Miracle-dz/UniFAR-FTUs huggingface dataset:
Genetic Susceptibility to Enteric Fever in Experimentally Challenged Human Volunteers

Infections with Salmonella enterica serovars Typhi and Paratyphi A cause an estimated 14 million cases of enteric fever annually. Here, the controlled nature of challenge studies is exploited to identify genetic variants associated with enteric fever susceptibility. ABSTRACT Infections with Salmonella enterica serovars Typhi and Paratyphi A cause an estimated 14 million cases of enteric fever annually. Here, the controlled nature of challenge studies is exploited to identify genetic variants associated with enteric fever susceptibility. Human challenge participants were genotyped by Illumina OmniExpress-24 BeadChip array (n = 176) and/or transcriptionally profiled by RNA sequencing (n = 174). While the study was underpowered to detect any single nucleotide polymorphisms (SNPs) significant at the whole-genome level, two SNPs within CAPN14 and MIATNB were identified with P < 10−5 for association with development of symptoms or bacteremia following oral S. Typhi or S. Paratyphi A challenge. Imputation of classical human leukocyte antigen (HLA) types from genomic and transcriptomic data identified HLA-B*27:05, previously associated with nontyphoidal Salmonella-induced reactive arthritis, as the HLA type most strongly associated with enteric fever susceptibility (P = 0.011). Gene sets relating to the unfolded protein response/heat shock and endoplasmic reticulum-associated protein degradation were overrepresented in HLA-B*27:05+ participants following challenge. Furthermore, intracellular replication of S. Typhi is higher in C1R cells transfected with HLA-B*27:05 (P = 0.02). These data suggest that activation of the unfolded protein response by HLA-B*27:05 misfolding may create an intracellular environment conducive to S. Typhi replication, increasing susceptibility to enteric fever.
Critical behaviour of the stochastic Wilson-Cowan model

Spontaneous brain activity is characterized by bursts and avalanche-like dynamics, with scale-free features typical of critical behaviour. The stochastic version of the celebrated Wilson-Cowan model has been widely studied as a system of spiking neurons reproducing non-trivial features of the neural activity, from avalanche dynamics to oscillatory behaviours. However, to what extent such phenomena are related to the presence of a genuine critical point remains elusive. Here we address this central issue, providing analytical results in the linear approximation and extensive numerical analysis. In particular, we present results supporting the existence of a bona fide critical point, where a second-order-like phase transition occurs, characterized by scale-free avalanche dynamics, scaling with the system size and a diverging relaxation time-scale. Moreover, our study shows that the observed critical behaviour falls within the universality class of the mean-field branching process, where the exponents of the avalanche size and duration distributions are, respectively, −3/2 and −2. We also provide an accurate analysis of the system behaviour as a function of the total number of neurons, focusing on the time correlation functions of the firing rate in a wide range of the parameter space. Author summary Networks of spiking neurons are introduced to describe some features of the brain activity, which are characterized by burst events (avalanches) with power-law distributions of size and duration. The observation of this kind of noisy behaviour in a wide variety of real systems led to the hypothesis that neuronal networks work in the proximity of a critical point. This hypothesis is at the core of an intense debate. At variance with previous claims, here we show that a stochastic version of the Wilson-Cowan model presents a phenomenology in agreement with the existence of a bona fide critical point for a particular choice of the relative synaptic weight between excitatory and inhibitory neurons. The system behaviour at this point shows all features typical of criticality, such as diverging timescales, scaling with the system size and scale-free distributions of avalanche sizes and durations, with exponents corresponding to the mean-field branching process. Our analysis unveils the critical nature of the observed behaviours.
Default Mode Network spatial configuration varies across task domains

Recent developments in network neuroscience suggest reconsidering what we thought we knew about the Default Mode Network (DMN). Although this network has always been seen as unitary and associated with the resting state, a new deconstructive line of research is pointing out that the DMN could be divided into multiple subsystems supporting different functions. By now, it is well known that the DMN is not only deactivated by tasks, but also involved in affective, mnestic, and social paradigms, among others. Nonetheless, it is starting to become clear that the array of activities in which it is involved, might also be extended to more extrinsic functions. The present meta-analytic study is meant to push this boundary a bit further. The BrainMap database was searched for all experimental paradigms activating the DMN, and their activation maps were then computed. An additional map of task-induced deactivations was also created. A Multidimensional Scaling indicated that such maps could be arranged along an anatomo-psychological gradient, which goes from midline core activations, associated with the most internal functions, to the involvement of lateral cortices in more external tasks. Further investigations suggested that such extrinsic mode is especially related to reward, semantic, and emotional functions. However, an important finding was that the variability of task-induced DMN anatomic redistribution was hard to recapitulate, as none of the maps, or any linear combination of them, could represent the whole space of its dynamical reconfiguration. Altogether, our findings suggest that the DMN may be characterized by a richer functional diversity and a more spatial complexity than previously suggested.
DHA but not EPA induces the trans-differentiation of C2C12 cells into white-like adipocytes phenotype

Muscle derived stem cells (MDSCs) and myoblast play an important role in myotube regeneration when muscle tissue is injured. However, these cells can be induced to differentiate into adipocytes once exposed to PPARγ activator like EPA and DHA that are highly suggested during pregnancy. The objective of this study aims at determining the identity of trans-differentiated cells by exploring the effect of EPA and DHA on C2C12 undergoing differentiation into brown and white adipocytes. DHA but not EPA committed C2C12 cells reprograming into white like adipocyte phenotype. Also, DHA promoted the expression of lipolysis regulating genes but had no effect on genes regulating β-oxidation referring to its implication in lipid re-esterification. Furthermore, DHA impaired C2C12 cells differentiation into brown adipocytes through reducing the thermogenic capacity and mitochondrial biogenesis of derived cells independent of UCP1. Accordingly, DHA treated groups showed an increased accumulation of lipid droplets and suppressed mitochondrial maximal respiration and spare respiratory capacity. EPA, on the other hand, reduced myogenesis regulating genes, but no significant differences were observed in the expression of adipogenesis key genes. Likewise, EPA suppressed the expression of WAT signature genes indicating that EPA and DHA have an independent role on white adipogeneis. Unlike DHA treatment, EPA supplementation had no effect on the differential of C2C12 cells into brown adipocytes. In conclusion, DHA is a potent adipogenic and lipogenic factor that can change the metabolic profile of muscle cells by increasing myocellular fat.
Invariant representation of physical stability in the human brain

Successful engagement with the world requires the ability to predict what will happen next. Here we investigate how the brain makes the most basic prediction about the physical world: whether the situation in front of us is stable, and hence likely to stay the same, or unstable, and hence likely to change in the immediate future. Specifically, we ask if judgements of stability can be supported by the kinds of representations that have proven to be highly effective at visual object recognition in both machines and brains, or instead if the ability to determine the physical stability of natural scenes may require generative algorithms that simulate the physics of the world. To find out, we measured responses in both convolutional neural networks (CNNs) and the brain (using fMRI) to natural images of physically stable versus unstable scenarios. We find no evidence for generalizable representations of physical stability in either standard CNNs trained on visual object and scene classification (ImageNet), or in the human ventral visual pathway, which has long been implicated in the same process. However, in fronto-parietal regions previously implicated in intuitive physical reasoning we find both scenario-invariant representations of physical stability, and higher univariate responses to unstable than stable scenes. These results demonstrate abstract representations of physical stability in the dorsal but not ventral pathway, consistent with the hypothesis that the computations underlying stability entail not just pattern classification but forward physical simulation.
Copper dependent ERK1/2 phosphorylation is essential for the viability of neurons and not glia

Intracellular Copper [Cu(I)] has been hypothesized to play role in the differentiation of the neurons. This necessitates understanding the role of Cu(I) not only in the neurons but also in the glia considering their anatomical proximity, contribution towards ion homeostasis, neuronal physiology, and neurodegeneration. In this study we did a systematic investigation of the changes in the cellular copper homeostasis during neuronal and glial differentiation and the pathways triggered by them. Our study demonstrates increased mRNA for the plasma membrane copper transporter CTR1 leading to an increased Cu(I) during neuronal (PC-12) differentiation. ATP7A is retained in the Trans Golgi Network (TGN) despite high Cu(I) demonstrating its utilization in triggering the pathways towards the neuronal differentiation. One of these pathways is ERK1/2 phosphorylation accompanying the differentiation of both PC-12 and human fetal brain derived neuronal progenitor cells. The study demonstrates that the ERK1/2 phosphorylation is essential for the viability of the neurons. In contrast, differentiated C-6 (glia) cells contain low intracellular copper and significant downregulation of the ERK1/2 phosphorylation. Interestingly ATP7A shows vesicular localization despite the low copper in the glia. In addition to the TGN in the perinuclear region, ATP7A localizes into RAB11 positive recycling endosomes in the glial neurites, not observed in the neurons. Our study demonstrates role of the copper dependent ERK1/2 phosphorylation in the neuronal differentiation. Whereas glial differentiation largely involves sequestration of Cu(I) into the endosomes potentially (i) for ready release to the neurons (ii) rendering cytosolic copper unavailable for pathways like the ERK1/2 activation.
Two subsets of human marginal zone B cells resolved by global analysis of lymphoid tissues and blood

B cells generate antibodies that are essential for immune protection. Major events driving B cell responses occur in lymphoid tissues, which guide antigen acquisition and support cellular interactions, yet complexities of B cell subsets in human lymphoid tissues are poorly understood. Here we perform undirected, global profiling of B cells in matched human lymphoid tissues from deceased transplant organ donors and tracked dissemination of B cell clones. In addition to identifying unanticipated features of tissue-based B cell differentiation, we resolve two clonally independent subsets of marginal zone B cells that differ in cell surface and transcriptomic profiles, tendency to disseminate, distribution bias within splenic marginal zone microenvironment and immunoglobulin repertoire diversity and hypermutation frequency. Each subset is represented in spleen, gut-associated lymphoid tissue, mesenteric lymph node, and also blood. Thus, we provide clarity and diffuse controversy surrounding human MZB - the ‘elephant in the room’ of human B cell biology.
Electrophysiological signatures of brain aging in autism spectrum disorder

Emerging evidence suggests that aging processes may be altered in adults with autism spectrum disorder (ASD). However, it remains unclear if oscillatory slowing, a key neurophysiological change in the aging brain, manifests atypically in this population. This study sought to examine patterns of age-related oscillatory slowing in adults with ASD, captured by reductions in the brain’s peak alpha frequency. Resting-state EEG data from adults (18-70 years) with ASD (N=93) and age-matched neurotypical (NT) controls (N=87) were pooled from three independent datasets. A robust curve-fitting procedure quantified the peak frequency of alpha oscillations (7-13Hz) across all brain regions. Associations between peak alpha frequency and age were assessed and compared between groups. Consistent with characteristic patterns of oscillatory slowing, peak alpha frequency was negatively associated with age across the entire sample (p<.0001). A significant group by age interaction revealed that this relationship was more pronounced in adults with ASD (p<.01), suggesting that that age-related oscillatory slowing may be accelerated in this population. Scalable EEG measures such as peak alpha frequency could provide insights into neural aging that are crucially needed to inform care plans and preventive interventions that can promote successful aging in ASD.
Anxiety-Related Frontocortical Activity Is Associated With Dampened Stressor Reactivity in the Real World

Negative affect is a fundamental dimension of human emotion. When extreme, it contributes to a variety of adverse outcomes, from physical and mental illness to divorce and premature death. Mechanistic work in animals and neuroimaging research in humans and monkeys have begun to reveal the broad contours of the neural circuits governing negative affect, but the relevance of these discoveries to everyday distress remains incompletely understood. Here, we used a combination of approaches—including neuroimaging assays of threat anticipation and emotional-face perception and more than 10,000 momentary assessments of emotional experience—to demonstrate that individuals who showed greater activation in a cingulo-opercular circuit during an anxiety-eliciting laboratory paradigm experienced lower levels of stressor-dependent distress in their daily lives (ns = 202–208 university students). Extended amygdala activation was not significantly related to momentary negative affect. These observations provide a framework for understanding the neurobiology of negative affect in the laboratory and in the real world.
GlucoCEST MRI for the early evaluation response to chemotherapeutic and metabolic treatments in a murine triple negative breast cancer: a comparison with [18F]F-FDG-PET

Purpose Triple-negative breast cancer (TNBC) patients have usually poor outcome after chemotherapy and early prediction of therapeutic response would be helpful. [18F]F-FDG-PET/CT acquisitions are often carried out to monitor variation in metabolic activity associated to response to the therapy, despite moderate accuracy and radiation exposure limit its application. The glucoCEST technique relies on the use of unlabelled D-glucose to assess glucose uptake with conventional MRI scanners and is currently under active investigations at clinical level. This work aims at validating the potential of MRI-glucoCEST in monitoring early therapeutic responses in a TNBC tumor murine model. Procedures Breast tumor (4T1) bearing mice were treated with doxorubicin or dichloroacetate for one week. PET/CT with [18F]F-FDG and MRI-glucoCEST were performed at baseline and after 3 cycles of treatment. Metabolic changes measured with [18F]F-FDG-PET and glucoCEST were compared and evaluated with changes in tumor volumes. Results Doxorubicin treated mice showed a significant decrease in tumor growth when compared to the control group. GlucoCEST imaging provided early metabolic response after three cycles of treatment, conversely, no variations were detect by in [18F]F-FDG uptake. Dichloroacetate treated mice did not show any decrease either in tumor volume or in tumor metabolic activity as assessed by both glucoCEST and [18F]F-FDG-PET. Conclusions Early metabolic changes during doxorubicin treatment can be predicted by glucoCEST imaging that appears more sensitive than [18F]F-FDG-PET in reporting on early therapeutic response. These findings support the view that glucoCEST may be a sensitive technique for monitoring metabolic response, but future studies are needed to explore the accuracy of this approach in other tumor types and treatments.
Antagonistic effects of chemical mixtures on the oxidative stress response are silenced by heat stress and reversed under dietary restriction

Chemical agents released into the environment can induce oxidative stress in organisms, which is detrimental for health. Although environmental exposures typically incorporate multiple chemicals, organismal studies on oxidative stress derived from chemical agents commonly study exposures to individual compounds. In this work, we explore how chemical mixtures drive the oxidative stress response under various conditions in the nematode C. elegans, by quantitatively assessing levels of gst-4 expression. Our results indicate that naphthoquinone mixtures drive responses differently than individual components, and that altering environmental conditions, such as increased heat and reduced food availability, result in dramatically different oxidative stress responses mounted by C. elegans. When exposed to heat, the oxidative stress response is diminished. Notably, when exposed to limited food, the oxidative stress response specific to juglone is significantly heightened, while identified antagonistic interactions between some naphthoquinone components in mixtures are abolished. This implies that organismal responses to xenobiotics is confounded by environment and stressor interactions. Given the high number of variables under study, and their potential combinations, a simplex centroid design was used to capture such non-trivial response over the design space. This makes the case for the adoption of Design of Experiments approaches as they can greatly expand the experimental space probed in noisy biological readouts, and in combinatorial experiments. Our results also reveal gaps in our current knowledge of the organismal oxidative stress response, which can be addressed by employing sophisticated design of experiments approaches to identify significant interactions.
OCRbayes: A Bayesian hierarchical modeling framework for Seahorse extracellular flux oxygen consumption rate data analysis

Background Mitochondrial dysfunction is involved in many complex diseases. Efficient and accurate evaluation of mitochondrial functionality is crucial for understanding pathology as well as facilitating novel therapeutic developments. As a popular platform, Seahorse extracellular flux (XF) analyzer is widely used for measuring mitochondrial oxygen consumption rate (OCR) in living cells. A hidden feature of Seahorse XF OCR data is that it has a complex data structure, caused by nesting and crossing between measurement cycles, wells and plates. Surprisingly, statistical analysis of Seahorse XF data has not received sufficient attention, and current methods completely ignore the complex data structure, impairing the robustness of statistical inference. Results To rigorously incorporate the complex structure into data analysis, here we developed a Bayesian hierarchical modeling framework, OCRbayes, and demonstrated its applicability based on analysis of published data sets. Conclusions We showed that OCRbayes can analyze Seahorse XF OCR experimental data derived from either single or multiple plates. Moreover, OCRbayes has potential to be used for diagnosing patients with mitochondrial diseases.
Finger representation in the cortex of the congenitally blind

Hand representation in the primary somatosensory cortex (S1) is thought to be shaped by experience. Individuals with congenital blindness rely on their sense of touch for completing daily tasks that in sighted people would be informed by vision, and possess superior tactile acuity. It has therefore been proposed that their S1 hand representation should differ from that of sighted individuals. Alternatively, it has been proposed that the improved tactile acuity in blind individuals is due to cross-modal plasticity, when regions in the occipital and temporal cortex are typically used for processing vision become activated by touch. We probed finger representation using psychophysics and 7T fMRI (1 mm3 resolution) in three individuals with bilateral anophthalmia, a rare condition in which both eyes fail to develop, as well as sighted controls. Despite anophthalmic individuals’ increased reliance on touch and superior tactile acuity, we found no evidence that they had more pronounced hand representation in S1. This is in line with recent research highlighting the stability of early sensory cortex, despite altered sensorimotor experience in adulthood. Unlike sighted controls, anophthalmic individuals activated the left human middle temporal complex (hMT+) during finger movement. This area did not express any hallmark of typical sensorimotor organisation, suggesting this and previously reported activity does not indicate low-level sensorimotor hand representation. However, left hMT+ contained some single finger information, beyond that found in sighted controls. This latter finding suggests that when the developmentally flexible area hMT+ is unaffected by retinal input, it can acquire novel cross-modal processes, which are potentially unrelated to the area’s function in sighted people. As such, our findings highlight the opportunity for other organising principles, beyond domain specific plasticity, in shaping cross-modal reorganisation.
SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway

Pathogenesis of COVID-19 is associated with a hyperinflammatory response; however, the precise mechanism of SARS-CoV-2-induced inflammation is poorly understood. Here we investigated direct inflammatory functions of major structural proteins of SARS-CoV-2. We observed that spike (S) protein potently induces inflammatory cytokines and chemokines including IL-6, IL-1ß, TNFa, CXCL1, CXCL2, and CCL2, but not IFNs in human and mouse macrophages. No such inflammatory response was observed in response to membrane (M), envelope (E), and neucleocapsid (N) proteins. When stimulated with extracellular S protein, human lung epithelial cells A549 also produce inflammatory cytokines and chemokines. Interestingly, epithelial cells expressing S protein intracellularly are non-inflammatory, but elicit an inflammatory response in macrophages when co-cultured. Biochemical studies revealed that S protein triggers inflammation via activation of the NF-κB pathway in a MyD88-dependent manner. Further, such an activation of the NF-κB pathway is abrogated in Tlr2-deficient macrophages. Consistently, administration of S protein induces IL-6, TNF-a, and IL-1 ß in wild-type, but not Tlr2-deficient mice. Together these data reveal a mechanism for the cytokine storm during SARS-CoV-2 infection and suggest that TLR2 could be a potential therapeutic target for COVID-19.