Miracle-dz/UniFAR-FTUs huggingface dataset:
Monocyte-derived transcriptome signature indicates antibody-dependent cellular phagocytosis as the primary mechanism of vaccine-induced protection against HIV-1

A gene signature previously correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus (SIV) and SHIV challenge models in non-human primates (NHP). In this report we investigated presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanism for protection. The absence of this gene signature in the DNA/rAd5 human vaccine trial which did not show efficacy, strengthens our hypothesis that this signature is only enriched in studies that demonstrated protection. This gene signature was enriched in the partially effective RV144 human trial that administered the ALVAC/protein vaccine, and we find that the signature associates with both decreased risk of HIV-1 acquisition and increased vaccine efficacy. Total RNA-seq in a clinical trial that used the same vaccine regimen as the RV144 HIV vaccine implicated antibody-dependent cellular phagocytosis (ADCP) as a potential mechanism of vaccine protection. CITE-seq profiling of 53 surface markers and transcriptomes of 53,777 single cells from the same trial, showed that genes in this signature were primarily expressed in cells belonging to the myeloid lineage including monocytes, which are major effector cells for ADCP. The consistent association of this transcriptome signature with vaccine efficacy represents a tool both to identify potential mechanisms, as with ADCP here, and to screen novel approaches to accelerate development of new vaccine candidates.
Functional characterization of splicing regulatory elements

Background RNA binding protein-RNA interactions mediate a variety of processes including pre-mRNA splicing, translation, decay, polyadenylation and many others. Previous high-throughput studies have characterized general sequence features associated with increased and decreased splicing of certain exons, but these studies are limited by not knowing the mechanisms, and in particular, the mediating RNA binding proteins, underlying these associations. Results Here we utilize ENCODE data from diverse data modalities to identify functional splicing regulatory elements and their associated RNA binding proteins. We identify features which make splicing events more sensitive to depletion of RNA binding proteins, as well as which RNA binding proteins act as splicing regulators sensitive to depletion. To analyze the sequence determinants underlying RBP-RNA interactions impacting splicing, we assay tens of thousands of sequence variants in a high-throughput splicing reporter called Vex-seq and confirm a small subset in their endogenous loci using CRISPR base editors. Finally, we leverage other large transcriptomic datasets to confirm the importance of RNA binding proteins which we designed experiments around and identify additional RBPs which may act as additional splicing regulators of the exons studied. Conclusions This study identifies sequence and other features underlying splicing regulation mediated specific RNA binding proteins, as well as validates and identifies other potentially important regulators of splicing in other large transcriptomic datasets.
Neuronal NADPH oxidase 2 in Parkinson’s disease pathogenesis

Mitochondrial dysfunction and oxidative stress are strongly implicated in the pathogenesis of Parkinson’s disease (PD) and there is evidence that mitochondrially-generated superoxide can activate NADPH oxidase 2 (NOX2), which is a major enzymatic generator of superoxide. Although NOX2 has been examined in the context of PD, previous studies have focused on microglial function; the role of neuronal NOX2 in PD pathogenesis remains to be defined. Here we devised and validated a proximity ligation assay for NOX2 activity and demonstrated that in human PD and 2 models thereof, neuronal NOX2 is highly active in substantia nigra dopamine neurons. Further, NOX2 activity is responsible for accumulation, post-translational modification and oligomerization of α-synuclein as well as activation of leucine-rich repeat kinase 2 (LRRK2). Administration of a brain-penetrant, specific NOX2 inhibitor prevented NOX2 activation and its downstream effects in vivo in a rat model of PD. We conclude that neuronal NOX2 is a major contributor to oxidative stress in PD, to α-synuclein pathology and to LRRK2 activation in idiopathic PD. In this context, NOX2 inhibitors hold potential as a disease-modifying therapy in PD. Summary In dopamine neuron, NADPH oxidase isoform 2 amplifies the oxidative stress-related pathogenic cascade in Parkinson’s disease
Plasmid co-infection: linking biological mechanisms to ecological and evolutionary dynamics

As infectious agents of bacteria and vehicles of horizontal gene transfer, plasmids play a key role in bacterial ecology and evolution. Plasmid dynamics are shaped not only by plasmid-host interactions, but also by ecological interactions between plasmid variants. These interactions are complex: plasmids can co-infect the same host cell and the consequences for the co-resident plasmid can be either beneficial or detrimental. Many of the biological processes that govern plasmid co-infection–from systems to exclude infection by other plasmids to interactions in the regulation of plasmid copy number per cell–are well characterised at a mechanistic level. Modelling plays a central role in translating such mechanistic insights into predictions about plasmid dynamics, and in turn, the impact of these dynamics on bacterial evolution. Theoretical work in evolutionary epidemiology has shown that formulating models of co-infection is not trivial, as some modelling choices can introduce unintended ecological assumptions. Here, we review how the biological processes that govern co-infection can be represented in a mathematical model, discuss potential modelling pitfalls, and analyse this model to provide general insights into how co-infection impacts eco-evolutionary outcomes. In particular, we demonstrate how beneficial and detrimental effects of co-infection give rise to frequency-dependent selection.
Leveraging the mass balances of cellular metabolism to infer absolute concentrations from relative abundance metabolomics data

Motivation As the large-scale study of metabolites and a direct readout of a system’s metabolic state, metabolomics has significant appeal as a source of information for many metabolic modelling platforms and other metabolic analysis tools. However, metabolomics data are typically reported in terms of relative abundances, which precluding use with tools where absolute concentrations are necessary. While chemical standards can be used to determine the absolute concentrations of metabolites, they are often time-consuming to run, expensive, or unavailable for many metabolites. A computational framework that can infer absolute concentrations without the use of chemical standards would be highly beneficial to the metabolomics community. Results We have developed and characterized MetaboPAC, a computational strategy that leverages the mass balances of a system to infer absolute concentrations in metabolomics datasets. MetaboPAC uses a kinetic equations approach and an optimization approach to predict the most likely response factors that describe the relationship between absolute concentrations and their relative abundances. We determined that MetaboPAC performed significantly better than the other approaches assessed on noiseless data when at least 60% of kinetic equations are known a priori. Under the most realistic conditions (low sampling frequency, high noise data), MetaboPAC significantly outperformed other methods in the majority of cases when 100% of the kinetic equations were known. For metabolomics datasets extracted from systems that are well-studied and have partially known kinetic structures, MetaboPAC can provide valuable insight about their absolute concentration profiles.
Stable choice coding during changes of mind

How do we choose the best action in a constantly-changing environment? Many natural decisions unfold in dynamic environments where newer observations carry better information about the present state of the world. Recent work has shown that rats can learn to optimally discount old evidence, updating their provisional decision when the environmental state changes. Provisional decisions are thought to be represented in the Frontal Orienting Fields (FOF), but this has only been tested in static environments where the provisional and final decisions are not easily dissociated. Here, we characterize the representation of accumulated evidence in rat FOF during decision-making in a dynamic environment. We find that FOF encodes evidence throughout decision formation with a temporal gain modulation that rises until the period when the animal may need to act. Using a behavioral model to predict the timing of changes of mind revealed that FOF neurons respond rapidly to these events, representing the new provisional decisions in their firing rates. Our results suggest that the FOF represents provisional decisions even in dynamic, uncertain environments, allowing for rapid motor execution when it is time to act.
Increasing temperature weakens the positive effect of genetic diversity on population growth

Genetic diversity and temperature increases associated with global climate change, are known to independently influence population growth and extinction risk. Whether increasing temperature may influence the effect of genetic diversity on population growth, however, is not known. We address this issue in the model protist system Tetrahymena thermophila. We test the hypothesis that at temperatures closer to the species thermal optimum (i.e., the temperature at which population growth is maximal), genetic diversity should have a weaker effect on population growth compared to temperatures away from the thermal optimum. To do so, we grew populations of T. thermophila with varying levels of genetic diversity at increasingly warmer temperatures and quantified their intrinsic population growth rate, r. We found that genetic diversity increases population growth at cooler temperatures, but that as temperature increases, this effect almost completely disappears. We also show that a combination of changes in the amount of expressed genetic diversity (G), plastic changes in population growth across temperatures (E), and strong GxE interactions, underlie this temperature effect. Our results uncover important but largely overlooked temperature effects that have implications for the management of small populations with depauperate genetic stocks in an increasingly warming world.
Endothelial Focal Adhesions Are Functional Obstacles for Leukocytes During Basolateral Crawling

An inflammatory response requires leukocytes to migrate from the circulation across the vascular lining into the tissue to clear the invading pathogen. Whereas a lot of attention is focused on how leukocytes make their way through the endothelial monolayer, it is less clear how leukocytes migrate underneath the endothelium before they enter the tissue. Upon finalization of the diapedesis step, leukocytes reside in the subendothelial space and encounter endothelial focal adhesions. Using TIRF microscopy, we show that neutrophils navigate around these focal adhesions. Neutrophils recognize focal adhesions as physical obstacles and deform to get around them. Increasing the number of focal adhesions by silencing the small GTPase RhoJ slows down basolateral crawling of neutrophils. However, apical crawling and diapedesis itself are not affected by RhoJ depletion. Increasing the number of focal adhesions drastically by expressing the Rac1 GEF Tiam1 make neutrophils to avoid migrating underneath these Tiam1-expressing endothelial cells. Together, our results show that focal adhesions mark the basolateral migration path of neutrophils.
Leptin and Obesity: Role and Clinical Implication

The peptide hormone leptin regulates food intake, body mass, and reproductive function and plays a role in fetal growth, proinflammatory immune responses, angiogenesis and lipolysis. Leptin is a product of the obese (ob) gene and, following synthesis and secretion from fat cells in white adipose tissue, binds to and activates its cognate receptor, the leptin receptor (LEP-R). LEP-R distribution facilitates leptin’s pleiotropic effects, playing a crucial role in regulating body mass via a negative feedback mechanism between adipose tissue and the hypothalamus. Leptin resistance is characterized by reduced satiety, over-consumption of nutrients, and increased total body mass. Often this leads to obesity, which reduces the effectiveness of using exogenous leptin as a therapeutic agent. Thus, combining leptin therapies with leptin sensitizers may help overcome such resistance and, consequently, obesity. This review examines recent data obtained from human and animal studies related to leptin, its role in obesity, and its usefulness in obesity treatment.
Combining QTL Mapping and Transcriptomics to Decipher the Genetic Architecture of Phenolic Compounds Metabolism in the Conifer White Spruce

Conifer forests worldwide are becoming increasingly vulnerable to the effects of climate change. Although the production of phenolic compounds (PCs) has been shown to be modulated by biotic and abiotic stresses, the genetic basis underlying the variation in their constitutive production level remains poorly documented in conifers. We used QTL mapping and RNA-Seq to explore the complex polygenic network underlying the constitutive production of PCs in a white spruce (Picea glauca) full-sib family for 2 years. QTL detection was performed for nine PCs and differentially expressed genes (DEGs) were identified between individuals with high and low PC contents for five PCs exhibiting stable QTLs across time. A total of 17 QTLs were detected for eight metabolites, including one major QTL explaining up to 91.3% of the neolignan-2 variance. The RNA-Seq analysis highlighted 50 DEGs associated with phenylpropanoid biosynthesis, several key transcription factors, and a subset of 137 genes showing opposite expression patterns in individuals with high levels of the flavonoids gallocatechin and taxifolin glucoside. A total of 19 DEGs co-localized with QTLs. Our findings represent a significant step toward resolving the genomic architecture of PC production in spruce and facilitate the functional characterization of genes and transcriptional networks responsible for differences in constitutive production of PCs in conifers.
Tumor Immune Microenvironment and Its Related miRNAs in Tumor Progression

MiRNA is a type of small non-coding RNA, by regulating downstream gene expression that affects the progression of multiple diseases, especially cancer. MiRNA can participate in the biological processes of tumor, including proliferation, invasion and escape, and exhibit tumor enhancement or inhibition. The tumor immune microenvironment contains numerous immune cells. These cells include lymphocytes with tumor suppressor effects such as CD8+ T cells and natural killer cells, as well as some tumor-promoting cells with immunosuppressive functions, such as regulatory T cells and myeloid-derived suppressor cells. MiRNA can affect the tumor immune microenvironment by regulating the function of immune cells, which in turn modulates the progression of tumor cells. Investigating the role of miRNA in regulating the tumor immune microenvironment will help elucidate the specific mechanisms of interaction between immune cells and tumor cells, and may facilitate the use of miRNA as a predictor of immune disorders in tumor progression. This review summarizes the multifarious roles of miRNA in tumor progression through regulation of the tumor immune microenvironment, and provides guidance for the development of miRNA drugs to treat tumors and for the use of miRNA as an auxiliary means in tumor immunotherapy.
Proglucagon-Derived Peptides as Therapeutics

Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With description of the precursor proglucagon, we now appreciate that glucagon was just the first proglucagon-derived peptide (PGDP) to be characterised. Other bioactive members of the PGDP family include glucagon-like peptides -1 and -2 (GLP-1 and GLP-2), oxyntomodulin (OXM), glicentin and glicentin-related pancreatic peptide (GRPP), with these being produced via tissue-specific processing of proglucagon by the prohormone convertase (PC) enzymes, PC1/3 and PC2. PGDP peptides exert unique physiological effects that influence metabolism and energy regulation, which has witnessed several of them exploited in the form of long-acting, enzymatically resistant analogues for treatment of various pathologies. As such, intramuscular glucagon is well established in rescue of hypoglycaemia, while GLP-2 analogues are indicated in the management of short bowel syndrome. Furthermore, since approval of the first GLP-1 mimetic for the management of Type 2 diabetes mellitus (T2DM) in 2005, GLP-1 therapeutics have become a mainstay of T2DM management due to multifaceted and sustainable improvements in glycaemia, appetite control and weight loss. More recently, longer-acting PGDP therapeutics have been developed, while newfound benefits on cardioprotection, bone health, renal and liver function and cognition have been uncovered. In the present article, we discuss the physiology of PGDP peptides and their therapeutic applications, with a focus on successful design of analogues including dual and triple PGDP receptor agonists currently in clinical development.
Positive Selection in Gene Regulatory Factors Suggests Adaptive Pleiotropic Changes During Human Evolution

Gene regulatory factors (GRFs), such as transcription factors, co-factors and histone-modifying enzymes, play many important roles in modifying gene expression in biological processes. They have also been proposed to underlie speciation and adaptation. To investigate potential contributions of GRFs to primate evolution, we analyzed GRF genes in 27 publicly available primate genomes. Genes coding for zinc finger (ZNF) proteins, especially ZNFs with a Krüppel-associated box (KRAB) domain were the most abundant TFs in all genomes. Gene numbers per TF family differed between all species. To detect signs of positive selection in GRF genes we investigated more than 3,000 human GRFs with their more than 70,000 orthologs in 26 non-human primates. We implemented two independent tests for positive selection, the branch-site-model of the PAML suite and aBSREL of the HyPhy suite, focusing on the human and great ape branch. Our workflow included rigorous procedures to reduce the number of false positives: excluding distantly similar orthologs, manual corrections of alignments, and considering only genes and sites detected by both tests for positive selection. Furthermore, we verified the candidate sites for selection by investigating their variation within human and non-human great ape population data. In order to approximately assign a date to positively selected sites in the human lineage, we analyzed archaic human genomes. Our work revealed with high confidence five GRFs that have been positively selected on the human lineage and one GRF that has been positively selected on the great ape lineage. These GRFs are scattered on different chromosomes and have been previously linked to diverse functions. For some of them a role in speciation and/or adaptation can be proposed based on the expression pattern or association with human diseases, but it seems that they all contributed independently to human evolution. Four of the positively selected GRFs are KRAB-ZNF proteins, that induce changes in target genes co-expression and/or through arms race with transposable elements. Since each positively selected GRF contains several sites with evidence for positive selection, we suggest that these GRFs participated pleiotropically to phenotypic adaptations in humans.
Commentary: Stereotactic Body Radiotherapy vs. Radiofrequency Ablation in the Treatment of Hepatocellular Carcinoma: A Meta-Analysis

We were very interested in reading the article by Pan et al. (1), which included 10 studies involving 2,732 patients to compare the efficacy of stereotactic body radiotherapy (SBRT) and radiofrequency ablation (RFA) in the treatment of hepatocellular carcinoma (HCC). We appreciate the writing intention of this meta-analysis. However, there are several issues in the article, which are worthy of comment and adequate emphasis. Firstly, local tumor recurrence (LTR) can be assessed only by ensuring that the tumor is completely ablated, that is to say, complete ablation of the tumor can be confirmed by imaging standards (2). Actually, for the two treatment methods currently discussed, only RFA can achieve the immediate posttreatment evaluation. It is worth noting that the imaging findings of HCC treated with SBRT changed gradually over time, and the weakening of the enhancement of HCC tends to precede the reduction in tumor size. As a matter of fact, the imaging findings of HCC after SBRT were not consistent with those of other focal therapies. At present, response evaluation criteria for solid tumors (RECIST) are placed on the basis of changes in tumor size, but the necrotic areas after SBRT are not considered in RECIST. Although the modified RECIST (mRECIST) and the European Association for the Study of Liver (EASL) criteria take into consideration live tumor within the lesion, the SBRT post-reaction for HCC has not been verified. Secondly, despite the fact that the definition of LTR after RAF is very clear, the imaging evaluation of LTR after SBRT is particularly complicated and controversial. What included in the current assessment mainly are as follows: changes in the size of the target lesion, changes in internal enhancement characteristics, and assessment of necrosis by evaluating unenhanced areas within the tumor. Since the imaging manifestations of tumor imaging gradually change over time, the timing of imaging after SBRT is also important in evaluating treatment effects. Actually, after SBRT, the tumor is divided into three stages, including acute stage (<3 months), subacute stage (3–6 months), and chronic stage (3). In the acute stage and the subacute stage, the arterial phase
Does Oral Apigenin Have Real Potential for a Therapeutic Effect in the Context of Human Gastrointestinal and Other Cancers?

Apigenin (4′, 5, 7-trihydroxyflavone) is a plant flavone that has been found to have various actions against cancer cells. We evaluated available evidence to determine whether it is feasible for apigenin to have such effects in human patients. Apigenin taken orally is systemically absorbed and recirculated by enterohepatic and local intestinal pathways. Its bioavailability is in the region of 30%. Once absorbed from the oral route it reaches maximal circulating concentration (Cmax) after a time (Tmax) of 0.5–2.5h, with an elimination half-life (T1/2) averaging 2.52 ± 0.56h. Using a circulating concentration for efficacy of 1–5μmol/L as the target, we evaluated data from both human and rodent pharmacokinetic studies to determine if a therapeutic concentration would be feasible. We find that oral intake of dietary materials would require heroic ingestion amounts and is not feasible. However, use of supplements of semi-purified apigenin in capsule form could reach target blood levels using amounts that are within the range currently acceptable for other supplements and medications. Modified formulations or parenteral injection are suitable but may not be necessary. Further work with direct studies of pharmacokinetics and clinical outcomes are necessary to fully evaluate whether apigenin will contribute to a useful clinical strategy, but given emerging evidence that it may interact beneficially with chemotherapeutic drugs, this is worthy of emphasis. In addition, more effective access to intestinal tissues from the oral route raises the possibility that apigenin may be of particular relevance to gastrointestinal disorders including colorectal cancer.