard, this review provides an overview on the gut bacteria in preterm neonates’ meconium and stool. More than 50% of preterm meconium contains bacteria and the proportion increases with lower gestational age. Researchers revealed that the gut bacterial diversity is reduced in preterm infants at risk for LONS and NEC. Nevertheless, the association between gut dysbacteriosis and NEC is inconclusive with regards to relative bacteria abundance and between-sample beta diversity indices. With most studies show a disruption of the Proteobacteria and Firmicutes preceding the NEC. Hence, this review sheds light on whether gut bacteria at birth either alone or in combination with postnatal gut dysbacteriosis are associated with mortality and the morbidity of LONS and NEC in very preterm infants.
Augmentation of pulmonary arterial growth in single ventricle patients by interim selective shunts.

Stenosis or diffuse hypoplasia of central pulmonary arteries (PA) is common in patients with single ventricle physiology, often requiring surgical patching. Such repairs are prone to failure, particularly with low pressure venous flow (bidirectional cavopulmonary connection or Fontan). We describe our experience of disconnection of central pulmonary arteries and selective systemic-PA shunt to the hypoplastic vessel. Single ventricle patients (n=12) with diffuse left pulmonary artery (LPA) hypoplasia (LPA:RPA diameter <0.7) underwent PA disconnection (ligation clip) and selective arterial shunt to the LPA. Patients with ≤ mild atrioventricular valve regurgitation (AVVR), and no more than mild systolic dysfunction on echocardiogram were considered. Following systemic-LPA shunt, patients were re-assessed by cardiac catheterisation prior to further surgery, with follow-up catheterisation later performed and description of changes observed. Increased volume loading was well tolerated with no greater than mild AVVR and preserved systolic function (normal or mildly reduced). Selective arterial shunting increased the caliber of the LPA from 4.1 mm (1.2-5.6) to 6.5 mm (1.7-11.9) and this increase was preserved post-Fontan (6.7 mm (1.3-8.0)) (median (range)). Ventricular end diastolic pressure (EDP) increased with arterial shunting but resolved after shunt takedown and Fontan completion (median +3 and -4 mmHg respectively). Post-Fontan hospital length of stay was not prolonged (median 11 days, range 7-14). No deaths occurred. In univentricular hearts and PA hypoplasia, selective systemic-PA shunting physiologically increases the caliber of the distal vessels. In selected patients this can be done safely with maintenance of PA growth and resolution of the elevated EDP with Fontan completion.
Two Alternative Splicing Variants of AtERF73/HRE1, HRE1α and HRE1β, Have Differential Transactivation Activities in Arabidopsis

AtERF73/HRE1 is an AP2/ERF transcription factor in Arabidopsis and has two distinct alternative splicing variants, HRE1α and HRE1β. In this study, we examined the differences between the molecular functions of HRE1α and HRE1β. We found that HRE1α and HRE1β are both involved in hypoxia response and root development and have transactivation activity. Two conserved motifs in the C-terminal region of HRE1α and HRE1β, EELL and LWSY-like, contributed to their transactivation activity, specifically the four E residues in the EELL motif and the MGLWS amino acid sequence at the end of the LWSY-like motif. The N-terminal region of HRE1β also showed transactivation activity, mediated by the VDDG motif, whereas that of HRE1α did not. The transactivation activity of HRE1β was stronger than that of HRE1α in Arabidopsis protoplasts. Both transcription factors transactivated downstream genes via the GCC box. RNA-sequencing analysis further supported that both HRE1α and HRE1β might regulate gene expression associated with the hypoxia stress response, although they may transactivate different subsets of genes in downstream pathways. Our results, together with previous studies, suggested that HRE1α and HRE1β differentially transactivate downstream genes in hypoxia response and root development in Arabidopsis.
Citrus Flavonoids as Promising Phytochemicals Targeting Diabetes and Related Complications: A Systematic Review of In Vitro and In Vivo Studies

The consumption of plant-based food is important for health promotion, especially concerning the prevention and management of chronic diseases. Flavonoids are the main bioactive compounds in citrus fruits, with multiple beneficial effects, especially antidiabetic effects. We systematically review the potential antidiabetic action and molecular mechanisms of citrus flavonoids based on in vitro and in vivo studies. A search of the PubMed, EMBASE, Scopus, and Web of Science Core Collection databases for articles published since 2010 was carried out using the keywords citrus, flavonoid, and diabetes. All articles identified were analyzed, and data were extracted using a standardized form. The search identified 38 articles, which reported that 19 citrus flavonoids, including 8-prenylnaringenin, cosmosiin, didymin, diosmin, hesperetin, hesperidin, isosiennsetin, naringenin, naringin, neohesperidin, nobiletin, poncirin, quercetin, rhoifolin, rutin, sineesytin, sudachitin, tangeretin, and xanthohumol, have antidiabetic potential. These flavonoids regulated biomarkers of glycemic control, lipid profiles, renal function, hepatic enzymes, and antioxidant enzymes, and modulated signaling pathways related to glucose uptake and insulin sensitivity that are involved in the pathogenesis of diabetes and its related complications. Citrus flavonoids, therefore, are promising antidiabetic candidates, while their antidiabetic effects remain to be verified in forthcoming human studies.
Syk Inhibitors: New Computational Insights into Their Intraerythrocytic Action in Plasmodium falciparum Malaria

Resistance to antimalarial drugs has spread rapidly over the past few decades. The WHO recommends artemisinin-based combination therapies for the treatment of uncomplicated malaria, but unfortunately these approaches are losing their efficacy in large areas of Southeast Asia. In 2016, artemisinin resistance was confirmed in 5 countries of the Greater Mekong subregion. We focused our study on Syk inhibitors as antimalarial drugs. The Syk protein is present in human erythrocytes, and the membrane of protein band 3 is its major target following activation by oxidant stress. Tyr phosphorylation of band 3 occurs during P. falciparum growth, leading to the release of microparticles containing hemicromes and structural weakening of the host cell membrane, simplifying merozoite reinfection. Syk inhibitors block these events by interacting with the Syk protein’s catalytic site. We performed in vitro proteomics and in silico studies and compared the results. In vitro studies were based on treatment of the parasite’s cellular cultures with different concentrations of Syk inhibitors, while proteomics studies were focused on the Tyr phosphorylation of band 3 by Syk protein with the same concentrations of drugs. In silico studies were based on different molecular modeling approaches in order to analyze and optimize the ligand–protein interactions and obtain the highest efficacy in vitro. In the presence of Syk inhibitors, we observed a marked decrease of band 3 Tyr phosphorylation according to the increase of the drug’s concentration. Our studies could be useful for the structural optimization of these compounds and for the design of novel Syk inhibitors in the future.