Miracle-dz/UniFAR-FTUs huggingface dataset:
Low grade inflammation in the epileptic hippocampus contrasts with explosive inflammation occurring in the acute phase following status epilepticus in rats: translation to patients with epilepsy

There is still a lack of robust data, acquired identically and reliably from tissues either surgically resected from patients with mesial temporal lobe epilepsy (mTLE) or collected in animal models, to answer the question of whether the degree of inflammation of the hippocampus differs between mTLE patients, and between epilepsy and epileptogenesis. Here, using highly calibrated RTqPCR, we show that neuroinflammatory marker expression was highly variable in the hippocampus and the amygdala of mTLE patients. This variability was not associated with gender, age, duration of epilepsy, seizure frequency, and anti-seizure drug treatments. In addition, it did not correlate between the two structures and was reduced when the inflammatory status was averaged between the two structures. We also show that brain tissue not frozen within minutes after resection had significantly decreased housekeeping gene transcript levels, precluding the possibility of using post-mortem tissues to assess physiological baseline transcript levels in the hippocampus. We thus used rat models of mTLE, induced by status epilepticus (SE), that have the advantage of providing access to physiological baseline values. They indisputably indicated that inflammation measured during the chronic phase of epilepsy was much lower than the explosive inflammation occurring after SE, and was only detected when epilepsy was associated with massive neurodegeneration and gliosis. Comparison between the inter-individual variability measured in patients and that established in all epileptic and control rats suggests that some mTLE patients may have very low inflammation in the hippocampus, close to control values. However, the observation of elevated inflammation in the amygdala of some patients indicates that inflammation should be studied not only at the epileptic hippocampus, but also in the associated brain structures in order to have a more integrated view of the degree of inflammation present in brain networks involved in mesial temporal lobe epilepsy.
Synaptic signaling networks encode experience by assuming stimulus-specific and brain-region-specific states

A core network of ubiquitously expressed glutamate-synapse-associated proteins mediates activity-dependent synaptic plasticity throughout the brain, but the specific proteomic composition of synapses differs between brain regions. Here, we sought to classify the diversity of activity-dependent remodeling across brain regions using quantitative protein interaction network (PIN) analysis. We first compared the response of cultured neurons to distinct stimuli, and defined PIN parameters that differentiate input types. We next compared the response of three different brain regions maintained alive in vitro to an identical stimulus, and identified three qualitatively different PIN responses. Finally, we measured the PIN response following associative learning tasks, delay and trace eyeblink conditioning, in three brain regions, and found that the two forms of associative learning are distinguished from each other using brain-region-specific network mechanisms. We conclude that although the PIN of the glutamatergic post-synapse is expressed ubiquitously, its activity-dependent dynamics show remarkable stimulus-specific and brain-region-specific diversity.
Loss of STAT5 in adipocytes increases subcutaneous fat mass via sex-dependent and depot-specific pathways

The STAT (Signal Transducers and Activators of Transcription) family of transcription factors contributes to adipocyte development and function. STAT5A and STAT5B are induced during adipocyte differentiation and are primarily activated by growth hormone (GH). Studies in mice lacking adipocyte GH receptor or STAT5 support their roles in lipolysis-mediated reduction of adipose tissue mass. We have generated a mouse model lacking both STAT5 genes specifically in adipocytes (STAT5AKO). Notably, both sexes of STAT5AKO mice have increased inguinal adipose tissue without any changes in gonadal fat mass. However, both depots exhibit substantial differences in fat cell size. Study of STAT5AKO mice also have revealed that GH’s ability to induce insulin resistance is dependent upon STAT5 in adipocytes, but its ability to reduce adipose tissue mass is STAT5 independent. Additional observations, which were not predicted, indicate that the causes and regulation of increased fat mass in STAT5AKO mice are sex- and depot-dependent.
Neural dynamics of parametrically modulated human mechanical pain determined using whole-brain quantitative perfusion imaging

Arterial spin labelling (ASL) FMRI is a powerful tool to noninvasively image tonic and ongoing pain states in both healthy participants and patients. We used ASL to image the neural correlates of extended, parametrically modulated mechanical pain in healthy human participants. The aims of this study were to: i) assess if force-calibrated pin-prick probes could safely and robustly evoke tonic mechanical pain; ii) determine the neural correlates of the parametric changes in both the “force” of the stimulus and the “intensity” of the perception that this elicits using ASL; and iii) provide an initial assessment of the capacity for ALFF to differentiate painful versus non-painful tonic stimuli based on changes in the dynamics of the evoked signal. Our data confirm that it is possible to employ a stimulus force-locked design to induce robust, well maintained ongoing mechanical pain and to observe significant changes in rCBF relative to underlying component processes such as monitoring graded changes in the force applied to the skin (dACC, aMCC, pMCC, PCC, SI, SII, putamen, thalamus and the insula (anterior and posterior subsections); ipsilateral amygdala and hypothalamus; and the contralateral DLPFC) and tracking changes in the perceived intensity of the experience (: bilateral dACC, aMCC, pMCC, PCC, thalamus, SII and the cerebellum; and contralateral SI, insula (including the dpIns). Further exploration of the data using analyses targeting the spectral frequency aspects of the rCBF signal observed reveals that a collection of regions (e.g. the contralateral VLPFC, inferior frontal gyrus, insula (anterior, mid and posterior subsections), SII, putamen, OFC, amygdala, and the hippocampus) exhibit unique perfusion dynamics during extended painful stimulation compared to non-painful ‘touch’. Results from this study provide further validation for the application of ASL to image experimental pain in healthy human subjects while interrogation of the data offers unique insight into the dynamic signal changes underlying the perception of a tonic mechanical pain experience.
Neural Markers of Speech Comprehension: Measuring EEG Tracking of Linguistic Speech Representations, Controlling the Speech Acoustics

When listening to speech, our brain responses time lock to acoustic events in the stimulus. Recent studies have also reported that cortical responses track linguistic representations of speech. However, tracking of these representations is often described without controlling for acoustic properties. Therefore, the response to these linguistic representations might reflect unaccounted acoustic processing rather than language processing. Here, we evaluated the potential of several recently proposed linguistic representations as neural markers of speech comprehension. To do so, we investigated EEG responses to audiobook speech of 29 participants (22 females). We examined whether these representations contribute unique information over and beyond acoustic neural tracking and each other. Indeed, not all of these linguistic representations were significantly tracked after controlling for acoustic properties. However, phoneme surprisal, cohort entropy, word surprisal, and word frequency were all significantly tracked over and beyond acoustic properties. We also tested the generality of the associated responses by training on one story and testing on another. In general, the linguistic representations are tracked similarly across different stories spoken by different readers. These results suggests that these representations characterize the processing of the linguistic content of speech. SIGNIFICANCE STATEMENT For clinical applications, it would be desirable to develop a neural marker of speech comprehension derived from neural responses to continuous speech. Such a measure would allow for behavior-free evaluation of speech understanding; this would open doors toward better quantification of speech understanding in populations from whom obtaining behavioral measures may be difficult, such as young children or people with cognitive impairments, to allow better targeted interventions and better fitting of hearing devices.
Skin aging risk factors: A nationwide population study in Mongolia risk factors of skin aging

The world population is aging and no country is immune to the consequences. We are not aware of any country-specific skin aging risk factors data for the Mongolian people. Thus, we aimed to study the risk factors associated with skin aging in the Mongolian population. A population-based cross-sectional study of 2720 study participants 18 years of age and older was performed evaluating the severity of skin aging based on cutaneous microtopography. Questionnaire data and skin physiological measurements were obtained. The odds ratios for skin aging grades associated with risk factors were estimated using ordinal logistic regression. Study participant’s mean age was 45 years, ranging from 18 to 87. After adjustment for known risk factors, skin aging was associated with demographic risk factors such as increasing age (aOR=1.19, 95% CI 1.18-1.20), living in an urban area (aOR=1.31, 95% CI 1.12-1.55) and working outside (aOR=1.44, 95% CI 0.88-2.39) and lifestyle factors including non-usage of sunscreen cream (aOR=1.09 95% CI 0.87-1.37), being a smoker (aOR=1.32, 95% CI 1.09-1.61), having a higher body mass index (BMI) (aOR=1.04, 95% CI 1.02-1.06) and higher levels of sun exposure time (aOR=1.03, 95% CI 1.00-1.06) were significantly associated with higher skin aging grades. Having dry (aOR=1.94, 95% CI 1.45-2.59) and combination skin (aOR=1.62, 95% CI 1.22-2.16) types were also independent risk factors associated with skin aging. Having very low skin surface moisture at the T-zone (aOR=2.10, 95% CI 1.42-3.11) and U-zone (aOR=1.25, 95% CI 0.95-1.65) were significantly related to skin aging. Older age, urban living, harsh working conditions, living in a ger district were independent demographic risk factors related to skin aging. Not using sunscreen cream, smoking, higher BMI, greater levels of sun exposure were significant lifestyle risk factors. Having a skin type other than normal was a physiologic risk factor for skin aging.
Purkinje Cell Activity in Medial and Lateral Cerebellum During Suppression of Voluntary Eye Movements in Rhesus Macaques

Volitional suppression of responses to distracting external stimuli enables us to achieve our goals. This volitional inhibition of a specific behavior is supposed to be mainly mediated by the cerebral cortex. However, recent evidence supports the involvement of the cerebellum in this process. It is currently not known whether different parts of the cerebellar cortex play differential or synergistic roles in planning and execution of this behavior. Here, we measured Purkinje cell (PC) responses in the medial and lateral cerebellum in two rhesus macaques during a pro- and antisaccade task. During an antisaccade trial, non-human primates were instructed to make a saccadic eye movement away from a target, rather than towards it, as in prosaccade trials. Our data shows that the cerebellum plays an important role not only during execution of the saccades, but also during the volitional inhibition of eye movements towards the target. Simple Spike (SS) modulation during the instruction and execution period of pro- and antisaccades was prominent in PCs of both medial and lateral cerebellum. However, only the SS activity in the lateral cerebellar cortex contained information about trial identity and showed a stronger reciprocal interaction with complex spikes. Moreover, SS activity of different PC groups modulated bidirectionally in both regions, but the PCs that showed facilitating and suppressive activity were predominantly associated with instruction and execution, respectively. These findings show that different cerebellar regions and PC groups contribute to goal-directed behavior and volitional inhibition, but with different propensities, highlighting the rich repertoire of cerebellar control in executive functions. Significance Statement The antisaccade task is commonly used in research and clinical evaluation as a test of volitional and flexible control of behavior. It requires volitional suppression of prosaccades, a function that has been attributed to the neocortex. However, recent findings indicate that cerebellum also contributes to this behavior. We recorded from neurons in the medial and lateral cerebellum to evaluate their responses in this task. We found that both regions significantly modulated their activity during this task, but only cells in the lateral cerebellum encoded the stimulus identity in each trial. These results indicate that the cerebellum actively contributes to the control of flexible behavior and that lateral and medial cerebellum play different roles during volitional eye movements.
A statistical model for describing and simulating microbial community profiles

Many methods have been developed for statistical analysis of microbial community profiles, but due to the complex nature of typical microbiome measurements (e.g. sparsity, zero-inflation, nonindependence, and compositionality) and of the associated underlying biology, it is difficult to compare or evaluate such methods within a single systematic framework. To address this challenge, we developed SparseDOSSA (Sparse Data Observations for the Simulation of Synthetic Abundances): a statistical model of microbial ecological population structure, which can be used to parameterize real-world microbial community profiles and to simulate new, realistic profiles of known structure for methods evaluation. Specifically, SparseDOSSA’s model captures marginal microbial feature abundances as a zero-inflated log-normal distribution, with additional model components for absolute cell counts and the sequence read generation process, microbemicrobe, and microbe-environment interactions. Together, these allow fully known covariance structure between synthetic features (i.e. “taxa”) or between features and “phenotypes” to be simulated for method benchmarking. Here, we demonstrate SparseDOSSA’s performance for 1) accurately modeling human-associated microbial population profiles; 2) generating synthetic communities with controlled population and ecological structures; 3) spiking-in true positive synthetic associations to benchmark analysis methods; and 4) recapitulating an end-to-end mouse microbiome feeding experiment. Together, these represent the most common analysis types in assessment of real microbial community environmental and epidemiological statistics, thus demonstrating SparseDOSSA’s utility as a general-purpose aid for modeling communities and evaluating quantitative methods. An open-source implementation is available at http://huttenhower.sph. harvard.edu/sparsedossa2.
β-arrestin-mediated Angiotensin II type 1 Receptor Activation Promotes Pulmonary Vascular Remodeling in Pulmonary Hypertension

Objectives The goal of this study was to test whether a β-arrestin-biased agonist of the angiotensin II (AngII) type 1 receptor (AT1R), which acts as a vasodilator while not blocking cellular proliferation, would have positive effects compared to a balanced agonist, angiotensin II (AngII), or an antagonist, losartan, in pulmonary arterial hypertension (PAH). Background PAH is a disease of abnormal pulmonary vascular remodeling whose treatment has focused on targeting vasoactive substances, such as inhibiting endothelin signaling and promoting prostacyclin signaling. PAH medical therapies are thought to primarily act as vasodilators, although they may also have effects on pulmonary vascular remodeling. There are a number of reports that blocking AT1R signaling can be beneficial in preclinical models of PAH. The AT1R is a G protein-coupled receptor (GPCR) that promotes vasoconstriction through heterotrimeric G proteins but also signals via β-arrestins, which promote cardioprotective effects and vasodilation. Methods We compared the effects of a β-arrestin-biased AT1R agonist, TRV120023 (TRV023), to a balanced agonist (AngII) and an antagonist (losartan) in preclinical PAH models. Results In acute infusion studies, AngII increased right ventricular (RV) pressures while TRV023 did not. However, with chronic infusion in monocrotaline (MCT) PAH rats, TRV023 failed to improve hemodynamics or survival compared to AngII, while losartan significantly improved survival. Both TRV023 and AngII enhanced proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) from PAH patients, which was associated with the promotion of proliferative MAP kinase signaling. Conclusions β-arrestin-mediated AT1R signaling promotes vascular remodeling and worsens PAH, and suggests that the primary benefit of current PAH therapies is through pulmonary vascular reverse remodeling and not vasodilation.
Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress

Despite its prominence, the mechanisms through which the tumor suppressor p53 regulates most genes remain unclear. Recently, the regulatory factor X 7 (RFX7) emerged as a suppressor of lymphoid neoplasms, but its regulation and target genes mediating tumor suppression remain unknown. Here, we identify a novel p53-RFX7 signaling axis. Integrative analysis of the RFX7 DNA binding landscape and the RFX7-regulated transcriptome in three distinct cell systems reveals that RFX7 directly controls multiple established tumor suppressors, including PDCD4, PIK3IP1, MXD4, and PNRC1, across cell types and is the missing link for their activation in response to p53 and stress. RFX7 target gene expression correlates with cell differentiation and better prognosis in numerous cancer types. Interestingly, we find that RFX7 sensitizes cells to Doxorubicin by promoting apoptosis. Together, our work establishes RFX7’s role as a ubiquitous regulator of cell growth and fate determination and a key node in the p53 transcriptional program.
Within- and transgenerational plasticity of a temperate salmonid in response to thermal acclimation and acute temperature stress

Environmental temperatures associated with climate change are rising too rapidly for many species to adapt, threatening the persistence of taxa with limited capacities for thermal acclimation. We investigated the capacity for within- and transgenerational responses to increasing environmental temperatures in brook trout (Salvelinus fontinalis), a cold-adapted salmonid. Adult fish were acclimated to temperatures within (10□) and above (21□) their thermal optimum for six months before spawning, then mated in a full factorial breeding design to produce offspring from cold- and warm-acclimated parents as well as bidirectional crosses between parents from both temperature treatments. Offspring families were subdivided and reared at two acclimation temperatures (15□ and 19□) representing their current environment and a projected climate change scenario. Offspring thermal physiology was measured as the rate of oxygen consumption (MO2) during an acute change in temperature (+2□ h-1) to observe their MO2-temperature relationship. We also recorded resting MO2, the highest achieved (peak) MO2, and critical thermal maximum (CTM) as performance metrics. Within-generation plasticity was greater than transgenerational plasticity, with offspring acclimation temperature having demonstrable effects on peak MO2 and CTM. Transgenerational plasticity was evident as an elevated resting MO2 and the MO2-temperature relationship in offspring from warm-acclimated parents. Both parents contributed to offspring thermal responses, although the paternal effect was stronger. Although brook trout exhibit both within- and transgenerational plasticity for thermal physiology, it is unlikely that these will be sufficient for coping with long-term changes to environmental temperatures resulting from climate change. Summary Brook trout (Salvelinus fontinalis) exhibit within-generation and transgenerational plasticity for thermal performance, although neither response appears sufficient to cope with long-term climate change effects.
TCF-1 in CD4 T cells regulates GVHD severity and persistence

Graft-versus-host disease (GVHD) is a leading cause of mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Mature donor T cells in the graft mediate graft-versus-leukemia (GVL) responses against residual tumor cells, which may persist after pre-transplant conditioning regimens. Importantly, the same mature T cells also mediate GVHD. The transcription factor T Cell Factor-1 (TCF-1) is critical for T cell development in the thymus. Using a unique mouse model of allo-HSCT leading to GVHD, we investigated the role of TCF-1 in alloactivated T cell functioning and in GVHD. Here, we report that loss of TCF-1 in mature CD4 T cells reduces GVHD severity and persistence, improving survival of recipient mice. This was due to reduced proliferation, survival, and cytokine production of T cells, as well as increased exhaustion. Gene pathways involved in cytokine response, immune signaling, chemokine signaling, cell cycle, and T cell differentiation were altered by loss of TCF-1 in donor cells. Our companion paper shows that regulation of alloactivated CD4 T cells by TCF-1 differs from regulation of CD8 T cells, suggesting that TCF-1 plays a unique role in each subset. Therefore, targeting of TCF-1 or downstream signaling pathways may be an effective strategy for reducing GVHD following allo-HSCT.
Your pleasure is mine; when people share a musical emotional experience during a live music performance in a concert hall

Over the years, several publications have proposed that musical sound could be an ancestral emotional way of communication, thus positing an ancestral biological function for music. Understanding how musical emotions, and the pleasure derived from music regardless of the musical valence, can be shared between individuals is a fascinating question, and investigating it can shed light on the function of musical reward. Is the pleasure felt at the individual level transmitted on a collective level? And if so, how? We investigated these questions in a natural setting during an international competition for orchestra conductors. Participants (n=15) used a dedicated smartphone app to report their subjective emotional experiences in real time during a concert. We recorded participant’s electrodermal activity (EDA) and cerebral activity with electroencephalography (EEG). The overall behavioral real time ratings suggest a possible social influence on the reported and felt pleasure. The physically closer the participants, the more similar their reported pleasure. We estimated the inter-individual cerebral coherence, which indicates the degree of mutual cerebral information between pairs of participants in the frequency domain. The results show that when people simultaneously reported either high or low pleasure, their cerebral activities were closer than for simultaneous neutral pleasure reports. Participants’ skin conductance levels were also more coupled when reporting higher emotional degrees simultaneously. More importantly, the participants who were physically closer had higher cerebral coherence, but only when they simultaneously reported intense pleasure. We propose that mechanisms of emotional contagion and/or emotional resonance could explain why a form of ‘emotional connecting force’ could arise between people.