Miracle-dz/UniFAR-FTUs huggingface dataset:
Characterizing Enterotypes in Human Metagenomics: A Viral Perspective

The diversity and high genomic mutation rates of viral species hinder our understanding of viruses and their contributions to human health. Here we investigated the human fecal virome using previously published sequencing data of 2,690 metagenomes from seven countries. We found that the virome was dominated by double-stranded DNA viruses, and young children and adults showed dramatic differences in their fecal enterovirus composition. Beta diversity showed there were significantly higher distances to centroids in individuals with severe phenotypes, such as cirrhosis. In contrast, there were no significant differences in lengths to centroids or viral components between patients with mild phenotypes, such as hypertension. Enterotypes showed the same specific viruses and enrichment direction after independent determination of enterotypes in various projects. Confounding factors, such as different sequencing platforms and library construction, did not result in a batch effect to confuse enterotype assignment. The gut virome composition pattern could be described by two viral enterotypes, which supported a discrete, rather than a gradient, distribution. Compared with enterotype 2, enterotype 1 had a higher viral count and Shannon index, but a lower beta diversity, indicating more resistance to the external environment’s harmful effects. Disease was usually accompanied by a viral enterotype disorder. However, a sample outside of the enterotyping mathematical space of enterotype database did not necessarily indicate sickness. Therefore, the background context must be carefully considered when using a viral enterotype as a biomarker for disease prediction. The disease, second only to the enterotype, explains significant variation in viral community composition, implying that double-stranded DNA is relevant to human health. Our results of investigating a baseline viral database highlight important insights into the virome composition of human ecosystems, and provide an alternate biomarker for early disease screening.
Intermittent hypoxia enhances the expression of HIF1A by increasing the quantity and catalytic activity of KDM4A-C and demethylating H3K9me3 at the HIF1A locus

Cellular oxygen-sensing pathways are primarily regulated by hypoxia inducible factor-1 (HIF-1) in chronic hypoxia and are well studied. Intermittent hypoxia also occurs in many pathological conditions, yet little is known about its biological effects. In this study, we investigated how two proposed cellular oxygen sensing systems, HIF-1 and KDM4A-C, respond to cells exposed to intermittent hypoxia and compared to chronic hypoxia. We found that intermittent hypoxia increases HIF-1 activity through a pathway distinct from chronic hypoxia, involving the KDM4A, -B and -C histone lysine demethylases. Intermittent hypoxia increases the quantity and activity of KDM4A-C resulting in a decrease in H3K9 methylation. This contrasts with chronic hypoxia, which decreases KDM4A-C activity, leading to hypermethylation of H3K9. Demethylation of histones bound to the HIF1A gene in intermittent hypoxia increases HIF1A mRNA expression, which has the downstream effect of increasing overall HIF-1 activity and expression of HIF target genes. This study highlights how multiple oxygen-sensing pathways can interact to regulate and fine tune the cellular hypoxic response depending on the period and length of hypoxia.
A highly conserved host lipase deacylates oxidized phospholipids and ameliorates acute lung injury

Oxidized phospholipids have diverse biological activities, many of which can be pathological, yet how they are inactivated in vivo is not fully understood. Here we present evidence that a previously unsuspected host lipase, acyloxyacyl hydrolase (AOAH), can play a significant role in reducing the pro-inflammatory activities of two prominent products of phospholipid oxidation, 1-palmitoyl-2-glutaryl-sn-glycero-3- phosphocholine (PGPC) and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC). AOAH removed the sn-2 and sn-1 acyl chains from both lipids and reduced their ability to induce macrophage inflammasome activation and cell death in vitro and acute lung injury in vivo. In addition to transforming Gram-negative bacterial lipopolysaccharide from stimulus to inhibitor, its most studied activity, AOAH can inactivate these important danger-associated molecular pattern (DAMP) molecules and reduce tissue inflammation and cell death.
Emotional states as distinct configurations of functional brain networks

The conceptualization of emotional states as patterns of interactions between large-scale brain networks has recently gained support. Yet, few studies have directly examined the brain’s network structure during emotional experiences. Here, we investigated the brain’s functional network organization during experiences of sadness, amusement, and neutral states elicited by movies, in addition to a resting-state. We tested the effects of the experienced emotion on individual variability in the brain’s functional connectome. Next, for each state, we defined a community structure of the brain and quantified its segregation and integration. We found that sadness, relative to amusement, was associated with higher modular integration and increased connectivity of cognitive control networks: the salience and fronto-parietal networks. Moreover, in both the functional connectome and the emotional report, the similarity between individuals was dependent on the sex. Our results suggest that the experience of emotion is linked to a reconfiguration of whole-brain distributed, not emotion-specific, functional networks and that the brain’s topological structure carries information about the subjective emotional experience.
AMaLa: Analysis of Directed Evolution Experiments via Annealed Mutational Approximated Landscape

We present Annealed Mutational approximated landscape (AMaLa), a new method to infer fitness landscapes from Directed Evolution experiment sequencing data. Directed Evolution experiments typically start from a single wild-type sequence, which undergoes Darwinian in vitro evolution acted via multiple rounds of mutation and selection with respect to a target phenotype. In the last years, Directed Evolution is emerging as a powerful instrument to probe fitness landscapes under controlled experimental condition and, thanks to the use of high-throughput sequencing of the different rounds, as a relevant testing ground to develop accurate statistical models and inference algorithms. Fitness landscape modeling strategies, either use as input data the enrichment of variants abundances and hence require observing the same variants at different rounds, or they simply assume that the variants at the last sequenced round are the results of a sampling process at equilibrium. AMaLa aims at leveraging effectively the information encoded in the time evolution of all sequenced rounds. To do so, on the one hand we assume statistical sampling independence between sequenced rounds, and on the other we gauge all possible trajectories in sequence space with a time-dependent statistical weight consisting of two contributions: (i) a statistical energy term accounting for the selection process, (ii) a simple generalized Jukes-Cantor model to describe the purely mutational step. This simple scheme allows us to accurately describe the Directed Evolution dynamics in a concrete experimental setup and to infer a fitness landscape that reproduces correctly the measures of the phenotype under selection (e.g. antibiotic drug resistance), notably outperforming widely used inference strategies. We assess the reliability of AMaLa by showing how the inferred statistical model could be used to predict relevant structural properties of the wild-type sequence, and to reproduce the mutational effects of large scale functional screening not used to train the model.
FH loss in RPE cells causes retinal degeneration in a human RPE-porcine retinal explant co-culture model

Age-related Macular degeneration (AMD) is a degenerative disease of the macula affecting the elderly population. Treatment options are limited, partly due to the lack of understanding of AMD pathology and the sparse availability of research models, that replicate the complexity of the human macula and the intricate interplay of the genetic, aging and life-style risk factors contributing to AMD. One of the main genetic risks associated with AMD is located on Complement Factor H (CFH) gene, leading to an amino acid substitution in the FH protein (Y402H). However, the mechanism of how this FH variant promotes the onset of AMD remains unclear. Previously, we have shown that FH deprivation in RPE cells, via CFH silencing, leads to increased inflammation, metabolic impairment and vulnerability towards oxidative stress. In this study, we established a novel co-culture model comprised of CFH silenced RPE cells and porcine retinal explants derived from the visual streak of the porcine eyes, closely resembling the human macula. We show that retinae exposed to FH-deprived RPE cells show signs of retinal degeneration, with rod cells being the first cells to undergo degeneration. Moreover, via Raman analyses, we observe that the main changes involve the mitochondria and lipid composition of the co-cultured retinae upon FH loss. Interestingly, the detrimental effects of FH loss in RPE cells on the neuroretina were independent of glial cell activation and external complement sources. Moreover, we show that the co-culture model is also suitable for human retinal explants, and we observed a similar trend when RPE cells deprived of FH were co-cultured with human retinal explants from a single donor eye. Our findings highlight the importance of RPE derived FH for retinal homeostasis and provide a valuable model for AMD research.
Synaptic Mechanisms of Top-Down Control in the Non-Lemniscal Inferior Colliculus

Corticofugal projections to evolutionarily ancient, sub-cortical structures are ubiquitous across mammalian sensory systems. These “descending” pathways enable the neocortex to control ascending sensory representations in a predictive or feedback manner, but the underlying cellular mechanisms are poorly understood. Here we combine optogenetic approaches with in vivo and in vitro patch-clamp electrophysiology to study the projection from auditory cortex to the inferior colliculus (IC), a major descending auditory pathway that controls IC neuron feature selectivity, plasticity and auditory perceptual learning. Although individual auditory cortico-collicular synapses were generally weak, IC neurons often integrated inputs from multiple corticofugal axons that generated reliable, tonic depolarizations even during prolonged presynaptic activity. Latency measurements in vivo showed that descending signals reach the IC within 30 ms of sound onset, which in IC neurons corresponded to the peak of synaptic depolarizations evoked by short sounds. Activating ascending and descending pathways at latencies expected in vivo caused a NMDA receptor dependent, supra-linear EPSP summation, indicating that descending signals can non-linearly amplify IC neurons’ moment-to-moment acoustic responses. Our results shed light upon the synaptic bases of descending sensory control, and imply that heterosynaptic cooperativity contributes to the auditory cortico-collicular pathway’s role in plasticity and perceptual learning.
Trial-wise exposure to visual appetitive cues increases physiological arousal but not temporal discounting

Humans and many animals devalue future rewards as a function of time (temporal discounting). Increased discounting has been linked to various psychiatric conditions, including substance-use-disorders, behavioral addictions and obesity. Despite its high intra-individual stability, temporal discounting is partly under contextual control. One prominent manipulation that has been linked to increases in discounting is the exposure to highly arousing appetitive cues. However, results from trial-wise cue exposure studies appear highly mixed, and changes in physiological arousal were not adequately controlled. Here we tested the effects of appetitive (erotic), aversive and neutral visual cues on temporal discounting in thirty-five healthy male participants. The contribution of single-trial physiological arousal was assessed using comprehensive monitoring of autonomic activity (pupil size, heart rate, electrodermal activity). Physiological arousal was elevated following aversive and in particular erotic cues. In contrast to our pre-registered hypothesis, if anything, we observed decreased temporal discounting following erotic cue exposure. Aversive cues tended to increase decision noise. Computational modeling revealed that trial-wise arousal only accounted for minor variance over and above aversive and erotic condition effects, arguing against a general effect of physiological arousal on temporal discounting.
Fusion Oncogenes Are Associated With Increased Metastatic Capacity and Persistent Disease in Pediatric Thyroid Cancers

Background In 2014, data from a comprehensive multiplatform analysis of 496 adult papillary thyroid cancer samples reported by The Cancer Genome Atlas project suggested that reclassification of thyroid cancer into molecular subtypes, RAS-like and BRAF-like, better reflects clinical behavior than sole reliance on pathological classification. The aim of this study was to categorize the common oncogenic variants in pediatric differentiated thyroid cancer and investigate if mutation subtype classification correlated with the risk of metastasis and response to initial therapy in pediatric DTC. Methods Somatic cancer gene panel analysis was completed on DTC from 131 pediatric patients. DTC were categorized into RAS-mutant (H-K-NRAS), BRAF-mutant (BRAF p.V600E) and RET/NTRK fusion (RET, NTRK1 and NTRK3 fusions) to determine differences between subtype classification in regard to pathological data (AJCC TNM) as well as response to therapy 1-year after initial treatment had been completed. Results Mutation-based subtype categories were significant in most variables, including age at diagnosis, metastatic behavior, and the likelihood of remission at 1-year. Patients with RET/NTRK fusions were significantly more likely to have advanced lymph node and distant metastasis and less likely to achieve remission at one year than patients within RAS- or BRAF-mut subgroups. Conclusions Our data supports that genetic subtyping of pediatric DTC more accurately reflects clinical behavior than sole reliance on pathological classification with patients with RET/NTRK fusions having worse outcomes than those with BRAF-mutant disease. Future trials should consider inclusion of molecular subtype into risk stratification.
A single exposure to altered auditory feedback causes observable sensorimotor adaptation in speech

Sensory errors caused by perturbations to movement-related feedback induce two types of behavioral changes that oppose the perturbation: rapid compensation within a movement, as well as longer-term adaptation of subsequent movements. Although adaptation is hypothesized to occur whenever a sensory error is perceived (including after a single exposure to altered feedback), adaptation of articulatory movements in speech has only been observed after repetitive exposure to auditory perturbations, questioning both current theories of speech sensorimotor adaptation as well as the universality of more general theories of adaptation. Thus, positive evidence for the hypothesized single-exposure or “one-shot” learning would provide critical support for current theories of speech sensorimotor learning and control and align adaptation in speech more closely with other motor domains. We measured one-shot learning in a large dataset in which participants were exposed to intermittent, unpredictable auditory perturbations to their vowel formants (the resonant frequencies of the vocal tract that distinguish between different vowels). On each trial, participants spoke a word out loud while their first formant was shifted up, shifted down, or remained unshifted. We examined whether the perturbation on a given trial affected speech on the subsequent, unperturbed trial. We found that participants adjusted their first formant in the opposite direction of the preceding shift, demonstrating that learning occurs even after a single auditory perturbation as predicted by current theories of sensorimotor adaptation. While adaptation and the preceding compensation responses were correlated, this was largely due to differences across individuals rather than within-participant variation from trial to trial. These findings are more consistent with theories that hypothesize adaptation is driven directly by updates to internal control models than those that suggest adaptation results from incorporation of feedback responses from previous productions.
IQD1 Involvement in Hormonal Signaling and General Defense Responses Against Botrytis cinerea

IQ Domain 1 (IQD1) is a novel calmodulin-binding protein in A. thaliana, which was found to be a positive regulator of glucosinolate (GS) accumulation and plant defense responses against insects. We demonstrate here that the IQD1 overexpressing line (IQD1OXP) is more resistant also to the necrotrophic fungus Botrytis cinerea, whereas an IQD1 knockout line (iqd1-1) is much more sensitive. Furthermore, we show that IQD1 is upregulated by Jasmonic acid (JA) and downregulated by Salicylic acid (SA). Comparison of whole transcriptome expression between iqd1-1 and wild type revealed a substantial downregulation of genes involved in plant defense and hormone regulation. Further examination revealed a marked reduction of SA/JA signaling and increase in ethylene signaling genes in the iqd1-1 line. Moreover, quantification of SA, JA and abscisic acids in IQD1OXP and iqd1-1lines compared to WT showed a significant reduction in endogenous JA levels in the knockout line simultaneously with increased SA levels. Epistasis relations between IQD1OXP and mutants defective in plant-hormone signaling indicated that IQD1 acts upstream or parallel to the hormonal pathways (JA/ET and SA) in defense response against B. cinerea and in regulating GS accumulation and it is dependent on JAR1 controlling indole glucosinolate accumulation. As a whole, our results suggest that IQD1 is an important defensive protein against Botrytis cinerea in A. thaliana and is integrated into several important pathways such as plant microbe perception and hormone signaling. SIGNIFICANCE STATEMENT IQD1 is involved in glucosinolate accumulation and in general defense responses. JA activates IQD1 that acts upstream or parallel to JA/ET and SA signaling pathway while controlling glucosinolate accumulation and defense against Botrytis cinerea and it is dependent on JAR1 controlling indole glucosinolate accumulation.
Divining Deamidation and Isomerization in Therapeutic Proteins: Effect of Neighboring Residue

Deamidation of asparagine (ASN) and isomerization of aspartic acid (ASP) residues are among the most commonly observed spontaneous post-translational modifications (PTMs) in proteins. Understanding and predicting a protein sequence’s propensity for such PTMs can help expedite protein therapeutic discovery and development. In this study, we utilized proton-affinity calculations with semi-empirical quantum mechanics (QM) and µs long equilibrium molecular dynamics (MD) simulations to investigate mechanistic roles of structure and chemical environment in dictating spontaneous degradation of asparagine and aspartic acid residues in 131 clinical-stage therapeutic antibodies. Backbone secondary structure, side-chain rotamer conformation and solvent accessibility were found as three key molecular indicators of ASP isomerization and ASN deamidation. Comparative analysis of backbone dihedral angles along with N-H proton affinity calculations provides a mechanistic explanation for the strong influence of the identity of the n+1 residue on the rate of ASP/ASN degradation. With these findings, we propose a minimalistic physics-based classification model that can be leveraged to predict deamidation and isomerization propensity of therapeutic proteins.
COVID-19 Pandemic Worsening Gender Inequalities for Women and Girls in Sub-Saharan Africa

Pandemics such as COVID-19 have often resulted in international, national and sub-regional crises, with considerable inequities across many societies. With the already existing structural and socio-economic inequalities in sub-Saharan Africa, the stay-at-home orders, lockdowns, and shutdowns across the sub-regional states could worsen and have a tremendous impact on vulnerable groups. Numerous studies across a variety of contexts have well-documented gender, and cultures on varied health outcomes. However, these have not been contextualized in sub-Saharan Africa in the light of the COVID-19 pandemic. This mini review discusses the ways by which COVID-19 has impacted the lives of girls and women across sub-Saharan Africa and the strategies that can help mitigate these challenges. The mini review specifically shares light on a wide array of dimensions where the inequities exist. These include the disproportionate areas affected by COVID-19; household inequities; educational inequalities; work/employment inequalities; disparities related to healthcare, sexual and reproductive health as well as housing inequities. Conclusively, the review accentuates the need for sub-Saharan African countries to adopt low-cost preventive measures such as discouraging mass gatherings (e.g., local community gatherings), and face masking with non-medical cloth like masks for the local populace as these are crucial in managing the spread of the virus among disproportionate women population. For localities with limited access to handwashing facilities, alternative strategies like alcohol-based hand rub solutions could be deployed. The complex interrelated disparities require a broad set of policy actions to lessen the current burden faced by many women in sub-Saharan Africa.
Colonization Ability and Impact on Human Gut Microbiota of Foodborne Microbes From Traditional or Probiotic-Added Fermented Foods: A Systematic Review

A large subset of fermented foods act as vehicles of live environmental microbes, which often contribute food quality assets to the overall diet, such as health-associated microbial metabolites. Foodborne microorganisms also carry the potential to interact with the human gut microbiome via the food chain. However, scientific results describing the microbial flow connecting such different microbiomes as well as their impact on human health, are still fragmented. The aim of this systematic review is to provide a knowledge-base about the scientific literature addressing the connection between foodborne and gut microbiomes, as well as to identify gaps where more research is needed to clarify and map gut microorganisms originating from fermented foods, either traditional or added with probiotics, their possible impact on human gut microbiota composition and to which extent foodborne microbes might be able to colonize the gut environment. An additional aim was also to highlight experimental approaches and study designs which could be better standardized to improve comparative analysis of published datasets. Overall, the results presented in this systematic review suggest that a complex interplay between food and gut microbiota is indeed occurring, although the possible mechanisms for this interaction, as well as how it can impact human health, still remain a puzzling picture. Further research employing standardized and trans-disciplinary approaches aimed at understanding how fermented foods can be tailored to positively influence human gut microbiota and, in turn, host health, are therefore of pivotal importance.