Miracle-dz/UniFAR-FTUs huggingface dataset:
Altered flexor carpi radialis motor axon excitability properties after cerebrovascular stroke

Background Spinal motoneurons may become hyperexcitable after a stroke. Knowledge about motoneuron hyperexcitability remains clinically important as it may contribute to a number of phenomena including spasticity, flexion synergies, and abnormal limb postures. Hyperexcitability seems to occur more often in muscles that flex the wrist and fingers (forearm flexors) compared to other upper limb muscles. The cause of hyperexcitability remains uncertain but may involve plastic changes in motoneurons and their axons. Aim To characterize intrinsic membrane properties of flexor carpi radialis (FCR) motor axons after stroke using nerve excitability testing. Methods Nerve excitability testing using threshold tracking techniques was applied to characterize FCR motor axon properties in persons who suffered a first-time unilateral cortical/subcortical stroke 23 to 308 days earlier. The median nerve was stimulated at the elbow bilaterally in 16 male stroke subjects (51.4 ± 2.9 y) with compound muscle action potentials recorded from the FCR. Nineteen age-matched males (52.7 ± 2.4 y) were also tested to serve as controls. Results Axon parameters after stroke were consistent with bilateral hyperpolarization of the resting potential. Nonparetic and paretic side axons were modeled by a 2.6-fold increase in pump currents (IPumpNI) together with an increase (38%–33%) in internodal leak conductance (GLkI) and a decrease (23%–29%) in internodal H conductance (Ih) relative to control axons. A decrease (14%) in Na+ channel inactivation rate (Aah) was also needed to fit the paretic axon recovery cycle. “Fanning out” of threshold electrotonus and the resting I/V slope (stroke limbs combined) correlated with blood potassium [K+] (R = −0.61 to 0.62, p< 0.01) and disability (R = −0.58 to 0.55, p < 0.05), but not with spasticity, grip strength, or maximal FCR activity. Conclusion In contrast to our expectations, FCR axons were not hyperexcitable after stroke. Rather, FCR axons were found to be hyperpolarized bilaterally post stroke, and this was associated with disability and [K+]. Reduced FCR axon excitability may represent a kind of bilateral trans-synaptic homeostatic mechanism that acts to minimize motoneuron hyperexcitability.
The potential of sodium carbonate and Tiron extractions for the determination of silicon contents in plant samples—A method comparison using hydrofluoric acid digestion as reference

For the determination of silicon (Si) contents in plant materials several methods are in use, but as all of these methods exhibit specific advantages and drawbacks, none of them has become prevalent. Alkaline chemicals are widely used to extract Si from plant samples, because this method is comparably simple, fast, and cheap. However, a comprehensive method comparison between different alkaline extractions to different plant organs is still missing, as well as understanding of the relationship between Si content quantified with those methods and soil silicon availability. In our study we performed two different alkaline (sodium carbonate (Na2CO3) and Tiron) extractions to determine Si contents in husk and straw samples of winter wheat (Triticum aestivum). Results obtained from hydrofluoric (HF) acid digestion were used as reference as this method is assumed to completely dissolve Si in a plant material. We evaluated the efficacy of simple, single-step Na2CO3 and Tiron extractions in relation to complex, multistep HF extractions and analyzed the relationships between Si and phytolith contents in plant samples and plant available Si concentrations in corresponding soil samples. Irrespective of the plant material used (husk or straw) we found Tiron to be more efficient in Si extraction compared to Na2CO3. While Na2CO3 extractions systematically underestimated Si contents in the tested plant materials, the results of Tiron extractions were comparable to the results of HF digestions, at least for husk samples. Phytolith contents in plant samples were strongly positively correlated to Si contents obtained from extractions, especially in husk samples. Plant available Si in soil samples was also reflected best in husk Si contents. Based on our results we recommend the use of Tiron for the extraction of Si from plant materials as this method provided more reliable results compared to the Na2CO3 extraction.
Sex differences in pharmacological interventions and their effects on lifespan and healthspan outcomes: a systematic review

With an increasing aging population, the burden of age-related diseases magnifies. To alleviate this burden, geroprotection has been an area of intense research focus with the development of pharmacological interventions that target lifespan and/or healthspan. However, there are often sex differences, with compounds mostly tested in male animals. Given the importance of considering both sexes in preclinical research, this neglects potential benefits for the female population, as interventions tested in both sexes often show clear sexual dimorphisms in their biological responses. To further understand the prevalence of sex differences in pharmacological geroprotective intervention studies, we performed a systematic review of the literature according to the PRISMA guidelines. Seventy-two studies met our inclusion criteria and were classified into one of five subclasses: FDA-repurposed drugs, novel small molecules, probiotics, traditional Chinese medicine, and antioxidants, vitamins, or other dietary supplements. Interventions were analyzed for their effects on median and maximal lifespan and healthspan markers, including frailty, muscle function and coordination, cognitive function and learning, metabolism, and cancer. With our systematic review, we found that twenty-two out of sixty-four compounds tested were able to prolong both lifespan and healthspan measures. Focusing on the use of female and male mice, and on comparing their outcomes, we found that 40% of studies only used male mice or did not clarify the sex. Notably, of the 36% of pharmacologic interventions that did use both male and female mice, 73% of these studies showed sex-specific outcomes on healthspan and/or lifespan. These data highlight the importance of studying both sexes in the search for geroprotectors, as the biology of aging is not the same in male and female mice. Systematic Review Registration: [website], identifier [registration number].
Alterations in the gut microbiota and serum metabolomics of spontaneous cholestasis caused by loss of FXR signal in mice

Background: Farnesoid X receptor (FXR) is a key metabolic target of bile acids (BAs) and is also a target for drugs against several liver diseases. However, the contribution of FXR in the pathogenesis of cholestasis is still not fully understood. The purpose of this study is to provide a comprehensive insight into the metabolic properties of FXR-involved cholestasis in mice. Materials and methods: In this study, an alpha-naphthylisothiocyanate (ANIT)-induced cholestasis mouse model and FXR−/− mice were established to investigate the effect of FXR on cholestasis. The effect of FXR on liver and ileal pathology was evaluated. Simultaneously, Untargeted metabolomics combined with 16s rRNA gene sequencing analysis was applied to reveal the involvement of FXR in the pathogenesis of cholestasis. Results: The results showed that ANIT (75 mg/kg) induced marked cholestasis in WT and FXR −/− mice. It is noteworthy that FXR−/− mice developed spontaneous cholestasis. Compared with WT mice, significant liver and ileal tissue damage were found. In addition, 16s rRNA gene sequencing analysis revealed gut microbiota dysbiosis in FXR−/− mice and ANIT-induced cholestasis mice. Differential biomarkers associated with the pathogenesis of cholestasis caused by FXR knockout were screened using untargeted metabolomics. Notably, Lactobacillus_ johnsonii_FI9785 has a high correlation with the differential biomarkers associated with the pathogenesis and progression of cholestasis caused by FXR knockout. Conclusion: Our results implied that the disorder of the intestinal flora caused by FXR knockout can also interfere with the metabolism. This study provides novel insights into the FXR-related mechanisms of cholestasis.
Soluble biomarkers to predict clinical outcomes in non-small cell lung cancer treated by immune checkpoints inhibitors

Lung cancer remains the first cause of cancer-related death despite many therapeutic innovations, including immune checkpoint inhibitors (ICI). ICI are now well used in daily practice at late metastatic stages and locally advanced stages after a chemo-radiation. ICI are also emerging in the peri-operative context. However, all patients do not benefit from ICI and even suffer from additional immune side effects. A current challenge remains to identify patients eligible for ICI and benefiting from these drugs. Currently, the prediction of ICI response is only supported by Programmed death-ligand 1 (PD-L1) tumor expression with perfectible results and limitations inherent to tumor-biopsy specimen analysis. Here, we reviewed alternative markers based on liquid biopsy and focused on the most promising biomarkers to modify clinical practice, including non-tumoral blood cell count such as absolute neutrophil counts, platelet to lymphocyte ratio, neutrophil to lymphocyte ratio, and derived neutrophil to lymphocyte ratio. We also discussed soluble-derived immune checkpoint-related products such as sPD-L1, circulating tumor cells (detection, count, and marker expression), and circulating tumor DNA-related products. Finally, we explored perspectives for liquid biopsies in the immune landscape and discussed how they could be implemented into lung cancer management with a potential biological–driven decision.
A single intranasal dose of human mesenchymal stem cell-derived extracellular vesicles after traumatic brain injury eases neurogenesis decline, synapse loss, and BDNF-ERK-CREB signaling

An optimal intranasal (IN) dose of human mesenchymal stem cell-derived extracellular vesicles (hMSC-EVs), 90 min post-traumatic brain injury (TBI), has been reported to prevent the evolution of acute neuroinflammation into chronic neuroinflammation resulting in the alleviation of long-term cognitive and mood impairments. Since hippocampal neurogenesis decline and synapse loss contribute to TBI-induced long-term cognitive and mood dysfunction, this study investigated whether hMSC-EV treatment after TBI can prevent hippocampal neurogenesis decline and synapse loss in the chronic phase of TBI. C57BL6 mice undergoing unilateral controlled cortical impact injury (CCI) received a single IN administration of different doses of EVs or the vehicle at 90 min post-TBI. Quantifying neurogenesis in the subgranular zone-granule cell layer (SGZ-GCL) through 5′-bromodeoxyuridine and neuron-specific nuclear antigen double labeling at ~2 months post-TBI revealed decreased neurogenesis in TBI mice receiving vehicle. However, in TBI mice receiving EVs (12.8 and 25.6 × 109 EVs), the extent of neurogenesis was matched to naive control levels. A similar trend of decreased neurogenesis was seen when doublecortin-positive newly generated neurons were quantified in the SGZ-GCL at ~3 months post-TBI. The above doses of EVs treatment after TBI also reduced the loss of pre-and post-synaptic marker proteins in the hippocampus and the somatosensory cortex. Moreover, at 48 h post-treatment, brain-derived neurotrophic factor (BDNF), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), and phosphorylated cyclic AMP response-element binding protein (p-CREB) levels were downregulated in TBI mice receiving the vehicle but were closer to naïve control levels in TBI mice receiving above doses of hMSC-EVs. Notably, improved BDNF concentration observed in TBI mice receiving hMSC-EVs in the acute phase was sustained in the chronic phase of TBI. Thus, a single IN dose of hMSC-EVs at 90 min post-TBI can ease TBI-induced declines in the BDNF-ERK-CREB signaling, hippocampal neurogenesis, and synapses.
Socs3 expression in myeloid cells modulates the pathogenesis of dextran sulfate sodium (DSS)-induced colitis

Introduction Myeloid cells play a critical role in the pathogenesis of Inflammatory Bowel Diseases (IBDs), including Ulcerative Colitis (UC) and Crohn’s Disease (CD). Dysregulation of the JAK/STAT pathway is associated with many pathological conditions, including IBD. Suppressors Of Cytokine Signaling (SOCS) are a family of proteins that negatively regulate the JAK/STAT pathway. Our previous studies identified that mice lacking Socs3 in myeloid cells developed a hyper-activated phenotype of macrophages and neutrophils in a pre-clinical model of Multiple Sclerosis. Methods To better understand the function of myeloid cell Socs3 in the pathogenesis of colitis, mice with Socs3 deletion in myeloid cells (Socs3 ΔLysM) were utilized in a DSS-induced colitis model. Results Our results indicate that Socs3 deficiency in myeloid cells leads to more severe colitis induced by DSS, which correlates with increased infiltration of monocytes and neutrophils in the colon and increased numbers of monocytes and neutrophils in the spleen. Furthermore, our results demonstrate that the expression of genes related to the pathogenesis and diagnosis of colitis such as Il1β, Lcn2, S100a8 and S100a9 were specifically enhanced in Socs3-deficient neutrophils localized to the colon and spleen. Conversely, there were no observable differences in gene expression in Ly6C+ monocytes. Depletion of neutrophils using a neutralizing antibody to Ly6G significantly improved the disease severity of DSS-induced colitis in Socs3-deficient mice. Discussion Thus, our results suggest that deficiency of Socs3 in myeloid cells exacerbates DSS-induced colitis and that Socs3 prevents overt activation of the immune system in IBD. This study may provide novel therapeutic strategies to IBD patients with hyperactivated neutrophils.
Insights into the epigenetics of chronic rhinosinusitis with and without nasal polyps: a systematic review

Background Epigenetics facilitates insights on the impact of host environment on the genesis of chronic rhinosinusitis (CRS) through modulations of host gene expression and activity. Epigenetic mechanisms such as DNA methylation cause reversible but heritable changes in gene expression over generations of progeny, without altering the DNA base-pair sequences. These studies offer a critical understanding of the environment-induced changes that result in host predisposition to disease and may help in developing novel biomarkers and therapeutics. The goal of this systematic review is to summarize the current evidence on epigenetics of CRS with a focus on chronic rhinosinusitis with nasal polyps (CRSwNP) and highlight gaps that merit further research. Methods A systematic review of the English language literature was performed to identify investigations related to epigenetic studies in subjects with CRS. Results The review identified 65 studies. These have focused on DNA methylation and non-coding RNAs, with only a few on histone deacetylation, alternative polyadenylation, and chromatin accessibility. Studies include those investigating in vivo and in vitro changes or both. Studies also include animal models of CRS. Almost all have been conducted in Asia. The genome-wide studies of DNA methylation found differences in global methylation between CRSwNP and controls, while others specifically found significant differences in methylation of the CpG sites of the thymic stromal lymphopoietin (TSLP), IL-8, and PLAT. In addition, DNA methyltransferase inhibitors and histone deacetylase inhibitors were studied as potential therapeutic agents. Majority of the studies investigating non-coding RNAs focused on micro-RNAs (miRNA) and found differences in global expression of miRNA levels. These studies also revealed some previously known as well as novel targets and pathways such as tumor necrosis factor alpha, TGF beta-1, IL-10, EGR2, aryl hydrocarbon receptor, PI3K/AKT pathway, mucin secretion, and vascular permeability. Overall, the studies have found a dysregulation in pathways/genes involving inflammation, immune regulation, tissue remodeling, structural proteins, mucin secretion, arachidonic acid metabolism, and transcription. Conclusions Epigenetic studies in CRS subjects suggest that there is likely a major impact of the environment. However, these are association studies and do not directly imply pathogenesis. Longitudinal studies in geographically and racially diverse population cohorts are necessary to quantify genetic vs. environmental risks for CRSwNP and CRS without nasal polyps and assess heritability risk, as well as develop novel biomarkers and therapeutic agents.
Machine learning and integrative analysis identify the common pathogenesis of azoospermia complicated with COVID-19

Background Although more recent evidence has indicated COVID-19 is prone to azoospermia, the common molecular mechanism of its occurrence remains to be elucidated. The aim of the present study is to further investigate the mechanism of this complication. Methods To discover the common differentially expressed genes (DEGs) and pathways of azoospermia and COVID-19, integrated weighted co-expression network (WGCNA), multiple machine learning analyses, and single-cell RNA-sequencing (scRNA-seq) were performed. Results Therefore, we screened two key network modules in the obstructive azoospermia (OA) and non-obstructive azoospermia (NOA) samples. The differentially expressed genes were mainly related to the immune system and infectious virus diseases. We then used multiple machine learning methods to detect biomarkers that differentiated OA from NOA. Enrichment analysis showed that azoospermia patients and COVID-19 patients shared a common IL-17 signaling pathway. In addition, GLO1, GPR135, DYNLL2, and EPB41L3 were identified as significant hub genes in these two diseases. Screening of two different molecular subtypes revealed that azoospermia-related genes were associated with clinicopathological characteristics of age, hospital-free-days, ventilator-free-days, charlson score, and d-dimer of patients with COVID-19 (P < 0.05). Finally, we used the Xsum method to predict potential drugs and single-cell sequencing data to further characterize whether azoospermia-related genes could validate the biological patterns of impaired spermatogenesis in cryptozoospermia patients. Conclusion Our study performs a comprehensive and integrated bioinformatics analysis of azoospermia and COVID-19. These hub genes and common pathways may provide new insights for further mechanism research.
Adenoid lymphocyte heterogeneity in pediatric adenoid hypertrophy and obstructive sleep apnea

Introduction Adenoid hypertrophy is the main cause of obstructive sleep apnea in children. Previous studies have suggested that pathogenic infections and local immune system disorders in the adenoids are associated with adenoid hypertrophy. The abnormalities in the number and function of various lymphocyte subsets in the adenoids may play a role in this association. However, changes in the proportion of lymphocyte subsets in hypertrophic adenoids remain unclear. Methods To identify patterns of lymphocyte subsets in hypertrophic adenoids, we used multicolor flow cytometry to analyze the lymphocyte subset composition in two groups of children: the mild to moderate hypertrophy group (n = 10) and the severe hypertrophy group (n = 5). Results A significant increase in naïve lymphocytes and a decrease in effector lymphocytes were found in severe hypertrophic adenoids. Discussion This finding suggests that abnormal lymphocyte differentiation or migration may contribute to the development of adenoid hypertrophy. Our study provides valuable insights and clues into the immunological mechanism underlying adenoid hypertrophy.
Cross-sectional and longitudinal comparison of health-related quality of life and mental well-being between persons with and without post COVID-19 condition

Background Still little is known about the impact of post COVID-19 condition (PC) on health-related quality of life (HRQOL) and mental well-being. We compared participants with PC with three groups: an acute COVID-19 infection (AC) only, at least one chronic condition (CC) but no COVID-19, or no condition at all, healthy (PH). Between these disease groups, we also estimated and compared HRQOL and mental well-being change over time. Methods Participants from six countries (Greece, Italy, Netherlands, Sweden, United Kingdom and United States) completed two web-based questionnaires (T1 = April–May 2020 and T2 = April–June 2022). Primary outcomes were HRQOL, measured by EQ-5D-5L and EQ VAS, and mental well-being (measured by World Health Organisation-Five (WHO-5) Well-Being Index, Patient Health Questionnaire (PHQ)-9 and General Anxiety Disorder (GAD)-7). All analyses were stratified by the disease groups. Results In total, 4,999 participants filled out both surveys: 240 were in PC, 107 in AC, 1798 in CC and 2,854 in PH. At T2, the mean EQ-5D-5L index values for the PC, AC, CC and PH groups were 0.70, 0.73, 0.75 and 0.92 (p < .001), respectively. Mean EQ VAS scores were 66, 65, 68 and 81 (p < .001), respectively. Poor mental well-being, depression and anxiety mean values were highest in the PC group (47.7; 9.1; 7.4), followed by the AC group (51.1; 7.7; 5.7), CC group (56.1; 5.2; 4.2) and the PH group (65.6; 2.8; 2.5), respectively (p < .001 between groups). Over time, HRQOL deteriorated in all groups, apart from the PH group. We observed the largest deterioration in the CC (EQ-5D-5L index: Δ0.03, p < .001) and AC group (EQ VAS: Δ6.3, p < .001). For the mental well-being outcomes, deterioration for WHO-5 and PHQ-9 were largest in the AC group (Δ4.8, p = .016; Δ-1.3, p = .012). Rates for GAD-7 improved for the PH and CC groups (PH: Δ1.27, CC: Δ0.56, p < .001). Conclusions In the cross-sectional analysis, participants with PC had the worst HRQOL and mental well-being compared to the other groups. In terms of change since the start of the COVID-19 pandemic, HRQOL and mental well-being deterioration was highest among AC participants and had a lower impact among PC participants, most likely due to pre-existing chronic disease.