Miracle-dz/UniFAR-FTUs huggingface dataset:
Catalytic Descriptors to Investigate Catalytic Power in the Reaction of Haloalkane Dehalogenase Enzyme with 1,2-Dichloroethane

Enzymes play a fundamental role in many biological processes. We present a theoretical approach to investigate the catalytic power of the haloalkane dehalogenase reaction with 1,2-dichloroethane. By removing the three main active-site residues one by one from haloalkane dehalogenase, we found two reactive descriptors: one descriptor is the distance difference between the breaking bond and the forming bond, and the other is the charge difference between the transition state and the reactant complex. Both descriptors scale linearly with the reactive barriers, with the three-residue case having the smallest barrier and the zero-residue case having the largest. The results demonstrate that, as the number of residues increases, the catalytic power increases. The predicted free energy barriers using the two descriptors of this reaction in water are 23.1 and 24.2 kcal/mol, both larger than the ones with any residues, indicating that the water solvent hinders the reactivity. Both predicted barrier heights agree well with the calculated one at 25.2 kcal/mol using a quantum mechanics and molecular dynamics approach, and also agree well with the experimental result at 26.0 kcal/mol. This study shows that reactive descriptors can also be used to describe and predict the catalytic performance for enzyme catalysis.
Effect of Coxsackievirus B4 Infection on the Thymus: Elucidating Its Role in the Pathogenesis of Type 1 Diabetes

The thymus gland is a primary lymphoid organ for T-cell development. Various viral infections can result in disturbance of thymic functions. Medullary thymic epithelial cells (mTECs) are important for the negative selection of self-reactive T-cells to ensure central tolerance. Insulin-like growth factor 2 (IGF2) is the dominant self-peptide of the insulin family expressed in mTECs and plays a crucial role in the intra-thymic programing of central tolerance to insulin-secreting islet β-cells. Coxsackievirus B4 (CVB4) can infect and persist in the thymus of humans and mice, thus hampering the T-cell maturation and differentiation process. The modulation of IGF2 expression and protein synthesis during a CVB4 infection has been observed in vitro and in vivo in mouse models. The effect of CVB4 infections on human and mouse fetal thymus has been studied in vitro. Moreover, following the inoculation of CVB4 in pregnant mice, the thymic function in the fetus and offspring was disturbed. A defect in the intra-thymic expression of self-peptides by mTECs may be triggered by CVB4. The effects of viral infections, especially CVB4 infection, on thymic cells and functions and their possible role in the pathogenesis of type 1 diabetes (T1D) are presented.
Context-Aware Graph Inference With Knowledge Distillation for Visual Dialog

Visual dialog is a challenging task that requires the comprehension of the semantic dependencies among implicit visual and textual contexts. This task can refer to the relational inference in a graphical model with sparse contextual subjects (nodes) and unknown graph structure (relation descriptor); how to model the underlying context-aware relational inference is critical. To this end, we propose a novel context-aware graph (CAG) neural network. We focus on the exploitation of fine-grained relational reasoning with object-level dialog-historical co-reference nodes. The graph structure (relation in dialog) is iteratively updated using an adaptive top-<inline-formula><tex-math notation="LaTeX">$K$</tex-math><alternatives><mml:math><mml:mi>K</mml:mi></mml:math><inline-graphic xlink:href="wang-ieq1-3085755.gif"/></alternatives></inline-formula> message passing mechanism. To eliminate sparse useless relations, each node has dynamic relations in the graph (different related <inline-formula><tex-math notation="LaTeX">$K$</tex-math><alternatives><mml:math><mml:mi>K</mml:mi></mml:math><inline-graphic xlink:href="wang-ieq2-3085755.gif"/></alternatives></inline-formula> neighbor nodes), and only the most relevant nodes are attributive to the context-aware relational graph inference. In addition, to avoid negative performance caused by linguistic bias of history, we propose a pure visual-aware knowledge distillation mechanism named CAG-Distill, in which image-only visual clues are used to regularize the joint dialog-historical contextual awareness at the object-level. Experimental results on VisDial v0.9 and v1.0 datasets show that both CAG and CAG-Distill outperform comparative methods. Visualization results further validate the remarkable interpretability of our graph inference solution.
Sensor Network for Analyzing Upper Body Strategies in Parkinson’s Disease versus Normative Kinematic Patterns

In rehabilitation, the upper limb function is generally assessed using clinical scales and functional motor tests. Although the Box and Block Test (BBT) is commonly used for its simplicity and ease of execution, it does not provide a quantitative measure of movement quality. This study proposes the integration of an ecological Inertial Measurement Units (IMUs) system for analysis of the upper body kinematics during the execution of a targeted version of BBT, by able-bodied persons with subjects with Parkinson’s disease (PD). Joint angle parameters (mean angle and range of execution) and hand trajectory kinematic indices (mean velocity, mean acceleration, and dimensionless jerk) were calculated from the data acquired by a network of seven IMUs. The sensors were applied on the trunk, head, and upper limb in order to characterize the motor strategy used during the execution of BBT. Statistics revealed significant differences (p < 0.05) between the two groups, showing compensatory strategies in subjects with PD. The proposed IMU-based targeted BBT protocol allows to assess the upper limb function during manual dexterity tasks and could be used in the future for assessing the efficacy of rehabilitative treatments.
The Density of Group I mGlu5 Receptors Is Reduced along the Neuronal Surface of Hippocampal Cells in a Mouse Model of Alzheimer’s Disease

Metabotropic glutamate receptor subtype 5 (mGlu5) is implicated in the pathophysiology of Alzheimer’s disease (AD). However, its alteration at the subcellular level in neurons is still unexplored. Here, we provide a quantitative description on the expression and localisation patterns of mGlu5 in the APP/PS1 model of AD at 12 months of age, combining immunoblots, histoblots and high-resolution immunoelectron microscopic approaches. Immunoblots revealed that the total amount of mGlu5 protein in the hippocampus, in addition to downstream molecules, i.e., Gq/11 and PLCβ1, was similar in both APP/PS1 mice and age-matched wild type mice. Histoblots revealed that mGlu5 expression in the brain and its laminar expression in the hippocampus was also unaltered. However, the ultrastructural techniques of SDS-FRL and pre-embedding immunogold demonstrated that the subcellular localisation of mGlu5 was significantly reduced along the neuronal surface of hippocampal principal cells, including CA1 pyramidal cells and DG granule cells, in APP/PS1 mice at 12 months of age. The decrease in the surface localisation of mGlu5 was accompanied by an increase in its frequency at intracellular sites in the two neuronal populations. Together, these data demonstrate, for the first time, a loss of mGlu5 at the plasma membrane and accumulation at intracellular sites in different principal cells of the hippocampus in APP/PS1 mice, suggesting an alteration of the excitability and synaptic transmission that could contribute to the cognitive dysfunctions in this AD animal model. Further studies are required to elucidate the specificity of mGlu5-associated molecules and downstream signalling pathways in the progression of the pathology.
CX-5461 Enhances the Efficacy of APR-246 via Induction of DNA Damage and Replication Stress in Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking targeted therapy. Here, we evaluated the anti-cancer activity of APR-246, a P53 activator, and CX-5461, a RNA polymerase I inhibitor, in the treatment of TNBC cells. We tested the efficacy of individual and combination therapy of CX-5461 and APR-246 in vitro, using a panel of breast cancer cell lines. Using publicly available breast cancer datasets, we found that components of RNA Pol I are predominately upregulated in basal-like breast cancer, compared to other subtypes, and this upregulation is associated with poor overall and relapse-free survival. Notably, we found that the treatment of breast cancer cells lines with CX-5461 significantly hampered cell proliferation and synergistically enhanced the efficacy of APR-246. The combination treatment significantly induced apoptosis that is associated with cleaved PARP and Caspase 3 along with Annexin V positivity. Likewise, we also found that combination treatment significantly induced DNA damage and replication stress in these cells. Our data provide a novel combination strategy by utilizing APR-246 in combination CX-5461 in killing TNBC cells that can be further developed into more effective therapy in TNBC therapeutic armamentarium.
Telerehabilitation of Post-Stroke Patients as a Therapeutic Solution in the Era of the Covid-19 Pandemic

(1) Background: Due to the pandemic caused by the SARS-CoV-2 virus, rehabilitation centres have become less available for neurological patients. This is the result of efforts to physically distance society, to try to slow the spread of the pathogen. Health care facilities were mainly restricted to urgent cases, while most physiotherapy treatments, mainly for patients with chronic conditions, were suspended. Some countries have seen a reduction in acute stroke hospital admissions of from 50% to 80%. One solution to the above problem is the use of telerehabilitation in the home environment as an alternative to inpatient rehabilitation. (2) Aim of the study: The purpose of this review is to analyse the benefits and limitations of teletherapy in relation to the functional condition of post-stroke patients. (3) Methods: Selected publications from 2019 to 2021 on the telerehabilitation of stroke patients were reviewed. The review was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist. (4) Results: Studies have proven that teletherapy significantly improves the functional condition of post-stroke patients, resulting in improved quality of life and faster return to independence (while maintaining maximum possible precautions related to the SARS-CoV-2 virus pandemic). (5) Conclusions: Analysis of the study results showed comparable effectiveness of rehabilitation in the tele system to inpatient therapy. However, it should be emphasised that patients undergoing telerehabilitation must meet strict conditions to be eligible for this type of treatment program. However, the strength of the evidence itself supporting the effectiveness of this method ranks low due to the limited number of randomised control trials (RCT), small number of participants, and heterogeneous trials.
Pivotal Role for Cxcr2 in Regulating Tumor-Associated Neutrophil in Breast Cancer

Simple Summary Chemokines present in the tumor microenvironment are essential for the control of tumor progression. We show here that the knock-down of Cxcr2 in PyMT animals led to an increased growth of the primary tumor and lung metastasis. The analysis of tumor content of PyMT-Cxcr2−/− animals highlighted an increased infiltration of tumor associated neutrophils (TANs), mirrored by a decreased recruitment of tumor associated macrophages (TAMs) compared to PyMT animals. Analysis of PyMT-Cxcr2−/− TANs revealed that they lost their killing ability compared to PyMT-Cxcr2+/+ TANs and that they had a more pronounced pro-tumor TAN2 profile compared to PyMT TANs. PyMT-Cxcr2−/− TANs displayed an up-regulation of the pathways involved in reactive oxygen species (ROS) production and angiogenesis and factors favoring metastasis, but reduced apoptosis. In summary, our data reveal that a lack of Cxcr2 provides TANs with pro-tumor effects. Abstract Chemokines present in the tumor microenvironment are essential for the control of tumor progression. We show here that several ligands of the chemokine receptor Cxcr2 were up-regulated in the PyMT (polyoma middle T oncogene) model of breast cancer. Interestingly, the knock-down of Cxcr2 in PyMT animals led to an increased growth of the primary tumor and lung metastasis. The analysis of tumor content of PyMT-Cxcr2−/− animals highlighted an increased infiltration of tumor associated neutrophils (TANs), mirrored by a decreased recruitment of tumor associated macrophages (TAMs) compared to PyMT animals. Analysis of PyMT-Cxcr2−/− TANs revealed that they lost their killing ability compared to PyMT-Cxcr2+/+ TANs. The transcriptomic analysis of PyMT-Cxcr2−/− TANs showed that they had a more pronounced pro-tumor TAN2 profile compared to PyMT TANs. In particular, PyMT-Cxcr2−/− TANs displayed an up-regulation of the pathways involved in reactive oxygen species (ROS) production and angiogenesis and factors favoring metastasis, but reduced apoptosis. In summary, our data reveal that a lack of Cxcr2 provides TANs with pro-tumor effects.
The Impact of Simvastatin on Lipidomic Markers of Cardiovascular Risk in Human Liver Cells Is Secondary to the Modulation of Intracellular Cholesterol

Statins are the first-line lipid-lowering therapy for reducing cardiovascular disease (CVD) risk. A plasma lipid ratio of two phospholipids, PI(36:2) and PC(18:0_20:4), was previously identified to explain 58% of the relative CVD risk reduction associated with pravastatin, independent of a change in low-density lipoprotein-cholesterol. This ratio may be a potential biomarker for the treatment effect of statins; however, the underlying mechanisms linking this ratio to CVD risk remain unclear. In this study, we investigated the effect of altered cholesterol conditions on the lipidome of cultured human liver cells (Hep3B). Hep3B cells were treated with simvastatin (5 μM), cyclodextrin (20 mg/mL) or cholesterol-loaded cyclodextrin (20 mg/mL) for 48 h and their lipidomes were examined. Induction of a low-cholesterol environment via simvastatin or cyclodextrin was associated with elevated levels of lipids containing arachidonic acid and decreases in phosphatidylinositol species and the PI(36:2)/PC(18:0_20:4) ratio. Conversely, increasing cholesterol levels via cholesterol-loaded cyclodextrin resulted in reciprocal regulation of these lipid parameters. Expression of genes involved in cholesterol and fatty acid synthesis supported the lipidomics data. These findings demonstrate that the PI(36:2)/PC(18:0_20:4) ratio responds to changes in intracellular cholesterol abundance per se, likely through a flux of the n-6 fatty acid pathway and altered phosphatidylinositol synthesis. These findings support this ratio as a potential marker for CVD risk reduction and may be useful in monitoring treatment response.
Impacts of Thermal Environments on Health Risk: A Case Study of Harris County, Texas

The loss of green spaces in urbanized areas has triggered a potential thermal risk in the urban environment. While the existing literature has investigated the direct relationship between urban temperatures and health risks, little is known about causal relationships among key components of urban sustainability and health risks, through a pathway involving urban temperature. This study examined the multiple connections between urbanized land use, urban greenery, urban temperatures and health risks in Harris County, Texas. The census tract-level health data from the 500 Cities Project (Centers for Disease Control and Prevention) is used for analysis. Structural equation model analyses showed that the urban temperature played a mediating role in associations between urbanized land use, urban greenery and health risk. Urban vegetation is associated with a decrease in health risks, while urban land use has associations with an increase in health risks. Findings suggest that proactive policies tailored to provide rich urban greenery in a neighborhood can alleviate urban land use effects on health risks.
Investigation of a Novel Multicomponent Mycotoxin Detoxifying Agent in Amelioration of Mycotoxicosis Induced by Aflatoxin-B1 and Ochratoxin A in Broiler Chicks

The present study was designed to determine the efficacy of a novel multicomponent mycotoxin detoxifying agent (MMDA) containing modified zeolite (Clinoptilolite), Bacillus subtilis, B. licheniformis, Saccharomyces cerevisiae cell walls and silymarin against the deleterious effects of Aflatoxin B1 (AFB1) and Ochratoxin A (OTA) in broiler chicks. A total of 160 one-day-old Ross 308® broiler chicks were randomly allocated in four treatment groups, with four replicates, according to the following experimental design for 42 days. Group A received a basal diet; Group B received a basal diet contaminated with AFB1 and OTA at 0.1 mg/kg and 1 mg/kg, respectively; Group C received a basal diet contaminated with AFB1 and OTA and MMDA at 1 g/kg feed, and Group D received a basal diet contaminated with AFB1 and OTA and MMDA at 3 g/kg feed. Results showed that ingested mycotoxins led to significant (p ≤ 0.05) reduction in body weight and feed conversion from 25 days of age, induced histopathological changes, increased the pH of the intestinal content, and altered the biochemical profile of birds with significantly (p ≤ 0.05) increased aspartate aminotransferase (AST) values (p ≤ 0.05). On the other hand, the supplementation of MMDA significantly (p ≤ 0.05) improved the feed conversion ratio (FCR) during the second part of the study, diminished biochemical alterations, reduced pH in jejunal and ileal content, and E. coli counts in the caeca of birds (p ≤ 0.05). It may be concluded that the dietary supplementation of the MMDA partially ameliorated the adverse effects of AFB1 and OTA in broilers and could be an efficient tool in a mycotoxin control program.
Hepatic Nfe2l2 Is Not an Essential Mediator of the Metabolic Phenotype Produced by Dietary Methionine Restriction

The principal sensing of dietary methionine restriction (MR) occurs in the liver, where it activates multiple transcriptional programs that mediate various biological components of the response. Hepatic Fgf21 is a key target and essential endocrine mediator of the metabolic phenotype produced by dietary MR. The transcription factor, Nfe2l2, is also activated by MR and functions in tandem with hepatic Atf4 to transactivate multiple, antioxidative components of the integrated stress response. However, it is unclear whether the transcriptional responses linked to Nfe2l2 activation by dietary MR are essential to the biological efficacy of the diet. Using mice with liver-specific deletion of Nfe2l2 (Nfe2l2fl/(Alb)) and their floxed littermates (Nfe2l2fl/fl) fed either Control or MR diets, the absence of hepatic Nfe2l2 had no effect on the ability of the MR diet to increase FGF21, reduce body weight and adiposity, and increase energy expenditure. Moreover, the primary elements of the hepatic transcriptome were similarly affected by MR in both genotypes, with the only major differences occurring in induction of the P450-associated drug metabolism pathway and the pentose glucuronate interconversion pathway. The biological significance of these pathways is uncertain but we conclude that hepatic Nfe2l2 is not essential in mediating the metabolic effects of dietary MR.
Targeted Approaches to T-Cell Lymphoma

The T-cell lymphomas are a rare group of Non-Hodgkin’s lymphomas derived from mature T-lymphocytes. They are divided broadly into the Peripheral T-cell lymphomas and the Cutaneous T-cell lymphomas. Clinical outcomes vary widely but are generally unsatisfactory with current treatments. The development of an understanding of the various critical pathways in T-cell lymphogenesis and subsequent identification of therapeutic targets has led to a rapid expansion of the previously underwhelming T-cell lymphoma armament. This review aims to provide an up-to-date overview of the current state of targeted therapies in the T-cell lymphomas, including novel antibody-based treatments, small molecule inhibitors and immune-based therapies.
Comparison of Generalized Anxiety and Sleep Disturbance among Frontline and Second-Line Healthcare Workers during the COVID-19 Pandemic

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection, also known as COVID-19, has developed into an alarming situation around the world. Healthcare workers are playing the role of frontline defense to safeguard the lives of everyone during the COVID-19 pandemic. The present study aimed to investigate the anxiety levels and sleep quality among frontline and second-line healthcare workers during the COVID-19 pandemic. In this cross-sectional study, a validated, self-administered, electronic questionnaire was distributed through email to healthcare workers. The selection of 1678 healthcare workers was based on a convenience sampling technique. The General Anxiety Disorder-7 (GAD-7) and Pittsburgh Sleep Quality Index (PSQI) instrument scales were used to assess healthcare workers’ anxiety levels and sleep quality during the COVID-19 pandemic. Out of 1678 respondents, 1200 (71.5%) were frontline healthcare workers, while 478 (28.5%) were second-line healthcare workers. Among all the healthcare workers, 435 (25.92%) were experiencing moderate to severe anxiety. Among them, 713 (59.4%) frontline healthcare workers were experiencing anxiety in comparison with 277 (57.9%) second-line healthcare workers. Severe anxiety symptoms were seen in 137 (11.41%) frontline healthcare workers compared to 44 (9.20%) second-line healthcare workers. In total, 1376 (82.0%) healthcare workers were found to have poor sleep quality; 975 (58.10%) were frontline, and 407 (23.89%) were second-line healthcare workers. The highest poor sleep quality levels were found among 642 (84.6%) of the healthcare workers who work in frontline areas (emergency departments, intensive care units, and wards) compared to 734 (79.9%) of the healthcare workers who work in second-line areas. These findings provide a substantial contribution to the consolidation of evidence concerning the negative impact of the pandemic on the mental health of healthcare workers (HCWs). These results have established an association that the COVID-19 pandemic causes larger negative psychological symptoms in frontline healthcare workers, such as severe anxiety and poor sleep quality. Preventive measures to minimize anxiety levels and maintain sleep quality, addressing this issue nationally and globally, are essential to support the healthcare workers who are sacrificing their mental health for the future of our nations.