Miracle-dz/UniFAR-FTUs huggingface dataset:
Tuberous Sclerosis Complex cell‐derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers

Abstract Hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) is a feature of many solid tumours and is a key pathogenic driver in the inherited condition Tuberous Sclerosis Complex (TSC). Modulation of the tumour microenvironment by extracellular vesicles (EVs) is known to facilitate the development of various cancers. The role of EVs in modulating the tumour microenvironment and their impact on the development of TSC tumours, however, remains unclear. This study, therefore, focuses on the poorly defined contribution of EVs to tumour growth in TSC. We characterised EVs secreted from TSC2‐deficient and TSC2‐expressing cells and identified a distinct protein cargo in TSC2‐deficient EVs, containing an enrichment of proteins thought to be involved in tumour‐supporting signalling pathways. We show EVs from TSC2‐deficient cells promote cell viability, proliferation and growth factor secretion from recipient fibroblasts within the tumour microenvironment. Rapalogs (mTORC1 inhibitors) are the current therapy for TSC tumours. Here, we demonstrate a previously unknown intercellular therapeutic effect of rapamycin in altering EV cargo and reducing capacity to promote cell proliferation in the tumour microenvironment. Furthermore, EV cargo proteins have the potential for clinical applications as TSC biomarkers, and we reveal three EV‐associated proteins that are elevated in plasma from TSC patients compared to healthy donor plasma.
A selective mass scaling method for shear wave propagation analyses in nearly incompressible materials

This paper describes a selective mass scaling method which is designed for the analysis of wave propagation problems in nearly incompressible materials. The incompressibility of materials leads to a high value of the compressional wave speed, which makes the time step extremely small in explicit time integration method. The proposed selective mass scaling method selects the eigenfrequencies related to volumetric deformation modes to decrease them, while it keeps the shear eigenmodes unchanged. This makes the time step no longer limited by the compressional wave speed but by the shear wave speed. A significant reduction of CPU time is obtained with a good accuracy for transient problems in small strains on free or largely prestressed media. Copyright © 2016 John Wiley & Sons, Ltd.
Prevalence and Burden of Illness of Rome IV Chronic Idiopathic Constipation, Opioid-Induced Constipation, and Opioid-Exacerbated Constipation in the United States

INTRODUCTION: Chronic idiopathic constipation (CIC) and opioid-induced constipation (OIC) are disorders that negatively affect quality of life. We sought to assess the prevalence, symptom severity, and medication use among people with Rome IV CIC, OIC, and opioid-exacerbated constipation (OEC) using a nationally representative data set with nearly 89,000 people in the United States. METHODS: From May 3, 2020, to June 24, 2020, we recruited a representative sample of people in the United States ≥ 18 years to complete an online national health survey. The survey guided participants through the Rome IV CIC and OIC questionnaires, Patient-Reported Outcome Measurement Information System gastrointestinal scales (percentile 0–100; higher = more severe), and medication questions. Individuals with OEC were identified by asking those with OIC whether they experienced constipation before starting an opioid and whether their symptoms worsened afterward. RESULTS: Among the 88,607 participants, 5,334 (6.0%) had Rome IV CIC, and 1,548 (1.7%) and 335 (0.4%) had Rome IV OIC and OEC, respectively. When compared with people with CIC (Patient-Reported Outcome Measurement Information System score, 53.9 ± 26.5; reference), those with OIC (62.7 ± 28.0; adjusted P < 0.001) and OEC (61.1 ± 25.8, adjusted P = 0.048) had more severe constipation symptoms. People with OIC (odds ratio 2.72, 95% confidence interval 2.04–3.62) and OEC (odds ratio 3.52, 95% confidence interval 2.22–5.59) were also more likely to be taking a prescription medication for their constipation vs those with CIC. DISCUSSION: In this nationwide US survey, we found that Rome IV CIC is common (6.0%) while Rome IV OIC (1.7%) and OEC (0.4%) are less prevalent. Individuals with OIC and OEC have a higher burden of illness with respect to symptom severity and prescription constipation medication use.
Proposing the Simplification of the Multilayer Urban Canopy Model: Intercomparison Study of Four Models

Abstract The study proposes the simplification of the multilayer urban canopy model. Four types of multilayer urban canopy models—level 4, level 3, level 2, and level 1—are developed to reduce the computational load of the heat budget calculations at the wall surface. The level 4 model, which accounts for the wall directions and the vertical layer, is simplified in three ways: the level 3 model only accounts for the vertical layers, the level 2 model accounts for the wall directions, and the level 1 model accounts for neither the wall directions nor the vertical layer. From the simplification, compared to the level 4 model, the memory is reduced by 57%, 65%, and 72% for the level 3–level 1 models, respectively, when the vertical canopy layer is seven. At the same time, the CPU time is reduced by 67%, 70%, and 78% for the level 3–level 1 models. Then, each canopy model is compared with observations in Tokyo. The results show that the simulations from the four models are close to the observed ones, and the .
Determination of electric and thermoelectric properties of molecular junctions by AFM in peak force tapping mode

Molecular thin films, such as self-assembled monolayers (SAMs), offer the possibility of translating the optimised thermophysical and electrical properties of high-Seebeck-coefficient single molecules to scalable device architectures. However, for many scanning probe-based approaches attempting to characterise such SAMs, there remains a significant challenge in recovering single-molecule equivalent values from large-area films due to the intrinsic uncertainty of the probe-sample contact area coupled with film damage caused by contact forces. Here we report a new reproducible non-destructive method for probing the electrical and thermoelectric (TE) properties of small assemblies (10–103) of thiol-terminated molecules arranged within a SAM on a gold surface, and demonstrate the successful and reproducible measurements of the equivalent single-molecule electrical conductivity and Seebeck values. We have used a modified thermal-electric force microscopy approach, which integrates the conductive-probe atomic force microscope, a sample positioned on a temperature-controlled heater, and a probe-sample peak-force feedback that interactively limits the normal force across the molecular junctions. The experimental results are interpreted by density functional theory calculations allowing quantification the electrical quantum transport properties of both single molecules and small clusters of molecules. Significantly, this approach effectively eliminates lateral forces between probe and sample, minimising disruption to the SAM while enabling simultaneous mapping of the SAMs nanomechanical properties, as well as electrical and/or TE response, thereby allowing correlation of the film properties.
The inhibitory effect of quercetin-3-glucuronide on pulmonary injury in vitro and in vivo

Pulmonary injury is defined as a progressive inflammation. Extensive pro-inflammatory cytokines are secreted from alveolus, associated with the production of reactive oxygen species (ROS) and apoptosis. The model of endotoxin lipopolysaccharide (LPS)-stimulated lung cells has been applied to mimic the pulmonary injury. Some antioxidants and anti-inflammatory compounds can be used as chemopreventive agents of pulmonary injury. Quercetin-3-glucuronide (Q3G) has been showed to exert antioxidant, anti-inflammatory, anti-cancer, anti-aging and anti-hypertension effects. The aim of the study is to examine the inhibitory potential of Q3G on pulmonary injury and inflammation in vitro and in vivo. Firstly, human lung fibroblasts MRC-5 cells pre-treated with LPS were demonstrated to cause survival loss and ROS generation, were recovered by Q3G. Q3G also exhibited the anti-inflammatory effects on the LPS-treated cells with a reduction in the activation of NLRP3 [nucleotide-binding and oligomerization domain (NOD)-like receptor protein 3] inflammasome, leading to pyroptosis. Also, Q3G showed the anti-apoptotic effect in the cells might be mediated via inhibition of mitochondrial apoptosis pathway. To further explore in vivo pulmonary-protective effect of Q3G, C57BL/6 mice were intranasally exposed to a combination of LPS and elastase (LPS/E) to perform the pulmonary injury model. The results revealed that Q3G ameliorated pulmonary function parameters and lung edema in the LPS/E-induced mice. Q3G also suppressed the LPS/E-stimulated inflammation, pyroptosis and apoptosis in the lungs. Taken together, this study suggested the lung-protective potential of Q3G via downregulation of inflammation, pyroptotic and apoptotic cell death, contributing to its chemopreventive activity of pulmonary injury.
Development of a lateral flow immunoassays-based method for the screening of ractopamine in foods and evaluation of the optimal strategy in combination of screening and confirmatory tests

Ractopamine has been authorized as a feed additive and permitted in animal husbandry. With the establishment of the regulation to limit the concentration of ractopamine, a rapid screening method for ractopamine is urgently needed. Additionally, how to combine the screening and confirmatory tests of ractopamine is also critical to maximizing the efficiency of testing. Here, we developed a lateral flow immunoassays-based method for the screening of ractopamine in foods and proposed a cost-benefit analysis approach to optimize cost allocation between screening and confirmatory tests. After verifying the analytical and clinical performances of the screening method, a mathematical model was established to calculate the screening and confirmatory test results with various parameter settings, such as cost allocation, false-negative tolerance, and total budget size. The developed immunoassay-based screening test could successfully distinguish gravy samples with ractopamine levels over and lower than maximum residue limits (MRL). The area under curve (AUC) value of receiver operating characteristic (ROC) curve is 0.99. For the cost-benefit analysis, mathematical simulation indicated that when the samples are allocated to screening and confirmatory tests at the optimized cost allocation, the number of confirmed positive samples can increase by 26 times compared to the scenarios entirely relying on confirmatory testing. While conventional wisdom considers that screening should be carried out at low false-negative rates, such as 0.1%, our results indicated that the cutoff value of a screening test with a 20% false-negative rate at MRL could capture the maximum number of confirmed positive samples at a limited budget. Our work indicated that the participation of the screening method in ractopamine analysis and optimized cost allocation between screening and confirmatory tests could enhance the efficiency in detecting the positive samples, which provides a rational basis for decision-making in food safety enforcement for public health.
Metagenomic Sequencing of Two Cultures Grown on Chemically Deconstructed Plastic Products

We report the metagenome sequences of two microbial cultures that were grown with chemically deconstructed plastic products as their sole carbon source. These metagenomes will provide insights into the metabolic capabilities of cultures grown on deconstructed plastics and can serve as a starting point for the identification of novel plastic degradation mechanisms. ABSTRACT We report the metagenome sequences of two microbial cultures that were grown with chemically deconstructed plastic products as their sole carbon source. These metagenomes will provide insights into the metabolic capabilities of cultures grown on deconstructed plastics and can serve as a starting point for the identification of novel plastic degradation mechanisms.
Enhancers of the PAIR4 regulatory module promote distal VH gene recombination at the Igh locus

While extended loop extrusion across the entire Igh locus controls VH‐DJH recombination, local regulatory sequences, such as the PAIR elements, may also activate VH gene recombination in pro‐B‐cells. Here, we show that PAIR‐associated VH8 genes contain a conserved putative regulatory element (V8E) in their downstream sequences. To investigate the function of PAIR4 and its V8.7E, we deleted 890 kb containing all 14 PAIRs in the Igh 5′ region, which reduced distal VH gene recombination over a 100‐kb distance on either side of the deletion. Reconstitution by insertion of PAIR4‐V8.7E strongly activated distal VH gene recombination. PAIR4 alone resulted in lower induction of recombination, indicating that PAIR4 and V8.7E function as one regulatory unit. The pro‐B‐cell‐specific activity of PAIR4 depends on CTCF, as mutation of its CTCF‐binding site led to sustained PAIR4 activity in pre‐B and immature B‐cells and to PAIR4 activation in T‐cells. Notably, insertion of V8.8E was sufficient to activate VH gene recombination. Hence, enhancers of the PAIR4‐V8.7E module and V8.8E element activate distal VH gene recombination and thus contribute to the diversification of the BCR repertoire in the context of loop extrusion.
Longitudinal changes in brain structure and their relationship with subclinical psychiatric symptoms in parents who lost their only child in China

ABSTRACT Background: Losing an only child (Shidu) is a grievous traumatic event that may affect brain structure, even if it does not lead to psychiatric disorders. However, longitudinal changes in brain structure and their relationship to subclinical psychiatric symptoms (SPS) have not been well investigated in Shidu parents without any psychiatric disorders (SDNP). Objectives: This study aimed to investigate cross-sectional and longitudinal changes in cortical thickness and surface area in SDNP, and to explore their relationship with SPS. Methods: A total of 50 SDNP and 40 matched healthy controls (HC) were enrolled. All participants underwent structural MRI scans and clinical assessment at baseline and at the 5-year follow-up. Differences in brain structural phenotypes (cortical thickness, surface area, and their annual rate of change) between the SDNP and HC groups were compared using FreeSurfer. Correlations between significant brain structural phenotypes and SPS in the SDNP group were evaluated using multiple linear regressions. Results: The SDNP group showed a smaller surface area in the left inferior parietal cortex than the HC group at baseline and follow-up. The SDNP group showed slower rates of cortical thinning and surface area loss in several brain regions than the HC group from baseline to follow-up. Moreover, slower rates of cortical thinning in the left insula, superior frontal cortex, and superior temporal cortex were associated with greater reductions in avoidance, depression, and trauma re-experiencing symptoms scores over time in the SDNP group, respectively. Conclusions: Shidu trauma-induced structural abnormalities in the inferior parietal cortex may persist over time and be independent of the severity of psychiatric symptoms. The expansion of prefrontal, temporal, and insular cortex implicated in emotional regulation may contribute to improvements in psychiatric symptoms in Shidu parents. HIGHLIGHTS This study focused on longitudinal changes in cortical thickness and surface area and their relationship with subclinical psychiatric symptoms in Shidu parents without any psychiatric disorders. Shidu trauma-induced structural abnormalities in the inferior parietal cortex may persist over time and be independent of the severity of psychiatric symptoms. The expansion of prefrontal, temporal, and insular cortex implicated in emotional regulation may contribute to improvements in psychiatric symptoms in Shidu parents.
Lessons from the deep: mechanisms behind diversification of eukaryotic protein complexes

Genetic variation is the major mechanism behind adaptation and evolutionary change. As most proteins operate through interactions with other proteins, changes in protein complex composition and subunit sequence provide potentially new functions. Comparative genomics can reveal expansions, losses and sequence divergence within protein‐coding genes, but in silico analysis cannot detect subunit substitutions or replacements of entire protein complexes. Insights into these fundamental evolutionary processes require broad and extensive comparative analyses, from both in silico and experimental evidence. Here, we combine data from both approaches and consider the gamut of possible protein complex compositional changes that arise during evolution, citing examples of complete conservation to partial and total replacement by functional analogues. We focus in part on complexes in trypanosomes as they represent one of the better studied non‐animal/non‐fungal lineages, but extend insights across the eukaryotes by extensive comparative genomic analysis. We argue that gene loss plays an important role in diversification of protein complexes and hence enhancement of eukaryotic diversity.
Decentralized Robust H∞ Control of Large Scale Systems with Polytopic-Type Uncertainty

In this article, we present a decentralized robust stabilization and H∞ control for large-scale uncertain systems. The system is represented by a set of interconnected subsystems. We interest to the study of stability of the global system in closed loop using state feedback decentralized controllers. The stability conditions are presented in terms of LMI. In order to improve this first approach, we propose, through a criterion H∞, to study the robustness according the effects of interconnections between the subsystems. Some sufficient conditions, ensuring all the closed-loop stability, are supplied in terms of Linear Matrix Inequalities (LMIs) and the feedback gain matrix of each local controller is obtained by solving the LMIs. Finally, the practice examples are given to illustrate the efficiency of the proposed approach.
Effects of calcium chloride substitution on the physicochemical properties of Minas Frescal cheese

Abstract The aim in this research paper was to investigate the effect of using calcium monophosphate (MCP) and MCP mixed with commercial phosphates salts, in total or partial replacement of calcium chloride (CaCl2) in the manufacture of Minas Frescal cheese. Initially, model cheeses were made to perform the rheological analysis during the coagulation process. Of these, the five best treatments were chosen to carry out the production of Minas Frescal cheese, used only CaCl2 and MCP, and partial replacements of MCP + polyphosphate, MCP + potassium monophosphate (MKP) and MCP. The cheeses showed no significant difference in physicochemical composition, yield and syneresis, however, the cheese with partial replacement of CaCl2 by MCP + polyphosphate and MCP + MKP showed the highest hardness values, like the control. This demonstrates that it is possible to replace calcium chloride without significant changes in the physicochemical characteristics and yield of Minas Frescal cheese, and it is still possible to modulate the hardness of the cheese produced according to the type of calcium/phosphate source used. This allows the industry to replace the source of calcium in the manufacture of Minas Frescal cheese according to the desired hardness.
Life is pain: Fibromyalgia as a nexus of multiple liability distributions

Fibromyalgia is a complex disease of unclear etiology that is complicated by difficulties in diagnosis, treatment, and clinical heterogeneity. To clarify this etiology, healthcare‐based data are leveraged to assess the influences on fibromyalgia in several domains. Prevalence is less than 1% of females in our population register data, and about 1/10th that in males. Fibromyalgia often presents with co‐occurring conditions including back pain, rheumatoid arthritis, and anxiety. More comorbidities are identified with hospital‐associated biobank data, falling into three broad categories of pain‐related, autoimmune, and psychiatric disorders. Selecting representative phenotypes with published genome‐wide association results for polygenic scoring, we confirm genetic predispositions to psychiatric, pain sensitivity, and autoimmune conditions show associations with fibromyalgia, although these may differ by ancestry group. We conduct a genome‐wide association analysis of fibromyalgia in biobank samples, which did not result in any genome‐wide significant loci; further studies with increased sample size are necessary to identify specific genetic effects on fibromyalgia. Overall, fibromyalgia appears to have strong clinical and likely genetic links to several disease categories, and could usefully be understood as a composite manifestation of these etiological sources.
Steatotic hepatocyte‐derived extracellular vesicles promote β‐cell apoptosis and diabetes via microRNA‐126a‐3p

Extracellular vesicles (EVs) have emerged as a unique mediator of interorgan communications, playing important roles in the pathophysiologic process of various diseases, including diabetes and other metabolic diseases. Here, we reported that the EVs released by steatotic hepatocytes exerted a detrimental effect on pancreatic β cells, leading to β‐cell apoptosis and dysfunction. The effect was profoundly attributable to an up‐regulation of miR‐126a‐3p in the steatotic hepatocyte‐derived EVs. Accordingly, overexpression of miR‐126a‐3p promoted, whereas inhibition of miR‐126a‐3p prevented β‐cell apoptosis, through a mechanism related to its target gene, insulin receptor substrate‐2. Moreover, inhibition of miR‐126a‐3p by its specific antagomir was able to partially reverse the loss of β‐cell mass and ameliorate hyperglycaemia in diabetic mice. Thus, the findings reveal a novel pathogenic role of steatotic hepatocyte‐derived EVs, which mechanistically links nonalcoholic fatty liver disease to the development of diabetes.
Genetic characterization of a new candidate hemagglutinin subtype of influenza A viruses

ABSTRACT Avian influenza viruses (AIV) have been classified on the basis of 16 subtypes of hemagglutinin (HA) and 9 subtypes of neuraminidase. Here we describe genomic evidence for a new candidate HA subtype, nominally H19, with a large genetic distance to all previously described AIV subtypes, derived from a cloacal swab sample of a Common Pochard (Aythya ferina) in Kazakhstan, in 2008. Avian influenza monitoring in wild birds especially in migratory hotspots such as central Asia is an important approach to gain information about the circulation of known and novel influenza viruses. Genetically, the novel HA coding sequence exhibits only 68.2% nucleotide and 68.5% amino acid identity with its nearest relation in the H9 (N2) subtype. The new HA sequence should be considered in current genomic diagnostic AI assays to facilitate its detection and eventual isolation enabling further study and antigenic classification.