Weyl spin-momentum locking in a chiral topological semimetal.

Spin-orbit coupling in noncentrosymmetric crystals leads to spin-momentum locking - a directional relationship between an electron's spin angular momentum and its linear momentum. Isotropic orthogonal Rashba spin-momentum locking has been studied for decades, while its counterpart, isotropic parallel Weyl spin-momentum locking has remained elusive in experiments. Theory predicts that Weyl spin-momentum locking can only be realized in structurally chiral cubic crystals in the vicinity of Kramers-Weyl or multifold fermions. Here, we use spin- and angle-resolved photoemission spectroscopy to evidence Weyl spin-momentum locking of multifold fermions in the chiral topological semimetal PtGa. We find that the electron spin of the Fermi arc surface states is orthogonal to their Fermi surface contour for momenta close to the projection of the bulk multifold fermion at the Γ point, which is consistent with Weyl spin-momentum locking of the latter. The direct measurement of the bulk spin texture of the multifold fermion at the R point also displays Weyl spin-momentum locking. The discovery of Weyl spin-momentum locking may lead to energy-efficient memory devices and Josephson diodes based on chiral topological semimetals.

Core planar cell polarity genes VANGL1 and VANGL2 in predisposition to congenital vertebral malformations.

Congenital scoliosis (CS), affecting approximately 0.5 to 1 in 1,000 live births, is commonly caused by congenital vertebral malformations (CVMs) arising from aberrant somitogenesis or somite differentiation. While Wnt/ß-catenin signaling has been implicated in somite development, the function of Wnt/planar cell polarity (Wnt/PCP) signaling in this process remains unclear. Here, we investigated the role of Vangl1 and Vangl2 in vertebral development and found that their deletion causes vertebral anomalies resembling human CVMs. Analysis of exome sequencing data from multiethnic CS patients revealed a number of rare and deleterious variants in VANGL1 and VANGL2, many of which exhibited loss-of-function and dominant-negative effects. Zebrafish models confirmed the pathogenicity of these variants. Furthermore, we found that Vangl1 knock-in (p.R258H) mice exhibited vertebral malformations in a Vangl gene dose- and environment-dependent manner. Our findings highlight critical roles for PCP signaling in vertebral development and predisposition to CVMs in CS patients, providing insights into the molecular mechanisms underlying this disorder.

Measuring, visualizing, and diagnosing reference bias with biastools.

Many bioinformatics methods seek to reduce reference bias, but no methods exist to comprehensively measure it. Biastools analyzes and categorizes instances of reference bias. It works in various scenarios: when the donor's variants are known and reads are simulated; when donor variants are known and reads are real; and when variants are unknown and reads are real. Using biastools, we observe that more inclusive graph genomes result in fewer biased sites. We find that end-to-end alignment reduces bias at indels relative to local aligners. Finally, we use biastools to characterize how T2T references improve large-scale bias.

Prognostic value of left ventricular and left atrial strain imaging in moderate to severe aortic stenosis: Insights from an Asian population.

BACKGROUND: Data regarding the prognostic value of left atrial (LA) strain in aortic stenosis (AS) is scarce, especially in Asian population and moderate AS. METHOD: Left ventricular global longitudinal strain (LVGLS), LA reservoir strain (LASr), conduit strain (LAScd), and contractile strain (LASct) were measured using automated speckle-tracking echocardiography in consecutive patients with moderate or severe AS. The primary endpoint was a composite of all-cause death (ACD) and major adverse cardiovascular events (MACE; myocardial infarction, syncope, and heart failure hospitalization). RESULTS: Of 712 patients (mean age, 78 ± 12 years; 370 [52%] moderate AS; 342 [48%] severe AS), average LV ejection fraction (LVEF) was 68 with SD of 12%. At a median follow-up of 18 months (interquartile range, 11-26 months), the primary endpoint occurred in 93 patients (60 deaths and 35 MACEs) and 221 patients underwent surgical or transcatheter aortic valve replacement (AVR). In the entire cohort, separate multivariable models adjusted for age, Charlson index, symptomatic status, time-dependent AVR, AS-severity, LA volume index and LVEF demonstrated that only LASr was associated with MACE+ACD (Hazard ratio, 0.97; P = 0.014). Subgroup analysis for MACE+ACD demonstrated consistent prognostication for LASr in moderate and severe AS; LVGLS was prognostic only in severe AS (all P ≤ 0.023). The optimal MACE+ACD cutoff for LASr from spline curves was 21.3%. Adjusted Kaplan-Meier curves demonstrated better event-free survival in patients with LASr >21.3% versus those with LASr ≤21.3% (P = 0.04). CONCLUSIONS: In both moderate and severe AS, only LASr robustly predicted outcomes; thus, including LASr in the AS staging algorithm should be considered.

Clinical experience in intracranial stenting of Wingspan stent system under local anesthesia.

Objective: The use of endovascular treatments for symptomatic intracranial atherosclerosis disease (ICAD) remains contentious due to high periprocedural complications. Many centers resort to general anesthesia for airway protection and optimal periprocedural conditions; however, this approach lacks real-time monitoring of patients' neurological status during procedures. In this study, we employed intracranial stenting with the Wingspan system under local anesthesia to address this challenge. Methods: We conducted a retrospective study of 45 consecutive ICAD patients who underwent intracranial stenting with the Wingspan system at our hospital from August 2013 to May 2021. These stenting procedures were performed under local anesthesia in a hybrid operation room. Neurological assessments were conducted during the procedure. The patients with periprocedural complications were analyzed for the risk factors. Results: The study included 45 ICAD patients (median age 62 years; 35 male and 10 female individuals). Among them, 30 patients had anterior circulation ICAD, and 15 had posterior circulation ICAD. The periprocedural complication rate was 8.9% (4/45), with an overall mortality rate of 2.2% (1/45). Notably, no procedure-related perforation complications were found, and all ischemic complications occurred in the perforating bearing artery, specifically in patients with stents placed in the middle cerebral artery or basilar artery, while no complications were observed in the non-perforating bearing artery of the internal carotid artery and vertebral artery (p = 0.04). Conclusion: Our study demonstrates the safety and efficacy of the Wingspan stent system when performed on selected patients under local anesthesia. This approach seems to reduce procedural-related morbidity and be a safe intervention. In addition, it is crucial for surgeons to be aware that patients with perforator-bearing artery stenosis may be at a higher risk of complications.

Treatment of Undifferentiated Embryonal Sarcoma of the Liver in Children.

Undifferentiated embryonal sarcoma of the liver is a rare mesenchymal tumor with a highly malignant potential. It occurs almost exclusively in the pediatric population and typically has a poor outcome. Although previous studies have reported dismal prognoses, recent advances in combined treatment modalities, e.g., surgery and chemotherapy, have given cause for optimism. Even in those diseases not amenable to complete surgical resection or refractory diseases, other treatment modalities, such as liver transplant, have yielded promising results. This paper provides a review of the current treatment modalities for hepatic undifferentiated embryonal sarcoma in children.

Isoxanthohumol reduces neointimal hyperplasia through the apelin/AKT pathway.

The abnormal proliferation, migration, and inflammation of vascular smooth muscle cells (VSMCs) play crucial roles in the development of neointimal hyperplasia and restenosis. Exposure to inflammatory cytokines such as platelet-derived growth factor (PDGF)-BB and tumour necrosis factor-alpha (TNF-α) induces the transformation of contractile VSMCs into abnormal synthetic VSMCs. Isoxanthohumol (IXN) has significant anti-inflammatory, antiproliferative, and antimigratory effects. This study aimed to explore the therapeutic impact and regulatory mechanism of IXN in treating neointimal hyperplasia. The present findings indicate that IXN effectively hinders the abnormal proliferation, migration, and inflammation of VSMCs triggered by PDGF or TNF-α. This inhibition is primarily achieved through the modulation of the apelin/AKT or AKT pathway, respectively. In an in vivo model, IXN effectively reduced neointimal hyperplasia in denuded femoral arteries. These results suggest that IXN holds promise as a potential and innovative therapeutic candidate for the treatment of restenosis.

White and gray matter integrity evaluated by MRI-DTI can serve as noninvasive and reliable indicators of structural and functional alterations in chronic neurotrauma.

We aimed to evaluate whether white and gray matter microstructure changes observed with magnetic resonance imaging (MRI)-based diffusion tensor imaging (DTI) can be used to reflect the progression of chronic brain trauma. The MRI-DTI parameters, neuropathologic changes, and behavioral performance of adult male Wistar rats that underwent moderate (2.1 atm on day "0") or repeated mild (1.5 atm on days "0" and "2") traumatic brain injury (TBI or rmTBI) or sham operation were evaluated at 7 days, 14 days, and 1-9 months after surgery. Neurobehavioral tests showed that TBI causes long-term motor, cognitive and neurological deficits, whereas rmTBI results in more significant deficits in these paradigms. Both histology and MRI show that rmTBI causes more significant changes in brain lesion volumes than TBI. In vivo DTI further reveals that TBI and rmTBI cause persistent microstructural changes in white matter tracts (such as the body of the corpus callosum, splenium of corpus callus, internal capsule and/or angular bundle) of both two hemispheres. Luxol fast blue measurements reveal similar myelin loss (as well as reduction in white matter thickness) in ipsilateral and contralateral hemispheres as observed by DTI analysis in injured rats. These data indicate that the disintegration of microstructural changes in white and gray matter parameters analyzed by MRI-DTI can serve as noninvasive and reliable markers of structural and functional level alterations in chronic TBI.

Melatonin Enhanced Microglia M2 Polarization in Rat Model of Neuro-inflammation Via Regulating ER Stress/PPARδ/SIRT1 Signaling Axis.

Neuro-inflammation involves distinct alterations of microglial phenotypes, containing nocuous pro-inflammatory M1-phenotype and neuroprotective anti-inflammatory M-phenotype. Currently, there is no effective treatment for modulating such alterations. M1/M2 marker of primary microglia influenced by Melatonin were detected via qPCR. Functional activities were explored by western blotting, luciferase activity, EMSA, and ChIP assay. Structure interaction was assessed by molecular docking and LIGPLOT analysis. ER-stress detection was examined by ultrastructure TEM, calapin activity, and ERSE assay. The functional neurobehavioral evaluations were used for investigation of Melatonin on the neuroinflammation in vivo. Melatonin had targeted on Peroxisome Proliferator Activated Receptor Delta (PPARδ) activity, boosted LPS-stimulated alterations in polarization from the M1 to the M2 phenotype, and thereby inhibited NFκB-IKKß activation in primary microglia. The PPARδ agonist L-165,041 or over-expression of PPARδ plasmid (ov-PPARδ) showed similar results. Molecular docking screening, dynamic simulation approaches, and biological studies of Melatonin showed that the activated site was located at PPARδ (phospho-Thr256-PPARδ). Activated microglia had lowered PPARδ activity as well as the downstream SIRT1 formation via enhancing ER-stress. Melatonin, PPARδ agonist and ov-PPARδ all effectively reversed the above-mentioned effects. Melatonin blocked ER-stress by regulating calapin activity and expression in LPS-activated microglia. Additionally, Melatonin or L-165,041 ameliorated the neurobehavioral deficits in LPS-aggravated neuroinflammatory mice through blocking microglia activities, and also promoted phenotype changes to M2-predominant microglia. Melatonin suppressed neuro-inflammation in vitro and in vivo by tuning microglial activation through the ER-stress-dependent PPARδ/SIRT1 signaling cascade. This treatment strategy is an encouraging pharmacological approach for the remedy of neuro-inflammation associated disorders.

Mesenchymal stem cells reduce long-term cognitive deficits and attenuate myelin disintegration and microglia activation following repetitive traumatic brain injury.

The underlying mechanisms for the beneficial effects exerted by bone marrow-mesenchymal stem cells (BM-MSCs) in treating repetitive traumatic brain injury (rTBI)-induced long-term sensorimotor/cognitive impairments are not fully elucidated. Herein, we aimed to explore whether BM-MSCs therapy protects against rTBI-induced long-term neurobehavioral disorders in rats via normalizing white matter integrity and gray matter microglial response. Rats were subjected to repeated mild lateral fluid percussion on day 0 and day 3. On the fourth day post-surgery, MSCs groups received MSCs (4 × 106 cells/ml/kg, intravenously) and were assessed by the radial maze, Y maze, passive avoidance tests, and modified neurological severity scores. Hematoxylin & eosin, and Luxol fast blue stainings were used to examine the histopathology and white matter thickness. At the same time, immunofluorescence staining was used to investigate the numbers of tumor necrosis factor-alpha (TNF-α)-containing microglia in gray matter. Three to nine months after neurotrauma, rats displayed sensorimotor and cognitive impairments, reduced thickness in white matter, and over-accumulation of TNF-α-containing microglia and cellular damage in gray matter. Therapy with BM-MSCs significantly attenuated the rTBI-induced sensorimotor and cognitive impairments and all their complications. Mesenchymal stem cell therapy might accelerate the recovery of sensorimotor and cognitive impairments in rats with rTBI via normalizing myelin integrity and microglia response.

Fungal, but not bacterial, diversity and network complexity promote network stability during roadside slope restoration.

To restore degraded roadside ecosystems, conventional methods such as revegetation and soil amendment are frequently employed. However, our understanding of the long-term effects of these restoration approaches on soil microbial diversity and network complexity across different vegetation types remains poor, which contributes to poor restoration outcomes. In this study, we explored the effects of roadside slope restoration on microbial communities across different vegetation types at varying stages of restoration. We found that restoration time had a more pronounced impact on microbial diversity than specific vegetation type. As restoration progressed, microbial network complexity and fungal diversity increased, but bacterial diversity declined, suggesting that keystone taxa may contribute to network complexity. Interestingly, bacterial network complexity increased concomitant with decreasing network modularity and robustness, which may compromise system stability. Distinct vegetation types were associated with restoration-sensitive microbial communities at different restoration stages. Leguminouse and nitrogen-fixing plants, such as Albiziak alkora, Ginkgo biloba, Rhus chinensis, Rhapis excels, and Rubia cordifolia exhibited such associations after five years of restoration. These keystone taxa included Proteobacteria, Actinobacteria, Chloroflexi, Gemmatimonadota, and Myxococcota. We also found that bacterial alpha diversity was significantly correlated with restoration time, soil pH, moisture, available phosphate, nitrate nitrogen, and plant height, while fungal diversity was primarily shaped by restoration time. Together, our findings suggest that soil properties, environmental factors, vegetation type, and dominant species can be manipulated to guide the trajectory of ecological recovery by regulating the abundance of certain microbial taxa.

Risk Factors for Urinary Tract Infections in Children with Hematuria in the Emergency Department.

INTRODUCTION: Hematuria is a worrisome symptom in children and is sometimes associated with urinary tract infections (UTIs). This study aimed to identify useful clinical factors that can predict UTIs in hematuria patients without pyuria in the pediatric emergency department (ED). METHODS: We retrospectively recruited patients with hematuria from the pediatric ED. Clinical symptoms, urine biochemistry and microscopic examination results, and blood laboratory tests were analyzed to identify the predictors of UTIs. Patients were divided into the verbal group (age ≥ 2 years) and non-verbal group (age < 2 years) for identifying predictors of UTIs. Causes of hematuria were also investigated. RESULTS: A total of 161 patients with hematuria without pyuria were evaluated. Among symptoms, dysuria was significantly correlated with UTIs. Regarding urine biochemistry data, urine esterase and urine protein > 30 mg/dl were found to be significant parameters for predicting UTIs, while urine esterase and urine nitrite showed significant differences in children with age < 2 years. In the urine microscopic examinations, urine red blood cells (RBC) > 373/µL in children aged ≥ 2 years and urine RBC > 8/µL in children aged < 2 years were associated with UTIs. In addition, UTIs and urinary tract stones were found to be the top two causes of hematuria. CONCLUSIONS: Dysuria, urine esterase, urine nitrite, and urine protein may be useful parameters for predicting UTIs in pediatric patients with hematuria but no pyuria in the ED. In addition, a UTI was the most commonly identified etiology of hematuria without pyuria, followed by urinary tract stones.

In Vitro Insights into the Role of 7,8-Epoxy-11-Sinulariolide Acetate Isolated from Soft Coral Sinularia siaesensis in the Potential Attenuation of Inflammation and Osteoclastogenesis.

The balance between bone-resorbing osteoclasts and bone-forming osteoblasts is essential for the process of bone remodeling. Excessive osteoclast differentiation plays a pivotal role in the pathogenesis of bone diseases such as rheumatoid arthritis and osteoporosis. In the present study, we examined whether 7,8-epoxy-11-sinulariolide acetate (Esa), a marine natural product present in soft coral Sinularia siaesensis, attenuates inflammation and osteoclastogenesis in vitro. The results indicated that Esa significantly inhibited lipopolysaccharide (LPS)-induced inflammation model of RAW264.7 cells and suppressed receptor activator for nuclear factor-κB ligand (RANKL)-triggered osteoclastogenesis. Esa significantly down-regulated the protein expression of iNOS, COX-2, and TNF-α by inhibiting the NF-κB/MAPK/PI3K pathways and reducing the release of reactive oxygen species (ROS) in RAW264.7 macrophages. Besides, Esa treatment significantly inhibited osteoclast differentiation and suppressed the expression of osteoclast-specific markers such as NFATC1, MMP-9, and CTSK proteins. These findings suggest that Esa may be a potential agent for the maintenance of bone homeostasis associated with inflammation.

Research progress on the mechanism of probiotics regulating cow milk allergy in early childhood and its application in hypoallergenic infant formula.

Some infants and young children suffer from cow's milk allergy (CMA), and have always mainly used hypoallergenic infant formula as a substitute for breast milk, but some of these formulas can still cause allergic reactions. In recent years, it has been found that probiotic nutritional interventions can regulate CMA in children. Scientific and reasonable application of probiotics to hypoallergenic infant formula is the key research direction in the future. This paper discusses the mechanism and clinical symptoms of CMA in children. This review critically ex- amines the issue of how probiotics use intestinal flora as the main vector to combine with the immune system to exert physiological functions to intervene CMA in children, with a particular focus on four mechanisms: promoting the early establishment of intestinal microecological balance, regulating the body's immunity and alleviating allergic response, enhancing the intestinal mucosal barrier function, and destroying allergen epitopes. Additionally, it overviews the development process of hypoallergenic infant formula and the research progress of probiotics in hypoallergenic infant formula. The article also offers suggestions and outlines potential future research directions and ideas in this field.

A multicenter, randomized, double-blinded, placebo-controlled, phase â ¢ study evaluating the efficacy and safety of Xeligekimab (GR1501) in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Xeligekimab is a fully human monoclonal antibody that selectively neutralizes IL-17A and had shown potential efficacy in preliminary trials. OBJECTIVE: To evaluate the efficacy and safety of Xeligekimab in Chinese patients with moderate-to-severe psoriasis. METHODS: A total of 420 Chinese patients were randomized to 200 mg Xeligekimab every 2 weeks (n = 281) or placebo (n = 139) for the first 12 weeks, followed by extending the treatment schedule to GR1501 every 4 weeks for further 40 weeks. Efficacy was assessed by evaluating the Physician's Global Assessment (PGA) 0/1 and Psoriasis Area and Severity Index (PASI) 75/90/100 improvement. The safety profile was also evaluated. RESULTS: At week 12, The PASI 75/90/100 were achieved in 90.7%/74.4%/30.2%% patients in GR1501 group compared with 8.6%/1.4%/0% patients in placebo group, respectively. The PGA 0/1 were achieved in 74.4% patients of GR1501 group and 3.6% patients in placebo group, respectively. The PASI 75 and PGA 0/1 maintained until week 52. No unexpected adverse events were observed. CONCLUSION: Xeligekimab showed high efficacy and is well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.

Dichotomic Role of Low-Concentration EGCG in the Oxaliplatin Sensitivity of Colorectal Cancer Cells.

Although epigallocatechin-3-gallate (EGCG) can potentiate chemotherapeutic drugs at high concentrations, its clinical translation is hampered by exceeding possible concentration thresholds. This study proposes a dichotomous use of low-concentration EGCG in chemotherapy. During the first cycle of combined treatment with oxaliplatin (OXA), low-concentration EGCG antagonized the cytotoxic effect of OXA on colorectal cancer (CRC) cells. However, when OXA was subsequently administered, the sensitivity of CRC cells markedly increased. Although low-concentration EGCG counteracted OXA, it reduced the OXA-induced secretion of vascular endothelial growth factor by tumor cells, thereby contributing to the increase in the sensitivity of tumor cells to the second round of OXA treatment. Therefore, low-concentration EGCG showed potential as a viable adjunct to modulate chemosensitivity in CRC.

A Retrospective Observational Study to Evaluate Adjacent Segmental Degenerative Change with the Dynesys-Transition-Optima Instrumentation System.

BACKGROUND: This study evaluates the impact of hybrid dynamic stabilization using the Dynesys-Transition-Optima (DTO) system on adjacent segment disease (ASD) in lumbar spinal stenosis patients with spondylolisthesis. METHODS: From 2012 to 2020, 115 patients underwent DTO stabilization at a single center by a single neurosurgeon. After exclusions for lack of specific stabilization and incomplete data, 31 patients were analyzed. Follow-up was conducted at 6, 12, and 24 months postoperatively, assessing disc height, listhesis distance, and angular motion changes at L2-L3, L3-L4, and L5-S1. RESULTS: L3-L4 segment (the index level), demonstrated a delayed increase in listhesis distance, contrasting with earlier changes in other segments. At two years, L3-L4 exhibited less increase in listhesis distance and less disc height reduction compared to L2-L3 and L5-S1. Notably, the L3-L4 segment showed a significant reduction in angular motion change over two years. CONCLUSIONS: In conclusion, while ASD was not significantly prevented, the study indicates minor and delayed degeneration at the index level. The L3-L4 segment experienced reduced angular change in motion, suggesting a potential benefit of DTO in stabilizing this specific segment.

Advancements in Allergen Immunotherapy for the Treatment of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin condition that affects individuals of all age groups, manifesting as a spectrum of symptoms varying from mild to severe. Allergen immunotherapy (AIT) involves the administration of allergen extracts and has emerged as a potential treatment strategy for modifying immune responses. Its pathogenesis involves epidermal barrier dysfunction, microbiome imbalance, immune dysregulation, and environmental factors. Existing treatment strategies encompass topical steroids to systemic agents, while AIT is under investigation as a potential immune-modifying alternative. Several studies have shown reductions in the severity scoring of atopic dermatitis (SCORAD) scores, daily rescue medication use, and visual analog scale (VAS) scores following AIT. Biomarker changes include increased IgG4 levels and decreased eosinophil counts. This review provides valuable insights for future research and clinical practice, exploring AIT as a viable option for the management of AD.

The immunomodulatory effects of metformin in LPS-induced macrophages: an in vitro study.

OBJECTIVE: The study aimed to explore the immunomodulatory effects of clinically relevant concentrations of metformin on macrophages during sepsis, which is characterized by an initial hyperinflammatory phase followed by a period of immunosuppression.  METHODS: We employed the RAW 264.7 mouse macrophage cell line as an in vitro model to induce inflammatory responses and immune suppression through primary and secondary stimulation by lipopolysaccharide (LPS). The cells were exposed to clinically relevant concentrations of metformin, and their responses were gauged through cytotoxicity assays, enzyme-linked immunosorbent assay for cytokine quantification, and assessments of intracellular reactive oxygen species (ROS) production. Moreover, to probe the role of AMPK in mediating the effects of metformin, we conducted an AMP-activated protein kinase (AMPK) activity assay and knocked down AMPK using siRNA.  RESULTS: Our study revealed that clinically relevant concentrations of metformin considerably decreased the LPS-induced secretion of tumor necrosis factor-α and interleukin-6, which indicates the suppression of the initial hyperinflammatory response. Furthermore, metformin prevented LPS-induced immunosuppression. Notably, these immunomodulatory effects of metformin were not mediated by the activation of the AMPK pathway, as evidenced by the unaltered AMPK activity and siRNA experiments. The modulation of intracellular ROS levels emerged as the critical mechanism underlying the inhibition of hyperinflammation and impediment of immunosuppression by metformin. CONCLUSION: A certain therapeutic dose of metformin inhibited hyperinflammatory responses and alleviated immunosuppression in LPS-induced macrophages through the bidirectional modulation of intracellular ROS generation.