Aberration of the "gut-liver axis" contributes to the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we use multi-omics to analyze the gut microbiota composition and metabolic profile of patients with type-2 diabetes mellitus (T2DM). T2DM patients were screened for liver disease by blood tests, ultrasound, and liver stiffness measurements. Stool microbiota was analyzed by 16S rRNA gene sequencing; metabolomic profiling by Nuclear Magnetic Resonance spectroscopy and Ultra-High Performance-Mass Spectrometry. Microbiome and metabolic signatures were analyzed in the whole cohort and in matched subsets to identify signatures specific for steatosis (MASLD±) or fibrosis (Fibrosis±). Gut permeability was assessed in-vitro using monolayers of MDCK cells and trans-epithelial electric resistance (TEER). Cytokine profile was assessed in serum and stools.Overall, 285 patients were enrolled: 255 serum, 252 urine and 97 stool samples were analyzed. Anaeroplasma and Escherichia/Shigella ASVs were higher, while Butyricicoccus ASVs were lower in those with normal liver. In MASLD±, Butyricicoccus ASV was significantly higher in those with steatosis. In the Fibrosis±, Butyricicoccus ASV was significantly lower in those with fibrosis. Glycochenodeoxycholic acid-3-sulfate (G-UDCA-3S) appeared to be higher in MASLD with fibrosis. Fecal water from patients with MASLD and fibrosis caused the greatest drop in the TEER vs those with normal liver; this was reversed with protease inhibitors. Finally, fecal IL-13 was lower in MASLD with fibrosis. We identified microbiome signatures which were specific for steatosis and fibrosis and independent of other metabolic risk factors. Moreover, we conclude that protease-related gut permeability plays a role in those MASLD patients with fibrosis, and that disease progression is linked to a gut-liver axis which is at least partially independent of T2DM.
Abstract: The need for large-scale production of highly accurate simulated event samples for the extensive physics programme of the ATLAS experiment at the Large Hadron Collider motivates the development of new simulation techniques. Building on the recent success of deep learning algorithms, variational autoencoders and generative adversarial networks are investigated for modelling the response of the central region of the ATLAS electromagnetic calorimeter to photons of various energies. The properties of synthesised showers are compared with showers from a full detector simulation using geant4. Both variational autoencoders and generative adversarial networks are capable of quickly simulating electromagnetic showers with correct total energies and stochasticity, though the modelling of some shower shape distributions requires more refinement. This feasibility study demonstrates the potential of using such algorithms for ATLAS fast calorimeter simulation in the future and shows a possible way to complement current simulation techniques.
Charged particle reconstruction in the presence of many simultaneous proton–proton (pp) collisions in the LHC is a challenging task for the ATLAS experiment’s reconstruction software due to the combinatorial complexity. This paper describes the major changes made to adapt the software to reconstruct high-activity collisions with an average of 50 or more simultaneous pp interactions per bunch crossing (pile-up) promptly using the available computing resources. The performance of the key components of the track reconstruction chain and its dependence on pile-up are evaluated, and the improvement achieved compared to the previous software version is quantified. For events with an average of 60pp collisions per bunch crossing, the updated track reconstruction is twice as fast as the previous version, without significant reduction in reconstruction efficiency and while reducing the rate of combinatorial fake tracks by more than a factor two.
Early development is characterized by dynamic transitions in brain maturation, which may be impacted by environmental factors. Here, we sought to determine the effects of social isolation from postweaning and during adolescence on reward behavior and dopaminergic signaling in male rats. Subjects were socially isolated or group housed at postnatal day 21. Three weeks later, extracellular dopamine concentrations were examined in the medial prefrontal cortex (mPFC) and nucleus accumbens shell (NAc) during a feeding bout. Surprisingly, opposing effects were found in which increased mPFC dopamine concentrations were observed in group housed, but not isolated, rats. In stark contrast, increased dopamine levels were found in the NAc of isolated, but not group housed, rats. Moreover, the absence of an effect in the mPFC of the isolated rats could not be reversed by subsequent group housing, demonstrating the remarkable long-term effects on dopamine signaling dynamics. When provided a highly palatable food, the isolated subjects exhibited a dramatic increase in mPFC dopamine levels when the chocolate was novel, but no effects following chronic chocolate consumption. In contrast, the group housed subjects showed significantly increased dopamine levels only with chronic chocolate consumption. The dopamine changes were correlated with differences in behavioral measures. Importantly, the deficit in reward-related behavior during isolation could be reversed by microinjection of either dopamine or cocaine into the mPFC. Together, these data provide evidence that social isolation from postweaning and during adolescence alters reward-induced dopamine levels in a brain region-specific manner, which has important functional implications for reward-related behavior.
Family members and friends can play an important role in adolescents prosocial behavior. To better understand the relation between support and prosocial behavior in adolescence, its important to conduct longitudinal studies that distinguish between within-dyad variance and between-dyad variance. The current study investigated longitudinal associations between adolescents prosocial behavior, autonomy support, and emotional support from family and friends across adolescence. Across six annual years, 497 Dutch adolescents (284 boys; mean age T1 = 13.03 years, SDage = 0.46), fathers, mothers, siblings, and friends reported on their prosocial behavior. Adolescents also reported on perceived autonomy and emotional support. Between-dyads almost all associations of support and prosocial behavior of family members and friends with adolescents prosocial behavior were significant, with higher levels of adolescents prosocial behavior being associated with higher levels of prosocial behavior and support from fathers, mothers and friends. Within-dyads, several concurrent associations were significant, but within-dyads links between prosocial behavior and autonomy support are particularly driven by adolescent-mother or adolescent-sibling effects. This study highlights processes that occurred either at the between-dyad level or at the within-dyad level, but that varied per relationship type and that adolescents are the main catalysts in within-dyads changes in prosocial behavior and support. Preregistration: This study was preregistered on 20 January 2020 at https://osf.io/vxkm3/?view_only=dca87fd1585c444ba5cd5a00c22280ae .
RATIONALE: The causal relationship between undernutrition and response to anti-tuberculosis (TB) treatment and TB treatment outcomes among people with retreatment TB is understudied. OBJECTIVE: To evaluate the effect of undernutrition on treatment success and sputum smear conversion among people with retreatment drug-susceptible TB in Kampala, Uganda. METHODS: We conducted a quasi-experimental study utilizing propensity score weighting among people with retreatment drug-susceptible TB aged ≥ 15 years treated between 2012 and 2022 in Kampala. The primary exposure was undernutrition assessed using the mid-upper arm circumference at the time of TB diagnosis. The primary outcome was treatment success defined as cure or treatment completion at month 6. Sputum smear conversion was the secondary outcome and was measured as a change in sputum smear status from positive to negative at months 2, 5, and 6. We estimated the causal effect of undernutrition on the outcomes using a propensity-score weighted modified Poisson regression model with robust error variance. MEASUREMENTS AND MAIN RESULTS: Of the 605 participants, 432 (71.4 %) were male, 215 (35.5 %) were aged 25-34 years, 427 (70.6 %) had bacteriologically confirmed pulmonary TB, 133 (22.0 %) were undernourished and 398 (65.8 %) achieved treatment success. Of participants with bacteriologically confirmed pulmonary TB, 232 (59.0 %), 327 (59.3 %), and 360 (97.6 %) achieved sputum smear conversion at months 2, 5, and 6, respectively. Undernutrition reduced treatment success (RR 0.42, 95 % CI 0.32-0.55) as well as sputum smear conversion at months 2 (RR 0.45, 95 % CI 0.42-0.49) and 5 (RR 0.46, 95 % CI 0.43-0.51) but not month 6 (RR 0.99, 95 % CI 0.97-1.02). CONCLUSION: Undernutrition negatively impacts treatment outcomes. Therefore, nutritional assessment should be an integral component of TB care, with nutritional counseling and support offered to those undernourished to optimize their TB treatment response and outcomes.
Parkinson's disease (PD) etiology is associated with aggregation and accumulation of α-synuclein (α-syn) proteins in midbrain dopaminergic neurons. Emerging evidence suggests that in certain subtypes of PD, α-syn aggregates originate in the gut and subsequently spread to the brain. However, mechanisms that instigate α-syn aggregation in the gut have remained elusive. In the brain, the aggregation of α-syn is induced by oxidized dopamine. Such a mechanism has not been explored in the context of the gastrointestinal tract, a niche harboring 46% of the body's dopamine reservoirs. Here, we report that Enterobacteriaceae, a bacterial family prevalent in human gut microbiotas, induce α-syn aggregation. More specifically, our in vitro data indicate that respiration of nitrate by Escherichia coli K-12, which results in production of nitrite that mediates oxidation of Fe2+ to Fe3+, creates an oxidizing redox potential. These oxidizing conditions enabled the formation of dopamine-derived quinones and α-syn aggregates. Exposing nitrite, but not nitrate, to enteroendocrine STC-1 cells induced aggregation of α-syn that is natively expressed in these cells, which line the intestinal tract. Taken together, our findings indicate that bacterial nitrate reduction may be critical for initiating intestinal α-syn aggregation.
Dreaming is a universal human behavior that has inspired searches for meaning across many disciplines including art, psychology, religion, and politics, yet its function remains poorly understood. Given the suggested role of sleep in emotional memory processing, we investigated whether reported overnight dreaming and dream content are associated with sleep-dependent changes in emotional memory and reactivity, and whether dreaming plays an active or passive role. Participants completed an emotional picture task before and after a full night of sleep and they recorded the presence and content of their dreams upon waking in the morning. The results replicated the emotional memory trade-off (negative images maintained at the cost of neutral memories), but only in those who reported dreaming (Dream-Recallers), and not in Non-Dream-Recallers. Results also replicated sleep-dependent reductions in emotional reactivity, but only in Dream-Recallers, not in Non-Dream-Recallers. Additionally, the more positive the dream report, the more positive the next-day emotional reactivity is compared to the night before. These findings implicate an active role for dreaming in overnight emotional memory processing and suggest a mechanistic framework whereby dreaming may enhance salient emotional experiences via the forgetting of less relevant information.
Malignant astrocytomas are aggressive glioma tumors characterized by extensive hypoxia-induced, mito-chondria-dependent changes such as altered respiration, increased chymotrypsin-like (CT-L) proteasome activity, decreased apoptosis, drug resistance, stemness and increased invasiveness. Mitochondrial Lon Peptidase I (LonP1) overexpression and increased CT-L proteasome inhibitors activity are the biomarkers of aggressive high grade glioma phenotype, poor prognosis and found to be associated with recurrence and poor patient survival, and drugs targeting either LonP1 or the CT-L activity have anti-glioma activity in pre-clinical models. We here for the first time introduced and evaluated a novel small molecule, BT317, derived from coumarinic compound 4 (CC4) using structure-activity modeling which we found to inhibit both LonP1 and CT-L proteasome activity. Using gain-of-function and loss-of-function genetic models, we dis-covered that BT317 is more effective than the individual LonP1 or CT-L inhibition in increasing reactive oxy-gen species (ROS) generation and inducing apoptosis in high-grade astrocytoma lines. In vitro, BT317 had activity as a single agent but, more importantly, enhanced synergy with the standard of care commonly used chemotherapeutic temozolomide (TMZ). In orthotopic xenograft, patient derived glioma models, BT317 was able to cross the blood-brain barrier, to show selective activity at the tumor site and to demonstrate therapeutic efficacy both as a single agent and in combination with TMZ. BT317 defines an emerging class of dual LonP1, and CT-L proteasome inhibitors exhibited promising anti-tumor activity and could be a promising candidate for clinical translation in the space of malignant astrocytoma therapeutics.
Spindle-shaped waves of oscillations emerge in EEG scalp recordings during human and rodent non-REM sleep. The association of these 10-16 Hz oscillations with events during prior wakefulness suggests a role in memory consolidation. Human and rodent depth electrodes in the brain record strong spindles throughout the cortex and hippocampus, with possible origins in the thalamus. However, the source and targets of the spindle oscillations from the hippocampus are unclear. Here, we employed an in vitro reconstruction of four subregions of the hippocampal formation with separate microfluidic tunnels for single axon communication between subregions assembled on top of a microelectrode array. We recorded spontaneous 400-1000 ms long spindle waves at 10-16 Hz in single axons passing between subregions as well as from individual neurons in those subregions. Spindles were nested within slow waves. The highest amplitudes and most frequent occurrence suggest origins in CA3 neurons that send feed-forward axons into CA1 and feedback axons into DG. Spindles had 50-70% slower conduction velocities than spikes and were not phase-locked to spikes suggesting that spindle mechanisms are independent of action potentials. Therefore, consolidation of declarative-cognitive memories in the hippocampus may be separate from the more easily accessible consolidation of memories related to thalamic motor function.
