Miracle-dz/UniFAR-FTUs huggingface dataset:
Disrupted balance of T cells under natalizumab treatment in multiple sclerosis

Objective: To compare effects of natalizumab on inflammatory and regulatory T cells with regard to expression of α4-integrin (CD49d). Methods: Twenty-seven natalizumab-naive and 8 natalizumab-treated patients with multiple sclerosis (MS), 7 patients with neuromyelitis optica (NMO) or NMO spectrum disorder, and 8 healthy controls were included. The positive rate of CD49d was analyzed and compared among T helper 1 (Th1), T helper 17 (Th17), and regulatory T (Treg) cells (CD49d+Th1, CD49d+Th17, and CD49d+Treg, respectively). Results: Natalizumab treatment increased CD49d ratios, CD49d+Th1/CD49d+Treg, and CD49d+Th17/CD49d+Treg. This indicates larger reduction of the CD49d+ population in Treg cells than in Th1 or Th17 cells. The CD49d ratios of 2 patients who experienced exacerbation during natalizumab treatment were remarkably higher than those of the other natalizumab-treated patients. Natalizumab treatment increased the expression of TBX21, RORC, interferon (IFN)–γ, and interleukin (IL)–17A, and decreased the expression of FOXP3 in CD49d+ memory CD4 T cells. Natalizumab treatment also increased the amount of IFN-γ and IL-17A secreted by CD49d+ memory CD4 T cells. Conclusions: The reduction rate of the CD49d+ population in Treg cells was larger than that in Th1 or Th17 cells. Although the large reduction in CD49d+ population is beneficial for MS, the proinflammatory state of residual CD49d+ cells might, in part, explain the presence of disease activity under natalizumab treatment.
Deciphering the interstrand crosslink DNA repair network expressed by Trypanosoma brucei

Interstrand crosslinks (ICLs) represent a highly toxic form of DNA damage that can block essential biological processes including DNA replication and transcription. To combat their deleterious effects all eukaryotes have developed cell cycle-dependent repair strategies that coopt various factors from ‘classical’ DNA repair pathways to resolve such lesions. Here, we report that Trypanosoma brucei, the causative agent of African trypanosomiasis, possesses such systems that show some intriguing differences to those mechanisms expressed in other organisms. Following the identification of trypanosomal homologues encoding for CSB, EXO1, SNM1, MRE11, RAD51 and BRCA2, gene deletion coupled with phenotypic studies demonstrated that all the above factors contribute to this pathogen’s ICL REPAIRtoire with their activities split across two epistatic groups. We show that one network, which encompasses TbCSB, TbEXO1 and TbSNM1, may operate throughout the cell cycle to repair ICLs encountered by transcriptional detection mechanisms while the other relies on homologous recombination enzymes that together may resolve lesions responsible for the stalling of DNA replication forks. By unravelling and comparing the T. brucei ICL REPAIRtoire to those systems found in its host, targets amenable to inhibitor design may be identified and could be used alongside trypanocidal ICL-inducing agents to exacerbate their effects. Author summary Parasites belonging to the Trypanosoma brucei complex cause a human and animal infections collectively known as African trypanosomiasis. Drugs used against these diseases are problematic as medical supervision is required for administration, they are costly, have limited efficacy, may cause unwanted side effects while drug resistance is emerging. Against this backdrop, there is a need for new therapies targeting these neglected tropical diseases. Previous studies have shown compounds that induce DNA interstrand crosslinks (ICLs) formation are effective trypanocidal agents with the most potent invariably functioning as prodrugs. Despite the potential of ICL-inducing compounds to treat African trypanosomiasis little is known about the ICL repair mechanisms expressed by trypanosomes. Using a combination of gene deletion and epistatic analysis we report the first systematic dissection of how ICL repair might operate in T. brucei, a diverged eukaryote. It sheds light on the conservation and divergence of ICL repair in one of only a handful of protists that can be studied genetically, and offers the promise of developing or exploiting ICL-causing agents as new anti-parasite therapies. These findings emphasise the novelty and importance of understanding ICL repair in T. brucei and, more widely, in non-model eukaryotes.
Fifty Years of Energy Extraction from Rotating Black Hole: Revisiting Magnetic Penrose Process

Magnetic Penrose process (MPP) is not only the most exciting and fascinating process mining the rotational energy of black hole but it is also the favored astrophysically viable mechanism for high energy sources and phenomena. It operates in three regimes of efficiency, namely low, moderate and ultra, depending on the magnetization and charging of spinning black holes in astrophysical setting. In this paper, we revisit MPP with a comprehensive discussion of its physics in different regimes, and compare its operation with other competing mechanisms. We show that MPP could in principle foot the bill for powering engine of such phenomena as ultra-high-energy cosmic rays, relativistic jets, fast radio bursts, quasars, AGNs, etc. Further, it also leads to a number of important observable predictions. All this beautifully bears out the promise of a new vista of energy powerhouse heralded by Roger Penrose half a century ago through this process, and it has today risen in its magnetically empowered version of mid 1980s from a purely thought experiment of academic interest to a realistic powering mechanism for various high-energy astrophysical phenomena.
Are There Common Mechanisms Between the Hutchinson–Gilford Progeria Syndrome and Natural Aging?

The Hutchinson–Gilford progeria syndrome (HGPS) is a premature aging disease caused by mutations of the LMNA gene leading to increased production of a partially processed form of the nuclear fibrillar protein lamin A – progerin. Progerin acts as a dominant factor that leads to multiple morphological anomalies of cell nuclei and disturbances in heterochromatin organization, mitosis, DNA replication and repair, and gene transcription. Progerin-positive cells are present in primary fibroblast cultures obtained from the skin of normal donors at advanced ages. These cells display HGPS-like defects in nuclear morphology, decreased H3K9me3 and HP1, and increased histone H2AX phosphorylation marks of the DNA damage loci. Inhibition of progerin production in cells of aged non-HGPS donors in vivo increases the proliferative activity, H3K9me3, and HP1, and decreases the senescence markers p21, IGFBP3, and GADD45B to the levels of young donor cells. Thus, progerin-dependent mechanisms act in natural aging. Excessive activity of the same mechanisms may well be the cause of premature aging in HGPS. Telomere attrition is widely regarded to be one of the primary hallmarks of aging. Progerin expression in normal human fibroblasts accelerates the loss of telomeres. Changes in lamina organization may directly affect telomere attrition resulting in accelerated replicative senescence and progeroid phenotypes. The chronological aging in normal individuals and the premature aging in HGPS patients are mediated by similar changes in the activity of signaling pathways, including downregulation of DNA repair and chromatin organization, and upregulation of ERK, mTOR, GH-IGF1, MAPK, TGFβ, and mitochondrial dysfunction. Multiple epigenetic changes are common to premature aging in HGPS and natural aging. Recent studies showed that epigenetic systems could play an active role as drivers of both forms of aging. It may be suggested that these systems translate the effects of various internal and external factors into universal molecular hallmarks, largely common between natural and accelerated forms of aging. Drugs acting at both natural aging and HGPS are likely to exist. For example, vitamin D3 reduces the progerin production and alleviates most HGPS features, and also slows down epigenetic aging in overweight and obese non-HGPS individuals with suboptimal vitamin D status.
Thermodynamics and entropy of self-gravitating matter shells and black holes in 
d
 dimensions

The thermodynamic properties of self-gravitating spherical thin matter shells an black holes in $d>4$ dimensions are studied, extending previous analysis for $d=4$. The shell joins a Minkowski interior to a Tangherlini exterior, i.e., a Schwarzschild exterior in $d$ dimensions, with $d\geqslant4$, The junction conditions alone together with the first law of thermodynamics enable one to establish that the entropy of the thin shell depends only on its own gravitational radius. Endowing the shell with a power-law temperature equation of state allows to establish a precise form for the entropy and to perform a thermodynamic stability analysis for the shell. An interesting case is when the shell's temperature has the Hawking form, i.e., it is inversely proportional to the shell's gravitational radius. It is shown in this case that the shell's heat capacity is positive, and thus there is stability, for shells with radii in-between their own gravitational radius and the photonic radius, i.e., the radius of circular photon orbits, reproducing unexpectedly York's thermodynamic stability criterion for a $d=4$ black hole in the canonical ensemble. Additionally, the Euler equation for the matter shell is derived, the Bekenstein and holographic entropy bounds are studied, and the large $d$ limit is analyzed. Within this formalism the thermodynamic properties of black holes can be studied too. Putting the shell at its own gravitational radius, i.e., in the black hole situation, obliges one to choose precisely the Hawking temperature for the shell which in turn yields the Bekenstein-Hawking entropy. The stability analysis implies that the black hole is thermodynamically stable substantiating that in this configuration our system and York's canonical ensemble black hole are indeed the same system. Also relevant is the derivation in a surprising way of the Smarr formula for black holes in $d$ dimensions.
Population Based Augmentation: Efficient Learning of Augmentation Policy Schedules

A key challenge in leveraging data augmentation for neural network training is choosing an effective augmentation policy from a large search space of candidate operations. Properly chosen augmentation policies can lead to significant generalization improvements; however, state-of-the-art approaches such as AutoAugment are computationally infeasible to run for the ordinary user. In this paper, we introduce a new data augmentation algorithm, Population Based Augmentation (PBA), which generates nonstationary augmentation policy schedules instead of a fixed augmentation policy. We show that PBA can match the performance of AutoAugment on CIFAR-10, CIFAR-100, and SVHN, with three orders of magnitude less overall compute. On CIFAR-10 we achieve a mean test error of 1.46%, which is a slight improvement upon the current state-of-the-art. The code for PBA is open source and is available at this https URL.
Dashboard Mechanisms for Online Marketplaces

This paper gives a theoretical model for design and analysis of mechanisms for online marketplaces where a bidding dashboard enables the bid-optimization of long-lived agents. We assume that a good allocation algorithm exists when given the true values of the agents and we develop online winner-pays-bid and all-pay mechanisms that implement the same outcome of the algorithm with the aid of a bidding dashboard. The bidding dashboards that we develop work in conjunction with the mechanism to guarantee that bidding according to the dashboard is strategically equivalent (with vanishing utility difference) to bidding truthfully in the truthful implementation of the allocation algorithm. Our dashboard mechanism makes only a single call to the allocation algorithm in each stage.
Study on the Emulsifying Properties of Pomegranate Peel Pectin from Different Cultivation Areas

Pomegranate peel pectin is an important acidic anionic plant polysaccharide which can be used as a natural emulsifier. In order to study its emulsifying properties, this paper systematically analyses pomegranate peel pectin samples from Chinese Xinjiang, Sichuan and Yunnan provinces, through rheometer, interfacial rheometer, Zetasizer Nano-ZS and mastersizer. It is shown that pomegranate peel pectin can effectively reduce the oil-water interfacial tension, reaching an emulsion droplet size of only 0.507 μm, 0.669 μm and 0.569 μm, respectively, while the pectin concentration is 1.5% and the oil phase (MCT) is 10%. It has also shown that the extreme conditions of pH and ion strength can not significantly change its emulsion stability. However, freeze-thaw cycles can cause the pomegranate peel pectin emulsion to become less stable. Furthermore, the effects of decolourization, protein removal and dialysis on the emulsifying properties of pomegranate peel pectin are investigated using mastersizer rheometer and interfacial rheometer. It is found that the protein and pigment in pomegranate peel pectin have little effect on its emulsifying properties, while the results from dialyzed pectin show that the small molecule substances can reduce the emulsion particle size and increase the emulsion stability. The research outcomes of this study provide technical support for the further application of pomegranate peel pectin in the food industry.
Rewiring the Epigenetic Networks in MLL-Rearranged Leukemias: Epigenetic Dysregulation and Pharmacological Interventions

Leukemias driven by chromosomal translocation of the mixed-lineage leukemia gene (MLL or KMT2A) are highly prevalent in pediatric oncology. The poor survival rate and lack of an effective targeted therapy for patients with MLL-rearranged (MLL-r) leukemias emphasize an urgent need for improved knowledge and novel therapeutic approaches for these malignancies. The resulting chimeric products of MLL gene rearrangements, i.e., MLL-fusion proteins (MLL-FPs), are capable of transforming hematopoietic stem/progenitor cells (HSPCs) into leukemic blasts. The ability of MLL-FPs to reprogram HSPCs toward leukemia requires the involvement of multiple chromatin effectors, including the histone 3 lysine 79 methyltransferase DOT1L, the chromatin epigenetic reader BRD4, and the super elongation complex. These epigenetic regulators constitute a complicated network that dictates maintenance of the leukemia program, and therefore represent an important cluster of therapeutic opportunities. In this review, we will discuss the role of MLL and its fusion partners in normal HSPCs and hematopoiesis, including the links between chromatin effectors, epigenetic landscapes, and leukemia development, and summarize current approaches to therapeutic targeting of MLL-r leukemias.
Store-to-Leak Forwarding: Leaking Data on Meltdown-resistant CPUs

Meltdown and Spectre exploit microarchitectural changes the CPU makes during transient out-of-order execution. Using side-channel techniques, these attacks enable leaking arbitrary data from memory. As state-of-the-art software mitigations for Meltdown may incur significant performance overheads, they are only seen as a temporary solution. Thus, software mitigations are disabled on more recent processors, which are not susceptible to Meltdown anymore. In this paper, we show that Meltdown-like attacks are still possible on recent CPUs which are not vulnerable to the original Meltdown attack. We show that the store buffer---a microarchitectural optimization to reduce the latency for data stores---in combination with the TLB enables powerful attacks. We present several ASLR-related attacks, including a KASLR break from unprivileged applications, and breaking ASLR from JavaScript. We can also mount side-channel attacks, breaking the atomicity of TSX, and monitoring control flow of the kernel. Furthermore, when combined with a simple Spectre gadget, we can leak arbitrary data from memory. Our paper shows that Meltdown-like attacks are still possible, and software fixes are still necessary to ensure proper isolation between the kernel and user space.
The Role of Milk- and Soy-Based Protein in Support of Muscle Protein Synthesis and Muscle Protein Accretion in Young and Elderly Persons

The balance between muscle protein synthesis (MPS) and muscle protein breakdown (MPB) is dependent on protein consumption and the accompanying hyperaminoacidemia, which stimulates a marked rise in MPS and mild suppression of MPB. In the fasting state, however, MPS declines sharply and MPB is increased slightly. Ultimately, the balance between MPS and MPB determines the net rate of muscle growth. Accretion of new muscle mass beyond that of normal growth can occur following periods of intense resistance exercise. Such muscle accretion is an often sought-after goal of athletes. There needs to be, however, an increased appreciation of the role that preservation of muscle can play in offsetting morbidities associated with the sarcopenia of aging, such as type 2 diabetes and declines in metabolic rate that can lead to fat mass accumulation followed by the onset or progression of obesity. Emerging evidence shows that consumption of different types of proteins can have different stimulatory effects on the amplitude and possibly duration that MPS is elevated after feeding; this may be particularly significant after resistance exercise. This effect may be due to differences in the fundamental amino acid composition of the protein (i.e., its amino acid score) and its rate of digestion. Milk proteins, specifically casein and whey, are the highest quality proteins and are quite different in terms of their rates of digestion and absorption. New data suggest that whey protein is better able to support MPS than is soy protein, a finding that may explain the greater ability of whey protein to support greater net muscle mass gains with resistance exercise. This review focuses on evidence showing the differences in responses of MPS, and ultimately muscle protein accretion, to consumption of milk- and soy-based supplemental protein sources in humans.
A Missense Variant in SCN8A in Alpine Dachsbracke Dogs Affected by Spinocerebellar Ataxia

Spinocerebellar ataxias is an umbrella term for clinically- and neuropathologically-heterogeneous early-onset hereditary neurodegenerative diseases affecting several dog breeds. The purpose of this study is to identify the causative genetic variant associated with ataxia, tremor, and loss of balance in Alpine Dachsbracke dogs. We investigated two related litters in which four cases were reported. Neuropathology of two dogs revealed spongy degeneration associated with axonal degeneration. Combined genetic linkage and autozygosity analyses in four cases and eight related controls showed one critical disease-associated interval on chromosomes 27. Private whole-genome sequence variants of one ataxia case against 600 unrelated controls revealed one protein-changing variant within the critical interval in the SCN8A gene (c.4898G>T; p.Gly1633Val). Perfect segregation with the phenotype was confirmed by genotyping >200 Alpine Dachsbracke dogs. SCN8A encodes a voltage-gated sodium channel and the missense variant was predicted deleterious by three different in silico prediction tools. Pathogenic variants in SCN8A were previously reported in humans with ataxia, pancerebellar atrophy, and cognitive disability. Furthermore, cerebellar ataxia syndrome in the ‘jolting’ mutant mice is caused by a missense variant in Scn8a. Therefore, we considered the SCN8A:c.4898G>T variant to be the most likely cause for recessively inherited spinocerebellar ataxia in Alpine Dachsbracke dogs.
Cycling Performed on an Innovative Ergometer at Different Intensities-Durations in Men: Neuromuscular Fatigue and Recovery Kinetics.

The majority of studies have routinely measured neuromuscular (NM) fatigue with a delay (~1-3 min) after cycling exercises. This is problematic since NM fatigue can massively recover within the first 1-2 minutes after exercise. This study investigated the etiology of knee extensors (KE) NM fatigue and recovery kinetics in response to cycling exercises by assessing NM function as early as 10 s following cycling and up to 8 min of recovery. Ten young males performed different cycling exercises on different days: a Wingate (WING), a 10-min at severe-intensity (SEV), and a 90-min at moderate-intensity (MOD). Electrically evoked and isometric maximal voluntary contractions (IMVC) of KE were assessed before, after, and during recovery. SEV induced the highest decrease in IMVC. Peak twitch (Pt) was more reduced in WING and SEV than in MOD (p < 0.001), whereas voluntary activation (VA) decreased more after MOD than WING (p = 0.043). Regarding Pt and the ratio between low- and high-frequency doublet (i.e. low-frequency fatigue), recovery was faster for WING, whereas IMVC and high-frequency doublet recovered slower during MOD (P < 0.05). Our results confirm that peripheral fatigue is greater after WING and SEV, while central fatigue is greater following MOD. Peripheral fatigue can substantially recover within minutes after a supramaximal exercise while NM function recovered slower after prolonged, moderate-intensity exercise. This study provides an accurate estimation of NM fatigue and recovery kinetics due to dynamic exercise with large muscle mass by significantly shortening the delay for post-exercise measurements.
Computing Maximum Matchings in Temporal Graphs

Temporal graphs are graphs whose topology is subject to discrete changes over time. Given a static underlying graph $G$, a temporal graph is represented by assigning a set of integer time-labels to every edge $e$ of $G$, indicating the discrete time steps at which $e$ is active. We introduce and study the complexity of a natural temporal extension of the classical graph problem Maximum Matching, taking into account the dynamic nature of temporal graphs. In our problem, Maximum Temporal Matching, we are looking for the largest possible number of time-labeled edges (simply time-edges) $(e,t)$ such that no vertex is matched more than once within any time window of $\Delta$ consecutive time slots, where $\Delta \in \mathbb{N}$ is given. The requirement that a vertex cannot be matched twice in any $\Delta$-window models some necessary "recovery" period that needs to pass for an entity (vertex) after being paired up for some activity with another entity. We prove strong computational hardness results for Maximum Temporal Matching, even for elementary cases. To cope with this computational hardness, we mainly focus on fixed-parameter algorithms with respect to natural parameters, as well as on polynomial-time approximation algorithms.
Purine Biosynthesis Metabolically Constrains Intracellular Survival of Uropathogenic Escherichia coli

ABSTRACT The ability to de novo synthesize purines has been associated with the intracellular survival of multiple bacterial pathogens. Uropathogenic Escherichia coli (UPEC), the predominant cause of urinary tract infections, undergoes a transient intracellular lifestyle during which bacteria clonally expand into multicellular bacterial communities within the cytoplasm of bladder epithelial cells. Here, we characterized the contribution of the conserved de novo purine biosynthesis-associated locus cvpA-purF to UPEC pathogenesis. Deletion of cvpA-purF, or of purF alone, abolished de novo purine biosynthesis but did not impact bacterial adherence properties in vitro or in the bladder lumen. However, upon internalization by bladder epithelial cells, UPEC deficient in de novo purine biosynthesis was unable to expand into intracytoplasmic bacterial communities over time, unless it was extrachromosomally complemented. These findings indicate that UPEC is deprived of purine nucleotides within the intracellular niche and relies on de novo purine synthesis to meet this metabolic requirement.