Miracle-dz/UniFAR-FTUs huggingface dataset:
Diseases of the musculoskeletal system and connective tissue and risk of breast cancer: Mendelian randomization study in European and East Asian populations

Objective Associations between diseases of the musculoskeletal system and connective tissue (MSCTD) and breast cancer (BC) have not been elucidated completely. The purpose of this study was to investigate the associations of MSCTD, rheumatoid arthritis (RA), Sjogren syndrome (SS), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermatomyositis (DM), polymyositis (PM), osteoarthritis (OA) of hip or knee, and ankylosing spondylitis (AS) with BC in European populations and East Asian populations using Mendelian randomized (MR) analysis. Methods The genetic instruments linked to MSCTD, RA, SS, SLE, SSc, DM, PM, OA, and AS were chosen from the EBI database of complete genome-wide association studies (GWAS) summary data and the FinnGen consortium. The associations of genetic variants with BC were extracted from the Breast Cancer Association Consortium (BCAC). Two Sample MR was performed using summary data from GWAS, principally using the inverse variant weighted (IVW) method. Heterogeneity, pleiotropy, and sensitivity analyses were performed to evaluate the robustness of the results by weighted median, MR Egger, simple mode, weighted mode, and leave-one-out analysis. Results In the European population, causal relationships between RA and BC (OR=1.04, 95%CI: 1.01-1.07, P=0.023), AS and BC (OR=1.21, 95%CI: 1.06-1.36, P=0.013) were confirmed. IVW analysis showed DM (OR=0.98, 95%CI: 0.96-0.99, P=0.026) and PM (OR=0.98, 95%CI: 0.97-0.99, P=0.002) were associated with slightly decreased risks of estrogen receptor (ER)+ BC, and MSCTD was associated with an increased risk of ER- BC (OR=1.85, 95%CI: 1.27-2.44, P=0.039). There was no causal relationship between SLE, SS, SSc, OA, and BC, neither ER+ BC nor ER- BC. However, in the East Asian population, IVW analysis showed that RA (OR=0.94, 95%CI: 0.89-0.99, P=0.0096) and SLE (OR=0.95, 95%CI: 0.92-0.99, P=0.0058) was associated with decreased risks of BC. Conclusions This study suggests that causal relationships between patients with MSCTD and BC in the European population are different from those in the East Asian population, patients with RA and AS in the European population have an increased risk of BC, patients with MSCTD have increased risk of ER- BC in the European population, while patients with RA and SLE in the East Asian population have decreased risk of BC.
Therapeutic targeting of anoikis resistance in cutaneous melanoma metastasis

The acquisition of resistance to anoikis, the cell death induced by loss of adhesion to the extracellular matrix, is an absolute requirement for the survival of disseminating and circulating tumour cells (CTCs), and for the seeding of metastatic lesions. In melanoma, a range of intracellular signalling cascades have been identified as potential drivers of anoikis resistance, however a full understanding of the process is yet to be attained. Mechanisms of anoikis resistance pose an attractive target for the therapeutic treatment of disseminating and circulating melanoma cells. This review explores the range of small molecule, peptide and antibody inhibitors targeting molecules involved in anoikis resistance in melanoma, and may be repurposed to prevent metastatic melanoma prior to its initiation, potentially improving the prognosis for patients.
Brain region dependent molecular signatures and myelin repair following chronic demyelination

Multiple sclerosis (MS) is the most prevalent demyelinating disease of the central nervous system, characterized by myelin destruction, axonal degeneration, and progressive loss of neurological functions. Remyelination is considered an axonal protection strategy and may enable functional recovery, but the mechanisms of myelin repair, especially after chronic demyelination, remain poorly understood. Here, we used the cuprizone demyelination mouse model to investigate spatiotemporal characteristics of acute and chronic de- and remyelination and motor functional recovery following chronic demyelination. Extensive remyelination occurred after both the acute and chronic insults, but with less robust glial responses and slower myelin recovery in the chronic phase. Axonal damage was found at the ultrastructural level in the chronically demyelinated corpus callosum and in remyelinated axons in the somatosensory cortex. Unexpectedly, we observed the development of functional motor deficits after chronic remyelination. RNA sequencing of isolated brain regions revealed significantly altered transcripts across the corpus callosum, cortex and hippocampus. Pathway analysis identified selective upregulation of extracellular matrix/collagen pathways and synaptic signaling in the chronically de/remyelinating white matter. Our study demonstrates regional differences of intrinsic reparative mechanisms after a chronic demyelinating insult and suggests a potential link between long-term motor function alterations and continued axonal damage during chronic remyelination. Moreover, the transcriptome dataset of three brain regions and over an extended de/remyelination period provides a valuable platform for a better understanding of the mechanisms of myelin repair as well as the identification of potential targets for effective remyelination and neuroprotection for progressive MS.
Amomum subulatum: A treasure trove of anti-cancer compounds targeting TP53 protein using in vitro and in silico techniques

Cancer is a primary global health concern, and researchers seek innovative approaches to combat the disease. Clinical bioinformatics and high-throughput proteomics technologies provide powerful tools to explore cancer biology. Medicinal plants are considered effective therapeutic agents, and computer-aided drug design (CAAD) is used to identify novel drug candidates from plant extracts. The tumour suppressor protein TP53 is an attractive target for drug development, given its crucial role in cancer pathogenesis. This study used a dried extract of Amomum subulatum seeds to identify phytocompounds targeting TP53 in cancer. We apply qualitative tests to determine its phytochemicals (Alkaloid, Tannin, Saponin, Phlobatinin, and Cardic glycoside), and found that alkaloid composed of 9.4% ± 0.04% and Saponin 1.9% ± 0.05% crude chemical constituent. In the results of DPPH Analysis Amomum subulatum Seeds founded antioxidant activity, and then we verified via observing methanol extract (79.82%), BHT (81.73%), and n-hexane extract (51.31%) found to be positive. For Inhibition of oxidation, we observe BHT is 90.25%, and Methanol (83.42%) has the most significant proportion of linoleic acid oxidation suppression. We used diverse bioinformatics approaches to evaluate the effect of A. subulatum seeds and their natural components on TP53. Compound-1 had the best pharmacophore match value (53.92), with others ranging from 50.75 to 53.92. Our docking result shows the top three natural compounds had the highest binding energies (−11.10 to −10.3 kcal/mol). The highest binding energies (−10.9 to −9.2 kcal/mol) compound bonded to significant sections in the target protein’s active domains with TP53. Based on virtual screening, we select top phytocompounds for targets which highly fit based on pharmacophore score and observe these compounds exhibited potent antioxidant activity and inhibited cancer cell inflammation in the TP53 pathway. Molecular Dynamics (MD) simulations indicated that the ligand was bound to the protein with some significant conformational changes in the protein structure. This study provides novel insights into the development of innovative drugs for the treatment of cancer disorders.
Natural compounds ursolic acid and digoxin exhibit inhibitory activities to cancer cells in RORγ-dependent and -independent manner

Natural compounds ursolic acid (UA) and digoxin isolated from fruits and other plants display potent anti-cancer effects in preclinical studies. UA and digoxin have been at clinical trials for treatment of different cancers including prostate cancer, pancreatic cancer and breast cancer. However, they displayed limited benefit to patients. Currently, a poor understanding of their direct targets and mechanisms of action (MOA) severely hinders their further development. We previously identified nuclear receptor RORγ as a novel therapeutic target for castration-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC) and demonstrated that tumor cell RORγ directly activates gene programs such as androgen receptor (AR) signaling and cholesterol metabolism. Previous studies also demonstrated that UA and digoxin are potential RORγt antagonists in modulating the functions of immune cells such as Th17 cells. Here we showed that UA displays a strong activity in inhibition of RORγ-dependent transactivation function in cancer cells, while digoxin exhibits no effect at clinically relevant concentrations. In prostate cancer cells, UA downregulates RORγ-stimulated AR expression and AR signaling, whereas digoxin upregulates AR signaling pathway. In TNBC cells, UA but not digoxin alters RORγ-controlled gene programs of cell proliferation, apoptosis and cholesterol biosynthesis. Together, our study reveals for the first-time that UA, but not digoxin, acts as a natural antagonist of RORγ in the cancer cells. Our finding that RORγ is a direct target of UA in cancer cells will help select patients with tumors that likely respond to UA treatment.
Beta band oscillations in the motor thalamus are modulated by visuomotor coordination in essential tremor patients

Introduction Beta oscillations in sensorimotor structures contribute to the planning, sequencing, and stopping of movements, functions that are typically associated with the role of the basal ganglia. The presence of beta oscillations (13–30 Hz) in the cerebellar zone of the thalamus (the ventral intermediate nucleus – Vim) indicates that this rhythm may also be involved in cerebellar functions such as motor learning and visuomotor adaptation. Methods To investigate the possible role of Vim beta oscillations in visuomotor coordination, we recorded local field potential (LFP) and multiunit activity from the Vim of essential tremor (ET) patients during neurosurgery for the implantation of deep brain stimulation (DBS) electrodes. Using a computer, patients performed a visuomotor adaptation task that required coordinating center-out movements with incongruent visual feedback imposed by inversion of the computer display. Results The results show that, in ET, Vim beta oscillations of the LFP were lower during the incongruent center-out task than during the congruent orientation. Vim firing rates increased significantly during periods of low beta power, particularly on approach to the peripheral target. In contrast, beta power in the subthalamic nucleus of Parkinson’s disease (PD) patients did not differ significantly between the incongruent and the congruent orientation of the center-out task. Discussion The findings support the hypothesis that beta oscillations of the Vim are modulated by novel visuomotor tasks. The inverse relationship between the power of Vim-LFP beta oscillations and Vim firing rates suggest that the suppression of beta oscillations may facilitate information throughput to the thalamocortical circuit by modulation of Vim firing rates.
Gamma irradiation-induced genetic variability and its effects on the phenotypic and agronomic traits of groundnut (Arachis hypogaeaL.)

In order to increase genetic variability for the improvement of groundnut, two varieties, namely Kp29 and Fleur11, were treated with six different gamma irradiation doses. A significant effect of mutagenesis was distinctly observed in the stem lengths, roots, and survival percentage in both varieties. The radio-sensitivity test showed a mean lethal dose of 436.51Gy for Kp29 and 501.18 Gy for Fleur11. Furthermore, this study revealed putative mutants with variable agro-morphological traits. Seven chlorophyll mutants and various seed shape and color mutants were obtained. This study demonstrates the potency of gamma irradiation to induce high genetic variability that led to the emergence of certain mutations of economic importance.
Pro- and eukaryotic keystone taxa as potential bio-indicators for the water quality of subtropical Lake Dongqian

The microbial community plays an important role in the biogeochemical cycles in water aquatic ecosystems, and it is regulated by environmental variables. However, the relationships between microbial keystone taxa and water variables, which play a pivotal role in aquatic ecosystems, has not been clarified in detail. We analyzed the seasonal variation in microbial communities and co-occurrence network in the representative areas taking Lake Dongqian as an example. Both pro- and eukaryotic community compositions were more affected by seasons than by sites, and the prokaryotes were more strongly impacted by seasons than the eukaryotes. Total nitrogen, pH, temperature, chemical oxygen demand, dissolved oxygen and chlorophyll a significantly affected the prokaryotic community, while the eukaryotic community was significantly influenced by total nitrogen, ammonia, pH, temperature and dissolved oxygen. The eukaryotic network was more complex than that of prokaryotes, whereas the number of eukaryotic keystone taxa was less than that of prokaryotes. The prokaryotic keystone taxa belonged mainly to Alphaproteobacteria, Betaproteobacteria, Actinobacteria and Bacteroidetes. It is noteworthy that some of the keystone taxa involved in nitrogen cycling are significantly related to total nitrogen, ammonia, temperature and chlorophyll a, including Polaromonas, Albidiferax, SM1A02 and Leptolyngbya so on. And the eukaryotic keystone taxa were found in Ascomycota, Choanoflagellida and Heterophryidae. The mutualistic pattern between pro- and eukaryotes was more evident than the competitive pattern. Therefore, it suggests that keystone taxa could be as bio-indicators of aquatic ecosystems.
Deep learning-based electroencephalic diagnosis of tinnitus symptom

Tinnitus is a neuropathological phenomenon caused by the recognition of external sound that does not actually exist. Existing diagnostic methods for tinnitus are rather subjective and complicated medical examination procedures. The present study aimed to diagnose tinnitus using deep learning analysis of electroencephalographic (EEG) signals while patients performed auditory cognitive tasks. We found that, during an active oddball task, patients with tinnitus could be identified with an area under the curve of 0.886 through a deep learning model (EEGNet) using EEG signals. Furthermore, using broadband (0.5 to 50 Hz) EEG signals, an analysis of the EEGNet convolutional kernel feature maps revealed that alpha activity might play a crucial role in identifying patients with tinnitus. A subsequent time-frequency analysis of the EEG signals indicated that the tinnitus group had significantly reduced pre-stimulus alpha activity compared with the healthy group. These differences were observed in both the active and passive oddball tasks. Only the target stimuli during the active oddball task yielded significantly higher evoked theta activity in the healthy group compared with the tinnitus group. Our findings suggest that task-relevant EEG features can be considered as a neural signature of tinnitus symptoms and support the feasibility of EEG-based deep-learning approach for the diagnosis of tinnitus.
The association between isometric strength and cognitive function in adults with cerebral palsy

Background The literature supports quantifying the maximum force/tension generated by one’s forearm muscles such as the hand grip strength (HGS) to screen for physical and cognitive frailty in older adults. Thus, we postulate that individuals with cerebral palsy (CP), who are at higher risk for premature aging, could benefit from tools that objectively measure muscle strength as a functional biomarker to detect frailty and cognitive decline. This study assesses the clinical relevancy of the former and quantifies isometric muscle strength to determine its association with cognitive function in adults with CP. Methods Ambulatory adults with CP were identified from a patient registry and were enrolled into this study. Peak rate of force development (RFD) and maximum voluntary isometric contraction of the quadriceps were measured using a commercial isokinetic machine, while HGS was collected with a clinical dynamometer. Dominant and non-dominant side were identified. Standardized cognitive assessments, including the Wechsler Memory and Adult Intelligence Scales IV, Short Test of Mental Status, and the Patient-Reported Outcomes Measurement Information System (PROMIS®) were used to evaluate cognitive function. Results A total of 57 participants (32 females; mean age 24.3 [SD 5.3]; GMFCS levels I–IV) were included in the analysis. Although dominant and non-dominant RFD and HGS measures were associated with cognitive function, non-dominant peak RFD showed the strongest associations with cognitive function. Conclusion RFD capacity may reflect age-related neural and physical health and could be a better health indicator than HGS in the CP population.
Current understanding of genetic associations with delayed hypersensitivity reactions induced by antibiotics and anti-osteoporotic drugs

Drug-induced delayed hypersensitivity reactions (DHRs) is still a clinical and healthcare burden in every country. Increasing reports of DHRs have caught our attention to explore the genetic relationship, especially life-threatening severe cutaneous adverse drug reactions (SCARs), including acute generalized exanthematous pustulosis (AGEP), drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). In recent years, many studies have investigated the immune mechanism and genetic markers of DHRs. Besides, several studies have stated the associations between antibiotics-as well as anti-osteoporotic drugs (AOD)-induced SCARs and specific human leukocyte antigens (HLA) alleles. Strong associations between drugs and HLA alleles such as co-trimoxazole-induced DRESS and HLA-B*13:01 (Odds ratio (OR) = 45), dapsone-DRESS and HLA-B*13:01 (OR = 122.1), vancomycin-DRESS and HLA-A*32:01 (OR = 403), clindamycin-DHRs and HLA-B*15:27 (OR = 55.6), and strontium ranelate (SR)-SJS/TEN and HLA-A*33:03 (OR = 25.97) are listed. We summarized the immune mechanism of SCARs, update the latest knowledge of pharmacogenomics of antibiotics- and AOD-induced SCARs, and indicate the potential clinical use of these genetic markers for SCARs prevention in this mini review article.
High occurrence of hepatitis E virus in raw pork liver and pork liver pâté produced in the Canadian province of Quebec

The Hepatitis E virus is widespread throughout the world and causes sporadic cases of liver disease. In industrialized countries, its transmission is zoonotic, with pigs, deer, and wild boar being major reservoirs. Humans can be infected by ingesting raw or undercooked contaminated meat products. In the Canadian province of Quebec, HEV has been detected previously in pork liver and chops. In the present study, we analyzed 83 pork liver pâtés sold in local grocery stores and 79 raw pork livers obtained from Quebec hog processors. HEV RNA was extracted and detected by RT-qPCR. HEV RNA was amplified in 29% of the pâtés and 4% of the raw pork livers. Out of all amplified PCR-positive samples, only one showed a product during electrophoresis and was sent for sequencing. The resulting sequence matched a strain belonging to genotype 3 (HEV-3). This pilot study shows that HEV is present frequently in pork liver-based products in the province of Quebec.
Functional characterization of two 3-dehydroquinases of AroQ1 and AroQ2 in the shikimate pathway and expression of genes for the type III secretion system in Ralstonia solanacearum

The shikimate pathway is a general route for the biosynthesis of aromatic amino acids (AAAs) in many microorganisms. A 3-dehydroquinase, AroQ, controls the third step of the shikimate pathway that catalyzes the formation of 3-dehydroquinate from 3-dehydroshikimate via a trans-dehydration reaction. Ralstonia solanacearum harbors two 3-dehydroquinases, AroQ1 and AroQ2, sharing 52% similarity in amino acids. Here, we demonstrated that two 3-dehydroquinases, AroQ1 and AroQ2, are essential for the shikimate pathway in R. solanacearum. The growth of R. solanacearum was completely diminished in a nutriment-limited medium with the deletion of both aroQ1 and aroQ2, while substantially impaired in planta. The aroQ1/2 double mutant was able to replicate in planta but grew slowly, which was ~4 orders of magnitude less than the parent strain to proliferate to the maximum cell densities in tomato xylem vessels. Moreover, the aroQ1/2 double mutant failed to cause disease in tomato and tobacco plants, whereas the deletion of either aroQ1 or aroQ2 did not alter the growth of R. solanacearum or pathogenicity on host plants. Supplementary shikimic acid (SA), an important intermediate of the shikimate pathway, substantially restored the diminished or impaired growth of aroQ1/2 double mutant in a limited medium or inside host plants. The necessity of AroQ1 and AroQ2 on the pathogenicity of solanacearum toward host plants was partially due to insufficient SA inside host plants. Moreover, the deletion of both aroQ1 and aroQ2 significantly impaired the expression of genes for the type III secretion system (T3SS) both in vitro and in planta. Its involvement in the T3SS was mediated through the well-characterized PrhA signaling cascade and was independent of growth deficiency under nutrient-limited conditions. Taken together, R. solanacearum 3-dehydroquinases play important roles in bacterial growth, the expression of the T3SS, and pathogenicity in host plants. These results could extend our insights into the understanding of the biological function of AroQ and the sophisticated regulation of the T3SS in R. solanacearum.
Impact of sleep disorders on behavioral issues in preschoolers with autism spectrum disorder

Background Sleep disorders are one of the most common problems in children with Autism Spectrum Disorder (ASD). However, they often tend to be underdiagnosed and incorrectly treated in clinical practice. This study aims to identify sleep disorders in preschool children with ASD and to explore their relationship with the core symptoms of autism, the child’s developmental and cognitive level as well as the psychiatric comorbidities. Methods We recruited 163 preschool children with a diagnosis of ASD. The Children’s Sleep Habits Questionnaire (CSHQ) assessed sleep conditions. Multiple standardized tests were used to evaluate intellectual abilities, the presence of repetitive behaviors (through the Repetitive Behavior Scale-Revised), as well as the emotional-behavioral problems and the psychiatric comorbidities (through the Child Behavior Checklist -CBCL 11/2-5). Results The results showed that poor disorders had consistently higher scores in all areas assessed by the CSHQ and on the CBCL across all domains. The correlational analysis showed that severe sleep disorders were associated with higher scores in internalizing, externalizing, and total problems at the CBCL syndromic scales, and in all DSM-oriented CBCL subscales. Moreover, we found that the association between sleep disorders and restricted and repetitive behaviors (RRBs) is explained by the anxiety-related symptoms. Conclusion Based on these findings, the study recommends that screening for sleep problems followed by early intervention should constitute a routine part of clinical practice for children with ASD.