Miracle-dz/UniFAR-FTUs huggingface dataset:
A spectrum of verticality across genes

Lateral gene transfer (LGT) has impacted prokaryotic genome evolution, yet the extent to which LGT compromises vertical evolution across individual genes and individual phyla is unknown, as are the factors that govern LGT frequency across genes. Estimating LGT frequency from tree comparisons is problematic when thousands of genomes are compared, because LGT becomes difficult to distinguish from phylogenetic artefacts. Here we report quantitative estimates for verticality across all genes and genomes, leveraging a well-known property of phylogenetic inference: phylogeny works best at the tips of trees. From terminal (tip) phylum level relationships, we calculate the verticality for 19,050,992 genes from 101,422 clusters in 5,655 prokaryotic genomes and rank them by their verticality. Among functional classes, translation, followed by nucleotide and cofactor biosynthesis, and DNA replication and repair are the most vertical. The most vertically evolving lineages are those rich in ecological specialists such as Acidithiobacilli, Chlamydiae, Chlorobi and Methanococcales. Lineages most affected by LGT are the α-, β-, γ-, and δ- classes of Proteobacteria and the Firmicutes. The 2,587 eukaryotic clusters in our sample having prokaryotic homologues fail to reject eukaryotic monophyly using the likelihood ratio test. The low verticality of α-proteobacterial and cyanobacterial genomes requires only three partners—an archaeal host, a mitochondrial symbiont, and a plastid ancestor—each with mosaic chromosomes, to directly account for the prokaryotic origin of eukaryotic genes. In terms of phylogeny, the 100 most vertically evolving prokaryotic genes are neither representative nor predictive for the remaining 97% of an average genome. In search of factors that govern LGT frequency, we find a simple but natural principle: Verticality correlates strongly with gene distribution density, LGT being least likely for intruding genes that must replace a preexisting homologue in recipient chromosomes. LGT is most likely for novel genetic material, intruding genes that encounter no competing copy.
Psychotherapy and Art Therapy: A pilot study of group treatment for patients with traumatic brain injury

Here we investigated the efficacy of group Psychotherapy and Art Therapy in rebuilding self-identity after traumatic brain injury (TBI), assessing their effects on psychological aspects in twelve patients with severe TBI. Overall, the results show an increased ability to adapt to the experiences of life as well as a higher level of awareness, social functioning and emotional autoregulation. Furthermore, patients exhibited a reduction in depressive symptoms and in the perception of physical problems. Results highlight the importance of treatments focusing on the patients’ emotional needs, in addition to the classic rehabilitation (i.e. physiotherapy, cognitive therapy).
Transmission of Artemisinin-Resistant Malaria Parasites to Mosquitoes under Antimalarial Drug Pressure

Resistance to artemisinin-based combination therapy (ACT) in the Plasmodium falciparum parasite is threatening to reverse recent gains in reducing global deaths from malaria. While resistance manifests as delayed parasite clearance in patients, the phenotype can only spread geographically via the sexual stages and mosquito transmission. In addition to their asexual killing properties, artemisinin and its derivatives sterilize sexual male gametocytes. Whether resistant parasites overcome this sterilizing effect has not, however, been fully tested. ABSTRACT Resistance to artemisinin-based combination therapy (ACT) in the Plasmodium falciparum parasite is threatening to reverse recent gains in reducing global deaths from malaria. While resistance manifests as delayed parasite clearance in patients, the phenotype can only spread geographically via the sexual stages and mosquito transmission. In addition to their asexual killing properties, artemisinin and its derivatives sterilize sexual male gametocytes. Whether resistant parasites overcome this sterilizing effect has not, however, been fully tested. Here, we analyzed P. falciparum clinical isolates from the Greater Mekong Subregion, each demonstrating delayed clinical clearance and known resistance-associated polymorphisms in the Kelch13 (PfK13var) gene. As well as demonstrating reduced asexual sensitivity to drug, certain PfK13var isolates demonstrated a marked reduction in sensitivity to artemisinin in an in vitro male gamete formation assay. Importantly, this same reduction in sensitivity was observed when the most resistant isolate was tested directly in mosquito feeds. These results indicate that, under artemisinin drug pressure, while sensitive parasites are blocked, resistant parasites continue transmission. This selective advantage for resistance transmission could favor acquisition of additional host-specificity or polymorphisms affecting partner drug sensitivity in mixed infections. Favored resistance transmission under ACT coverage could have profound implications for the spread of multidrug-resistant malaria beyond Southeast Asia.
Plant-ImputeDB: an integrated multiple plant reference panel database for genotype imputation

Abstract Genotype imputation is a process that estimates missing genotypes in terms of the haplotypes and genotypes in a reference panel. It can effectively increase the density of single nucleotide polymorphisms (SNPs), boost the power to identify genetic association and promote the combination of genetic studies. However, there has been a lack of high-quality reference panels for most plants, which greatly hinders the application of genotype imputation. Here, we developed Plant-ImputeDB (http://gong_lab.hzau.edu.cn/Plant_imputeDB/), a comprehensive database with reference panels of 12 plant species for online genotype imputation, SNP and block search and free download. By integrating genotype data and whole-genome resequencing data of plants from various studies and databases, the current Plant-ImputeDB provides high-quality reference panels of 12 plant species, including ∼69.9 million SNPs from 34 244 samples. It also provides an easy-to-use online tool with the option of two popular tools specifically designed for genotype imputation. In addition, Plant-ImputeDB accepts submissions of different types of genomic variations, and provides free and open access to all publicly available data in support of related research worldwide. In general, Plant-ImputeDB may serve as an important resource for plant genotype imputation and greatly facilitate the research on plant genetic research.
Unintended uses, meanings, and consequences: HIV self-testing among female sex workers in urban Uganda

ABSTRACT Female sex workers (FSWs) are at increased risk of HIV and face significant barriers to clinic-based HIV testing, including provider stigma and privacy constraints. HIV self-testing (HIVST) has been proven to significantly increase HIV testing among FSWs. Less is known, however, about how FSWs make meaning of oral-fluid HIV self-tests, and the unintended ways they use and understand this novel technology. From October 2016 to March 2017, we conducted 61 in-depth interviews with FSWs (n = 31) in Kampala, Uganda. Eligible participants were: female, ≥18 years, exchanged sex for money or goods, and had not recently tested for HIV. We used inductive coding to identify emerging themes and re-arranged these into an adapted framework. Unintended desirable ways FSWs described self-testing included as a means to test others, to bolster their reputation as a health-conscious sex worker, and to avoid bearing witness to suffering at health facilities. Unintended undesirable meanings ascribed to self-testing included misunderstandings about how HIV is transmitted (via saliva versus blood) and whether self-tests also test for other infections. HIVST can increase FSWs’ knowledge of their own HIV status and that of their sexual partners, but messaging and intervention design must address misunderstandings and misuses of self-testing. Trial registration: ClinicalTrials.gov identifier: NCT02846402.
Immunotherapy and potential predictive biomarkers in the treatment of neuroendocrine neoplasia.

Neuroendocrine neoplasias (NENs) are a heterogeneous group of rare tumors scattered throughout the body. Surgery, locoregional or ablative therapies as well as maintenance treatments are applied in well-differentiated, low-grade NENs, whereas cytotoxic chemotherapy is usually applied in high-grade neuroendocrine carcinomas. However, treatment options for patients with advanced or metastatic NENs are limited. Immunotherapy has provided new treatment approaches for many cancer types, including neuroendocrine tumors, but predictive biomarkers of immune checkpoint inhibitors (ICIs) in the treatment of NENs have not been fully reported. By reviewing the literature and international congress abstracts, we summarize the current knowledge of ICIs, potential predicative biomarkers in the treatment of NENs, implications and efficacy of ICIs as well as biomarkers for NENs of gastroenteropancreatic system, lung NENs and Merkel cell carcinoma in clinical practice.
How Effective Is Conservation Biological Control in Regulating Insect Pest Populations in Organic Crop Production Systems?

Simple Summary Organic crop production systems typically rely on conservation biological control to increase and sustain natural enemies including parasitoids and predators that will regulate insect pest populations below damaging levels. The use of flowering plants or floral resources to attract and retain natural enemies in organic crop production systems has not been consistent, based on the scientific literature, and most importantly, many studies do not correlate an increase in natural enemies with a reduction in plant damage. This may be associated with the effects of intraguild predation or the negative effects that can occur when multiple natural enemies are present in an ecosystem. Consequently, although incorporating flowering plants into organic crop production systems may increase the natural enemy assemblages, more robust scientific studies are warranted to determine the actual effects of natural enemies in reducing plant damage associated with insect pest populations. Abstract Organic crop production systems are designed to enhance or preserve the presence of natural enemies, including parasitoids and predators, by means of conservation biological control, which involves providing environments and habitats that sustain natural enemy assemblages. Conservation biological control can be accomplished by providing flowering plants (floral resources) that will attract and retain natural enemies. Natural enemies, in turn, will regulate existing insect pest populations to levels that minimize plant damage. However, evidence is not consistent, based on the scientific literature, that providing natural enemies with flowering plants will result in an abundance of natural enemies sufficient to regulate insect pest populations below economically damaging levels. The reason that conservation biological control has not been found to sufficiently regulate insect pest populations in organic crop production systems across the scientific literature is associated with complex interactions related to intraguild predation, the emission of plant volatiles, weed diversity, and climate and ecosystem resources across locations where studies have been conducted.
Training Young Adult Peers in a Mobile Motivational Interviewing-Based Mentoring Approach to Upstream HIV Prevention.

Mentoring relationships are characterized by a sustained, high quality, and skill-building relationship between a protégé and mentor (Handbook of Youth Mentoring, Los Angeles, SAGE, 2014). Within prevention science, youth mentoring programs emphasize creating a specific context that benefits a young person. Program-sponsored relationships between youth and adults allow for creating a mentor-mentee partnership, but do not require the establishment of a strong bond in order to deliver prevention-focused activities and experiences (Handbook of Youth Mentoring, Los Angeles, SAGE, 2014). Motivational Interviewing (MI) is a counseling style used widely to promote health behavior change and in prevention interventions. As part of an upstream approach to HIV prevention, we combined mentoring and MI by training peer mentors to use MI skills in their interactions as part of a large RCT of a mobile life skills intervention for adolescent men who have sex with men (AMSM). Our training model developed for training peer mentors in MI skills resulted in peers reaching and exceeding established MI fidelity thresholds (e.g., mean percentage of complex reflections = 80%, mean reflection to question ratio = 2.2:1). We offer reflections on lessons learned and future directions for those researchers and practitioners who may benefit from adapting this blended approach for mentoring AMSM.
Salt stress reduces root water uptake in barley (Hordeum vulgare L.) through modification of the transcellular transport path.

The aim of the study was to understand the hydraulic response to salt stress of the root system of the comparatively salt-tolerant crop barley (Hordeum vulgare L.). We focused on the transcellular path of water movement across the root cylinder that involves the crossing of membranes. This path allows for selective water uptake, while excluding salt ions. Hydroponically grown plants were exposed to 100 mM NaCl for 5-7 days and analysed when 15-17d old. A range of complementary and novel approaches was used to determine hydraulic conductivity (Lp). This included analyses at cell, root and plant level and modeling of water flow. Apoplastic barrier formation and gene expression level of aquaporins (AQPs) was analysed. Salt stress reduced the Lp of root system through reducing water flow along the transcellular path. This involved changes in the activity and gene expression level of AQPs. Modeling of root Lp showed that the reduction in root Lp did not require added hydraulic resistances through apoplastic barriers at the endodermis. The bulk of data points to a near-perfect semipermeability of roots of control plants (solute reflection coefficient σ ~1.0). Roots of salt-stressed plants are almost as semipermeable (σ > 0.8). This article is protected by copyright. All rights reserved.
A Population-Based Study on the Association between Periodontal Disease and Major Lifestyle-Related Comorbidities in South Korea: An Elderly Cohort Study from 2002–2015

This study determined the association between periodontal disease (PD) and major lifestyle-related comorbidities (LCs) using the database of the nationwide population-based National Health Insurance Service–Elderly Cohort 2002–2015. A nationwide representative sample comprising 558,147 participants, aged 60 years, was analyzed. Univariate and multivariate logistic regression analyses adjusted for sociodemographic and economic factors (sex, age, household income, insurance status, health status, and living area) and major LCs (hypertension, diabetes mellitus, rheumatoid arthritis, osteoporosis, cerebral infarction, angina pectoris, myocardial infarction, erectile dysfunction, lipoprotein disorder, and obesity) were used to determine the association between PD and major LCs. Elderly participants with PD had a higher risk of major LCs (hypertension: odds ratio (OR) = 1.40, diabetes mellitus: OR = 1.22, rheumatoid arthritis: OR = 1.16, osteoporosis: OR = 1.37, erectile dysfunction: OR = 1.73, lipoprotein disorder: OR = 1.50, and obesity: OR = 1.59). Our longitudinal cohort study provided evidence that PD was significantly associated with major LCs in elderly participants. In particular, the association between PD and erectile dysfunction had the highest OR in the multivariate analyses.
Monoclonal Antibodies to Treat Multiple Myeloma: A Dream Come True

Immunotherapy is increasingly used in the treatment of multiple myeloma (MM). Monoclonal antibodies (mAbs) are safe and effective ways to elicit immunotherapeutic responses. In 2015, daratumumab has become the first mAb approved by the Food and Drug Administration for clinical use in MM and, in the last 5 years, a lot of clinical and preclinical research has been done to optimize the use of this drug class. Currently, mAbs have already become part of standard-of-care combinations for the treatment of relapsed/refractory MM and very soon they will also be used in the frontline setting. The success of simple mAbs (‘naked mAbs’) prompted the development of new types of molecules. Antibody–drug conjugates (ADCs) are tumor-targeting mAbs that release a cytotoxic payload into the tumor cells upon antigen binding in order to destroy them. Bispecific antibodies (BiAbs) are mAbs simultaneously targeting a tumor-associated antigen and an immune cell-associated antigen in order to redirect the immune cell cytotoxicity against the tumor cell. These different constructs produced solid preclinical data and promising clinical data in phase I/II trials. The aim of this review article is to summarize all the recent developments in the field, including data on naked mAbs, ADCs and BiAbs.
Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in β-Cells

Selective inhibition of histone deacetylase 3 (HDAC3) prevents glucolipotoxicity-induced β-cell dysfunction and apoptosis by alleviation of proapoptotic endoplasmic reticulum (ER) stress-signaling, but the precise molecular mechanisms of alleviation are unexplored. By unbiased microarray analysis of the β-cell gene expression profile of insulin-producing cells exposed to glucolipotoxicity in the presence or absence of a selective HDAC3 inhibitor, we identified Enhancer of zeste homolog 2 (EZH2) as the sole target candidate. β-Cells were protected against glucolipotoxicity-induced ER stress and apoptosis by EZH2 attenuation. Small molecule inhibitors of EZH2 histone methyltransferase activity rescued human islets from glucolipotoxicity-induced apoptosis. Moreover, EZH2 knockdown cells were protected against glucolipotoxicity-induced downregulation of the protective non-canonical Nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFκB) pathway. We conclude that EZH2 deficiency protects from glucolipotoxicity-induced ER stress, apoptosis and downregulation of the non-canonical NFκB pathway, but not from insulin secretory dysfunction. The mechanism likely involves transcriptional regulation via EZH2 functioning as a methyltransferase and/or as a methylation-dependent transcription factor.
Imipenem/Cilastatin/Relebactam Alone and in Combination against Pseudomonas aeruginosa in the In Vitro Pharmacodynamic Model

Combination therapy may enhance imipenem/cilastatin/relebactam’s (I/R) activity against Pseudomonas aeruginosa and suppress resistance development. Human-simulated unbound plasma concentrations of I/R at 1.25 g every 6 h (h), colistin at 360 mg daily, and amikacin at 25 mg/kg daily were reproduced alone and in combination against six imipenem-nonsusceptible P. aeruginosa isolates in an in vitro pharmacodynamic model over 24 h. ABSTRACT Combination therapy may enhance imipenem/cilastatin/relebactam’s (I/R) activity against Pseudomonas aeruginosa and suppress resistance development. Human-simulated unbound plasma concentrations of I/R at 1.25 g every 6 h (h), colistin at 360 mg daily, and amikacin at 25 mg/kg daily were reproduced alone and in combination against six imipenem-nonsusceptible P. aeruginosa isolates in an in vitro pharmacodynamic model over 24 h. For I/R alone, the mean reductions in CFU ± the standard errors by 24 h were −2.52 ± 0.49, −1.49 ± 0.49, −1.15 ± 0.67, and −0.61 ± 0.10 log10 CFU/ml against isolates with MICs of 1/4, 2/4, 4/4, and 8/4 μg/ml, respectively. Amikacin alone also resulted in 24 h CFU reductions consistent with its MIC, while colistin CFU reductions did not differ. Resistant subpopulations were observed after 24 h in 1, 4, and 3 I/R-, colistin-, and amikacin-exposed isolates, respectively. The combination of I/R and colistin resulted in synergistic (n = 1) or additive (n = 2) interactions against three isolates with 24-h CFU reductions ranging from −2.62 to −4.67 log10 CFU/ml. The combination of I/R and amikacin exhibited indifferent interactions against all isolates, with combined drugs achieving −0.51- to −3.33-log10 CFU/ml reductions. No resistant subpopulations were observed during I/R and colistin combination studies, and when added to amikacin, I/R prevented the emergence of amikacin resistance. Against these six multidrug-resistant P. aeruginosa, I/R alone achieved significant CFU reductions against I/R-susceptible isolates. Combinations of I/R plus colistin resulted in additivity or synergy against some P. aeruginosa, whereas the addition of amikacin did not provide further antibacterial efficacy against these isolates.
Distinct evolutionary dynamics of horizontal gene transfer in drug resistant and virulent clones of Klebsiella pneumoniae

Klebsiella pneumoniae (Kp) has emerged as an important cause of two distinct public health threats: multidrug resistant (MDR) healthcare-associated infections1 and community-acquired invasive infections, particularly pyogenic liver abscess2. The majority of MDR hospital outbreaks are caused by a subset of Kp clones with a high prevalence of acquired antimicrobial resistance (AMR) genes, while the majority of community-acquired invasive infections are caused by ‘hypervirulent’ clones that rarely harbour acquired AMR genes but have high prevalence of key virulence loci3–5. Worryingly, the last few years have seen increasing reports of convergence of MDR and the key virulence genes within individual Kp strains6, but it is not yet clear whether these represent a transient phenomenon or a significant ongoing threat. Here we perform comparative genomic analyses for 28 distinct Kp clones, including 6 hypervirulent and 8 MDR, to better understand their evolutionary histories and the risks of convergence. We show that MDR clones are highly diverse with frequent chromosomal recombination and gene content variability that far exceeds that of the hypervirulent clones. Consequently, we predict a much greater risk of virulence gene acquisition by MDR Kp clones than of resistance gene acquisition by hypervirulent clones.
Robust and clinically relevant prediction of response to anti-cancer drugs via network integration of molecular profiles

In order to tackle heterogeneity of cancer samples and high data space dimensionality, we propose a method NEAmarker for finding sensitive and robust biomarkers at the pathway level. In this method, scores from network enrichment analysis transform the original space of altered genes into a lower-dimensional space of pathways, which is then correlated with phenotype variables. The analysis was first done on in vitro anti-cancer drug screen datasets and then on clinical data. In parallel, we tested a panel of state-of-the-art enrichment methods. In this comparison, our method proved superior in terms of 1) universal applicability to different data types with a possibility of cross-platform integration, 2) consistency of the discovered correlates between independent drug screens, and 3) ability to explain differential survival of treated patients. Our new in vitro screen validated performance of the discovered multivariate models. Finally, NEAmarker was the only method to discover predictors of both in vitro response and patient survival given administration of the same drug.