Miracle-dz/UniFAR-FTUs huggingface dataset:
Modulating the Mechanical Activation of TRPV4 at the Cell-Substrate Interface

Ion channels activated by mechanical inputs are important force sensing molecules in a wide array of mammalian cells and tissues. The transient receptor potential channel, TRPV4, is a polymodal, nonselective cation channel that can be activated by mechanical inputs but only if stimuli are applied directly at the interface between cells and their substrate, making this molecule a context-dependent force sensor. However, it remains unclear how TRPV4 is activated by mechanical inputs at the cell-substrate interface, which cell intrinsic and cell extrinsic parameters might modulate the mechanical activation of the channel and how mechanical activation differs from TRPV4 gating in response to other stimuli. Here we investigated the impact of substrate mechanics and cytoskeletal components on mechanically evoked TRPV4 currents and addressed how point mutations associated with TRPV4 phosphorylation and arthropathy influence mechanical activation of the channel. Our findings reveal distinct regulatory modulation of TRPV4 from the mechanically activated ion channel PIEZO1, suggesting the mechanosensitivity of these two channels is tuned in response to different parameters. Moreover, our data demonstrate that the effect of point mutations in TRPV4 on channel activation are profoundly dependent on the gating stimulus.
Population Pharmacokinetics and Dose Optimization of Ganciclovir in Critically Ill Children

Objective: The present study aims to establish a population pharmacokinetic model of ganciclovir and optimize the dosing regimen in critically ill children suffering from cytomegalovirus related disease. Methods: A total of 104 children were included in the study. The population pharmacokinetic model was developed using the Phoenix NLME program. The final model was validated by diagnostic plots, nonparametric bootstrap, visual predictive check, and normalized prediction distribution errors. To further evaluate and optimize the dosing regimens, Monte Carlo simulations were performed. Moreover, the possible association between systemic exposure and hematological toxicity were also monitored in the assessment of adverse events. Results: The ganciclovir pharmacokinetics could be adequately described by a one-compartment model with first-order elimination along with body weight and estimated glomerular filtration rate as significant covariates. As showed in this study, the typical population parameter estimates of apparent volume of distribution and apparent clearance were 11.35 L and 5.23 L/h, respectively. Simulations indicated that the current regimen at a dosage of 10 mg/kg/d would result in subtherapeutic exposure, and elevated doses might be required to reach the target ganciclovir level. No significant association between neutropenia, the most frequent toxicity reported in our study (19.23%), and ganciclovir exposure was observed. Conclusion: A population pharmacokinetic model of intravenous ganciclovir for critically ill children with cytomegalovirus infection was successfully developed. Results showed that underdosing of ganciclovir was relatively common in critically ill pediatric patients, and model-based approaches should be applied in the optimizing of empiric dosing regimens.
A Look Into the Power of fNIRS Signals by Using the Welch Power Spectral Estimate for Deception Detection

Neuroimaging technologies have improved our understanding of deception and also exhibit their potential in revealing the origins of its neural mechanism. In this study, a quantitative power analysis method that uses the Welch power spectrum estimation of functional near-infrared spectroscopy (fNIRS) signals was proposed to examine the brain activation difference between the spontaneous deceptive behavior and controlled behavior. The power value produced by the model was applied to quantify the activity energy of brain regions, which can serve as a neuromarker for deception detection. Interestingly, the power analysis results generated from the Welch spectrum estimation method demonstrated that the spontaneous deceptive behavior elicited significantly higher power than that from the controlled behavior in the prefrontal cortex. Meanwhile, the power findings also showed significant difference between the spontaneous deceptive behavior and controlled behavior, indicating that the reward system was only involved in the deception. The proposed power analysis method for processing fNIRS data provides us an additional insight to understand the cognitive mechanism of deception.
SNP-Density Crossover Maps of Polymorphic Transposable Elements and HLA Genes Within MHC Class I Haplotype Blocks and Junction

The genomic region (~4 Mb) of the human major histocompatibility complex (MHC) on chromosome 6p21 is a prime model for the study and understanding of conserved polymorphic sequences (CPSs) and structural diversity of ancestral haplotypes (AHs)/conserved extended haplotypes (CEHs). The aim of this study was to use a set of 95 MHC genomic sequences downloaded from a publicly available BioProject database at NCBI to identify and characterise polymorphic human leukocyte antigen (HLA) class I genes and pseudogenes, MICA and MICB, and retroelement indels as haplotypic lineage markers, and single-nucleotide polymorphism (SNP) crossover loci in DNA sequence alignments of different haplotypes across the Olfactory Receptor (OR) gene region (~1.2 Mb) and the MHC class I region (~1.8 Mb) from the GPX5 to the MICB gene. Our comparative sequence analyses confirmed the identity of 12 haplotypic retroelement markers and revealed that they partitioned the HLA-A/B/C haplotypes into distinct evolutionary lineages. Crossovers between SNP-poor and SNP-rich regions defined the sequence range of haplotype blocks, and many of these crossover junctions occurred within particular transposable elements, lncRNA, OR12D2, MUC21, MUC22, PSORS1A3, HLA-C, HLA-B, and MICA. In a comparison of more than 250 paired sequence alignments, at least 38 SNP-density crossover sites were mapped across various regions from GPX5 to MICB. In a homology comparison of 16 different haplotypes, seven CEH/AH (7.1, 8.1, 18.2, 51.x, 57.1, 62.x, and 62.1) had no detectable SNP-density crossover junctions and were SNP poor across the entire ~2.8 Mb of sequence alignments. Of the analyses between different recombinant haplotypes, more than half of them had SNP crossovers within 10 kb of LTR16B/ERV3-16A3_I, MLT1, Charlie, and/or THE1 sequences and were in close vicinity to structurally polymorphic Alu and SVA insertion sites. These studies demonstrate that (1) SNP-density crossovers are associated with putative ancestral recombination sites that are widely spread across the MHC class I genomic region from at least the telomeric OR12D2 gene to the centromeric MICB gene and (2) the genomic sequences of MHC homozygous cell lines are useful for analysing haplotype blocks, ancestral haplotypic landscapes and markers, CPSs, and SNP-density crossover junctions.
The Impact of COVID-19 Quarantine on Patients With Dementia and Family Caregivers: A Nation-Wide Survey

Introduction Previous studies showed that quarantine for pandemic diseases is associated with several psychological and medical effects. The consequences of quarantine for COVID-19 pandemic in patients with dementia are unknown. We investigated the clinical changes in patients with Alzheimer’s disease and other dementias, and evaluated caregivers’ distress during COVID-19 quarantine. Methods The study involved 87 Italian Dementia Centers. Patients with Alzheimer’s Disease (AD), Dementia with Lewy Bodies (DLB), Frontotemporal Dementia (FTD), and Vascular Dementia (VD) were eligible for the study. Family caregivers of patients with dementia were interviewed by phone in April 2020, 45 days after quarantine declaration. Main outcomes were patients’ changes in cognitive, behavioral, and motor symptoms. Secondary outcomes were effects on caregivers’ psychological features. Results 4913 patients (2934 females, 1979 males) fulfilled the inclusion criteria. Caregivers reported a worsening in cognitive functions in 55.1% of patients, mainly in subjects with DLB and AD. Aggravation of behavioral symptoms was observed in 51.9% of patients. In logistic regression analysis, previous physical independence was associated with both cognitive and behavioral worsening (odds ratio 1.85 [95% CI 1.42–2.39], 1.84 [95% CI 1.43–2.38], respectively). On the contrary, pandemic awareness was a protective factor for the worsening of cognitive and behavioral symptoms (odds ratio 0.74 [95% CI 0.65–0.85]; and 0.72 [95% CI 0.63–0.82], respectively). Approximately 25.9% of patients showed the onset of new behavioral symptoms. A worsening in motor function was reported by 36.7% of patients. Finally, caregivers reported a high increase in anxiety, depression, and distress. Conclusion Our study shows that quarantine for COVID-19 is associated with an acute worsening of clinical symptoms in patients with dementia as well as increase of caregivers’ burden. Our findings emphasize the importance to implement new strategies to mitigate the effects of quarantine in patients with dementia.
Shift and Metabolic Potentials of Microbial Eukaryotic Communities Across the Full Depths of the Mariana Trench

Microbial eukaryotes are widespread and play important roles in marine ecosystems. However, their ecological characteristics in the deep sea (>1,000 m), especially hadal trenches, were largely unknown. Here, we investigated the diversity and metabolic potentials of microbial eukaryotes along the whole water column of the Mariana Trench by metagenomics. Our results showed clear depth-related distribution of microbial eukaryotic community and associated metabolic potentials. Surface seawater was dominated by phototrophic/mixotrophic groups (e.g., Dinoflagellata) and genes involved in biosynthesis (photosynthesis and fatty acid biosynthesis), while deep (bathypelagic and/or hadal) seawaters were enriched with heterotrophic groups (e.g., Bicoecea) and genes related to digestion (lysosomal enzymes and V-type ATPase) and carbohydrate metabolism. Co-occurrence analysis revealed high intra-domain connectivity, indicating that microbial eukaryotic composition was more influenced by microbial eukaryotes themselves than bacteria. Increased abundance of genes associated with unsaturated fatty acid biosynthesis likely plays a role in resisting high hydrostatic pressure. Top1 and hupB genes, responsible for the formation and stabilization of DNA structure, were unique and abundant in the hadal zone and thus may be helpful to stabilize DNA structure in the deep sea. Overall, our results provide insights into the distribution and potential adaptability of microbial eukaryotes in the hadal zone.
PfAP2-G2 Is Associated to Production and Maturation of Gametocytes in Plasmodium falciparum via Regulating the Expression of PfMDV-1

Gametocyte is the sole form of the Plasmodium falciparum which is transmissible to the mosquito vector. Here, we report that an Apicomplexan Apetala2 (ApiAP2) family transcription factor, PfAP2-G2 (Pf3D7_1408200), plays a role in the development of gametocytes in P. falciparum by regulating the expression of PfMDV-1 (Pf3D7_1216500). Reverse transcriptase-quantitative PCR (RT-qPCR) analysis showed that PfAP2-G2 was highly expressed in the ring stage. Indirect immunofluorescence assay showed nuclear localization of PfAP2-G2 in asexual stages. The knockout of PfAP2-G2 led to a ~95% decrease in the number of mature gametocytes with a more substantial influence on the production and maturation of the male gametocytes, resulting in a higher female/male gametocyte ratio. To test the mechanism of this phenotype, RNA-seq and RT-qPCR showed that disruption of PfAP2-G2 led to the down-regulation of male development gene-1 (PfMDV-1) in asexual stages. We further found that PfAP2-G2 was enriched at the transcriptional start site (TSS) of PfMDV-1 by chromatin immunoprecipitation and qPCR assay in both ring stage and schizont stage, which demonstrated that PfMDV-1 is one of the targets of PfAP2-G2. In addition, RT-qPCR also showed that PfAP2-G (Pf3D7_1222600), the master regulator for sexual commitment, was also down-regulated in the PfAP2-G2 knockout parasites in the schizont stage, but no change in the ring stage. This phenomenon suggested that PfAP2-G2 played a role at the asexual stage for the development of parasite gametocytes and warrants further investigations in regulatory pathways of PfAP2-G2.
The BpMYB4 Transcription Factor From Betula platyphylla Contributes Toward Abiotic Stress Resistance and Secondary Cell Wall Biosynthesis

The MYB (v-myb avian myeloblastosis viral oncogene homolog) family is one of the largest transcription factor families in plants, and is widely involved in the regulation of plant metabolism. In this study, we show that a MYB4 transcription factor, BpMYB4, identified from birch (Betula platyphylla Suk.) and homologous to EgMYB1 from Eucalyptus robusta Smith and ZmMYB31 from Zea mays L. is involved in secondary cell wall synthesis. The expression level of BpMYB4 was higher in flowers relative to other tissues, and was induced by artificial bending and gravitational stimuli in developing xylem tissues. The expression of this gene was not enriched in the developing xylem during the active season, and showed higher transcript levels in xylem tissues around sprouting and near the dormant period. BpMYB4 also was induced express by abiotic stress. Functional analysis indicated that expression of BpMYB4 in transgenic Arabidopsis (Arabidopsis thaliana) plants could promote the growth of stems, and result in increased number of inflorescence stems and shoots. Anatomical observation of stem sections showed lower lignin deposition, and a chemical contents test also demonstrated increased cellulose and decreased lignin content in the transgenic plants. In addition, treatment with 100 mM NaCl and 200 mM mannitol resulted in the germination rate of the over-expressed lines being higher than that of the wild-type seeds. The proline content in transgenic plants was higher than that in WT, but MDA content was lower than that in WT. Further investigation in birch using transient transformation techniques indicated that overexpression of BpMYB4 could scavenge hydrogen peroxide and O2. – and reduce cell damage, compared with the wild-type plants. Therefore, we believe that BpMYB4 promotes stem development and cellulose biosynthesis as an inhibitor of lignin biosynthesis, and has a function in abiotic stress resistance.
Synthesis and characterization of poly(m-aminophenol)-succinat

Poly(m-aminophenol) (PMAP) and poly(m-aminophenol)-succinat compound (PMAP-Suc) containing ester bridge were synthesized in this study. PMAP were synthesized by chemical oxidative polymerization of m-aminophenol (MAP) in HCl medium with ammonium peroxydisulphate (APS) as an initiator at different temperatures. The optimum polymerization conditions (temperature: 25 °C, reaction time: 4 h, normalized MAP/APS ratio, k: 0.625 and mol of MAP/mol of APS, r: 0.5) of PMAP were determined. PMAP was esterified in N-methyl pyrrolidone by using solution of succinic acid as cross-linking agent and concentrated sulphuric acid as catalyst under appropriate ambient conditions. The general scheme of esterification and cross-linking reaction for PMAP is proposed. These reactions were also evidenced by spectroscopic, thermal and surface morphology as well as structural characteristics relationship of macromolecules. The structures of PMAP and PMAP-Suc were characterized by solubility test, FTIR, 1H NMR and 13C NMR, UV–vis spectroscopy, thermal (TGA-DTA) and SEM analyses.
Characteristics of the Optimal Cognitive Behavioral Analysis System of Psychotherapy (CBASP) Therapist Role

The characteristics of the optimal CBASP therapist role for the treatment of the Persistent Depressive Disorder patient (chronic depression) is delineated in this paper. This paper contains the opinions and experiences of the creator of CBASP who has developed and revised the model over more than 4 decades. The paper is not a rigorous study nor a review of rigorous studies. The difficulties of the patient are briefly discussed and then the characteristics of the optimal clinical role are presented. The clinical role of CBASP, the only model to have been developed specifically to treat the chronically depressive patient, is unique in the field of psychotherapy. Four role categories describing the behavior of the best therapists are presented and discussed: (1) the therapist is able to enact a Disciplined Personal Involvement clinical role with the patient; (2) the therapist is able to implement an acquisition-learning approach to therapeutic administration; (3) the practitioner is able to adhere to the standards of CBASP technique administration; and finally, (4) the clinician is able to implement several facilitative interpersonal skills.
Integrating Somatic Mutations for Breast Cancer Survival Prediction Using Machine Learning Methods

Breast cancer is the most common malignancy in women, and because it has a high mortality rate, it is urgent to develop computational methods to increase the accuracy of breast cancer survival predictive models. Although multi-omics data such as gene expression have been extensively used in recent studies, the accurate prognosis of breast cancer remains a challenge. Somatic mutations are another important and promising data source for studying cancer development, and its effect on the prognosis of breast cancer remains to be further explored. Meanwhile, these omics datasets are high-dimensional and redundant. Therefore, we adopted multiple kernel learning (MKL) to efficiently integrate somatic mutation to currently molecular data including gene expression, copy number variation (CNV), methylation, and protein expression data for the prediction of breast cancer survival. Before integration, the maximum relevance minimum redundancy (mRMR) feature selection method was utilized to select features that present high relevance to survival and low redundancy among themselves for each type of data. The experimental results demonstrated that the proposed method achieved the most optimal performance and there was a remarkable improvement in the prediction performance when somatic mutations were included, indicating that somatic mutations are critical for improving breast cancer survival predictions. Moreover, mRMR was superior to other feature selection methods used in previous studies. Furthermore, MKL outperformed the other traditional classifiers in multi-omics data integration. Our analysis indicated that through employing promising omics data such as somatic mutations and harnessing the power of proper feature selection methods and effective integration frameworks, the breast cancer survival predictive accuracy can be further increased, thereby providing a more optimal clinical diagnosis and more effective treatment for breast cancer patients.
A Physical Perspective to the Inductive Function of Myelin—A Missing Piece of Neuroscience

Starting from the inductance in neurons, two physical origins are discussed, which are the coil inductance of myelin and the piezoelectric effect of the cell membrane. The direct evidence of the coil inductance of myelin is the opposite spiraling phenomenon between adjacent myelin sheaths confirmed by previous studies. As for the piezoelectric effect of the cell membrane, which has been well-known in physics, the direct evidence is the mechanical wave accompany with action potential. Therefore, a more complete physical nature of neural signals is provided. In conventional neuroscience, the neural signal is a pure electrical signal. In our new theory, the neural signal is an energy pulse containing electrical, magnetic, and mechanical components. Such a physical understanding of the neural signal and neural systems significantly improve the knowledge of the neurons. On the one hand, we achieve a corrected neural circuit of an inductor-capacitor-capacitor (LCC) form, whose frequency response and electrical characteristics have been validated by previous studies and the modeling fitting of artifacts in our experiments. On the other hand, a number of phenomena observed in neural experiments are explained. In particular, they are the mechanism of magnetic nerve stimulations and ultrasound nerve stimulations, the MRI image contrast issue and Anode Break Excitation. At last, the biological function of myelin is summarized. It is to provide inductance in the process of neural signal, which can enhance the signal speed in peripheral nervous systems and provide frequency modulation function in central nervous systems.
Chinese Medicine Formula PSORI-CM02 Alleviates Psoriatic Dermatitis via M-MDSCs and Th17 Crosstalk

Psoriasis is a chronic inflammatory skin disease that is associated with multiple coexisting conditions. Extensive literature suggests that psoriasis is a T-cell-mediated condition, and its pathogenesis is related to dysfunction of the immune system. Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous myeloid cells that have suppressive effects on T cells. MDSCs are present at very low levels in healthy individuals but can substantially expand in tumours or inflammatory conditions. PSORI-CM02, a Chinese medical formula designed based on the Chinese medicine theory (Blood Stasis), has been prescribed extensively for psoriasis therapy and shows a stable clinical effect and safety. This study discusses the mechanisms of MDSCs involved in disease development and therapeutic progress. Our data provides evidence that monocytic myeloid-derived suppressor cells (M-MDSCs) play a role in IMQ-induced psoriatic dermatitis. Functional characterization and correlation analysis indicated that MDSCs are positively correlated with Th17 cells. PSORI-CM02 alleviated IMQ-induced psoriatic dermatitis and suppressed the proliferation of Th17 cells via M-MDSC-induced Arg1 upregulation, suggesting M-MDSCs could be a novel therapeutic target for psoriasis, and PSORI-CM02 exerted its effects via the perturbation of M-MDSCs and Th17 cell crosstalk.
Transdermal Estrogen Therapy Improves Gains in Skeletal Muscle Mass After 12 Weeks of Resistance Training in Early Postmenopausal Women

Context Women show an accelerated loss of muscle mass around menopause, possibly related to the decline in estrogen. Furthermore, the anabolic response to resistance exercise seems to be hampered in postmenopausal women. Objective We aimed to test the hypothesis that transdermal estrogen therapy (ET) amplifies the skeletal muscle response to resistance training in early postmenopausal women. Design A double-blinded randomized controlled study. Setting Department of Public Health, Aarhus University, Denmark. Participants Thirty-one healthy, untrained postmenopausal women no more than 5 years past menopause. Intervention(s) Supervised resistance training with placebo (PLC, n = 16) or transdermal ET (n = 15) for 12 weeks. Main Outcome Measure(s) The primary outcome parameter was a cross-sectional area of quadriceps femoris measured by magnetic resonance imaging, and secondary parameters were fat-free mass (dual-energy X-ray absorptiometry), muscle strength, and functional tests. Results The increase in muscle cross-sectional area was significantly greater in the ET group (7.9%) compared with the PLC group (3.9%) (p < 0.05). Similarly, the increase in whole-body fat-free mass was greater in the ET group (5.5%) than in the PLC group (2.9%) (p < 0.05). Handgrip strength increased in ET (p < 0.05) but did not change in the PLC group. Muscle strength parameters, jumping height, and finger strength were all improved after the training period with no difference between groups. Conclusion The use of transdermal ET enhanced the increase in muscle mass in response to 12 weeks of progressive resistance training in early postmenopausal women.