Linear resistivity at van Hove singularities in twisted bilayer WSe2.

Different mechanisms driving a linear temperature dependence of the resistivity ρ ∼ T at van Hove singularities (VHSs) or metal-insulator transitions when doping a Mott insulator are being debated intensively with competing theoretical proposals. We experimentally investigate this using the exceptional tunability of twisted bilayer (TB) WSe2 by tracking the parameter regions where linear-in-T resistivity is found in dependency of displacement fields, filling, and magnetic fields. We find that even when the VHSs are tuned rather far away from the half-filling point and the Mott insulating transition is absent, the T-linear resistivity persists at the VHSs. When doping away from the VHSs, the T-linear behavior quickly transitions into a Fermi liquid behavior with a T2 relation. No apparent dependency of the linear-in-T resistivity, besides a rather strong change of prefactor, is found when applying displacement fields as long as the filling is tuned to the VHSs, including D ∼ 0.28 V/nm where a high-order VHS is expected. Intriguingly, such non-Fermi liquid linear-in-T resistivity persists even when magnetic fields break the spin-degeneracy of the VHSs at which point two linear in T regions emerge, for each of the split VHSs separately. This points to a mechanism of enhanced scattering at generic VHSs rather than only at high-order VHSs or by a quantum critical point during a Mott transition. Our findings provide insights into the many-body consequences arising out of VHSs, especially the non-Fermi liquid behavior found in moiré materials.

LncRNA HOTTIP as a diagnostic biomarker for acute respiratory distress syndrome in patients with sepsis and to predict the short-term clinical outcome: a case-control study.

BACKGROUND: The present research aims to investigate the clinical diagnostic value of LncRNA HOXA distal transcript antisense RNA (HOTTIP) in acute respiratory distress syndrome (ARDS) of sepsis and its predictive significance for mortality. METHODS: One hundred eighteenth patients with sepsis and 96 healthy individuals were enrolled. RT-qPCR to examine HOTTIP levels. The incidence of ARDS and death was recorded. The diagnostic significance of HOTTIP in sepsis ARDS was examined using ROC and logistic regression analysis. The correlation between HOTTIP and disease severity was evaluated using Pearson's coefficients. Kaplan-Meier analysis and COX regression were employed to examine the predictive significance of mortality. Validation of HOTTIP target miRNA by dual-luciferase assay. RESULTS: HOTTIP was persistently up-regulated in patients with ARDS sepsis than in patients without ARDS patients (P < 0.05). HOTTIP was a risk factor for the development of ARDS, which could be diagnosed in ARDS patients from non-ARDS patients (AUC = 0.847). Both the SOFA score (r = 0.6793) and the APACHE II score (r = 0.6384) were positively correlated with the HOTTIP levels. Furthermore, serum HOTTIP was an independent predictor of short-term mortality (HR = 4.813. 95%CI: 1.471-15.750, P = 0.009) and noticeably predicted the occurrence of short-term death (log rank = 0.020). miR-574-5p, a target miRNA for HOTTIP, was reduced in patients with sepsis ARDS and negatively correlated with HOTTIP. CONCLUSIONS: The presence of HOTTIP serves as a diagnostic biomarker for the occurrence of ARDS, exhibits correlation with disease severity, and provides predictive value of short-term mortality in sepsis patients. HOTTIP may be involved in ARDS progression by targeting miR-574-5p.

Proteomics and transcriptomics profiling reveals distinct aspects of kidney stone related genes in calculi rats.

BACKGROUNDS: Kidney stone also known as urolithiasis or nephrolithiasis, is one of the oldest diseases known to medicine, however, the gene expression changes and related kidney injury remains unclear. METHODS: A calculi rat model was developed via ethylene glycol- and ammonium chloride-induction. Integrated proteomic and transcriptomic analysis was performed to characterize the distinct gene expression profiles in the kidney of calculi rat. Differential expressed genes (DEGs) were sub-clustered into distinct groups according to the consistency of transcriptome and proteome. Gene Ontology and KEGG pathway enrichment was performed to analyze the functions of each sub-group of DEGs. Immunohistochemistry was performed to validated the expression of identified proteins. RESULTS: Five thousand eight hundred ninety-seven genes were quantified at both transcriptome and proteome levels, and six distinct gene clusters were identified, of which 14 genes were consistently dysregulated. Functional enrichment analysis showed that the calculi rat kidney was increased expression of injured & apoptotic markers and immune-molecules, and decreased expression of solute carriers & transporters and many metabolic related factors. CONCLUSIONS: The present proteotranscriptomic study provided a data resource and new insights for better understanding of the pathogenesis of nephrolithiasis, will hopefully facilitate the future development of new strategies for the recurrence prevention and treatment in patients with kidney stone disease.

Nanoscale reorganisation of synaptic proteins in Alzheimer's disease.

AIMS: Synaptic strength depends strongly on the subsynaptic organisation of presynaptic transmitter release and postsynaptic receptor densities, and their alterations are expected to underlie pathologies. Although synaptic dysfunctions are common pathogenic traits of Alzheimer's disease (AD), it remains unknown whether synaptic protein nano-organisation is altered in AD. Here, we systematically characterised the alterations in the subsynaptic organisation in cellular and mouse models of AD. METHODS: We used immunostaining and super-resolution stochastic optical reconstruction microscopy imaging to quantitatively examine the synaptic protein nano-organisation in both Aß1-42-treated neuronal cultures and cortical sections from a mouse model of AD, APP23 mice. RESULTS: We found that Aß1-42-treatment of cultured hippocampal neurons decreased the synaptic retention of postsynaptic scaffolds and receptors and disrupted their nanoscale alignment to presynaptic transmitter release sites. In cortical sections, we found that while GluA1 receptors in wild-type mice were organised in subsynaptic nanoclusters with high local densities, receptors in APP23 mice distributed more homogeneously within synapses. This reorganisation, together with the reduced overall receptor density, led to reduced glutamatergic synaptic transmission. Meanwhile, the transsynaptic alignment between presynaptic release-guiding RIM1/2 and postsynaptic scaffolding protein PSD-95 was reduced in APP23 mice. Importantly, these reorganisations were progressive with age and were more pronounced in synapses in close vicinity of Aß plaques with dense cores. CONCLUSIONS: Our study revealed a spatiotemporal-specific reorganisation of synaptic nanostructures in AD and identifies dense-core amyloid plaques as the major local inductor in APP23 mice.

Effects of the nutrient inhibition on the yield of DBPFPs by Microcystis aeruginosa.

The yield of three disinfection byproduct formation potentials (DBPFPs), including trichloromethane, dichloroacetic acid and trichloroacetic acid formation potential (TCMFP, DCAAFP and TCAAFP), by Microcystis aeruginosa under the nitrate and phosphate inhibition conditions was investigated. The results showed that excessive nitrate could inhibit the growth of M. aeruginosa, but the concentration of DBPFPs in the five fractions of algal metabolites, including hydrophilic extracellular organic matter (EOM), hydrophobic EOM, hydrophilic intracellular organic matter, hydrophobic intracellular organic matter and cell debris, only decreased slightly. Accordingly, the productivity of DBPFPs by M. aeruginosa increased by approximately 40% under the nitrate inhibition condition and the increased productivity of DBPFPs mainly came from EOM. The phosphate inhibition also performed a similar pattern with a lesser extent. The nutrient inhibition did not change the proportion of these three DPBFPs, and TCMFP accounted for approximately 87% of the total DBPFPs. The inhibition could promote M. aeruginosa to secrete more metabolites. However, the cyanobacteria tended to secrete more DBPFPs under the nitrate inhibition condition, which resulted in an increased specific DBPFP, while they tended to secrete more non-DBPFPs under the phosphate inhibition condition, which resulted in a decreased specific DBPFP.

Eighteen Novel Bioactive Peptides from Monkfish (Lophius litulon) Swim Bladders: Production, Identification, Antioxidant Activity, and Stability.

In the study, papain was chosen from five proteases to hydrolyze proteins of monkfish swim bladders for effectively utilizing monkfish (Lophius litulon) processing byproducts, and the hydrolysis conditions of papain were optimized as hydrolysis temperature of 65 °C, pH 7.5, enzyme dose 2.5% and time 5 h using single-factor and orthogonal experiments. Eighteen peptides were purified from the swim bladder hydrolysate of monkfish by ultrafiltration and gel permeation chromatography methods and identified as YDYD, QDYD, AGPAS, GPGPHGPSGP, GPK, HRE, GRW, ARW, GPTE, DDGGK, IGPAS, AKPAT, YPAGP, DPT, FPGPT, GPGPT, GPT and DPAGP, respectively. Among eighteen peptides, GRW and ARW showed significant DPPH· scavenging activities with EC50 values of 1.053 ± 0.003 and 0.773 ± 0.003 mg/mL, respectively; YDYD, QDYD, GRW, ARW and YPAGP revealed significantly HO· scavenging activities with EC50 values of 0.150 ± 0.060, 0.177 ± 0.035, 0.201 ± 0.013, 0.183 ± 0.0016 and 0.190 ± 0.010 mg/mL, respectively; YDYD, QDYD, ARW, DDGGK and YPAGP have significantly O2-· scavenging capability with EC50 values of 0.126 ± 0.0005, 0.112 ± 0.0028, 0.127 ± 0.0002, 0.128 ± 0.0018 and 0.107 ± 0.0002 mg/mL, respectively; and YDYD, QDYD and YPAGP showed strong ABTS+· scavenging ability with EC50 values of 3.197 ± 0.036, 2.337 ± 0.016 and 3.839 ± 0.102 mg/mL, respectively. YDYD, ARW and DDGGK displayed the remarkable ability of lipid peroxidation inhibition and Ferric-reducing antioxidant properties. Moreover, YDYD and ARW can protect Plasmid DNA and HepG2 cells against H2O2-induced oxidative stress. Furthermore, eighteen isolated peptides had high stability under temperatures ranging from 25-100 °C; YDYD, QDYD, GRW and ARW were more sensitive to alkali treatment, but DDGGK and YPAGP were more sensitive to acid treatment; and YDYD showed strong stability treated with simulated GI digestion. Therefore, the prepared antioxidant peptides, especially YDYD, QDYD, GRW, ARW, DDGGK and YPAGP from monkfish swim bladders could serve as functional components applied in health-promoting products because of their high-antioxidant functions.

Performance of a simplified scoring system for risk stratification in oral cancer and oral potentially malignant disorders screening.

BACKGROUND: Impact and efficiency of oral cancer and oral potentially malignant disorders screening are most realized in "at-risk" individuals. However, tools that can provide essential knowledge on individuals' risks are not applied in risk-based screening. This study aims to optimize a simplified risk scoring system for risk stratification in organized oral cancer and oral potentially malignant disorders screening. METHODS: Participants were invited to attend a community-based oral cancer and oral potentially malignant disorders screening program in Hong Kong. Visual oral examination was performed for all attendees and information on sociodemographic characteristics as well as habitual, lifestyle, familial, and comorbidity risk factors were obtained. Individuals' status of those found to have suspicious lesions following biopsy and histopathology were classified as positive/negative and this outcome was used in a multiple logistic regression analysis with variables collected during screening. Odds ratio weightings were then used to develop a simplified risk scoring system which was validated in an external cohort. RESULTS: Of 979 participants, 4.5% had positive status following confirmatory diagnosis. A 12-variable simplified risk scoring system with weightings was generated with an AUC, sensitivity, and specificity of 0.82, 0.71, and 0.78 for delineating high-risk cases. Further optimization on the validation cohort of 491 participants yielded a sensitivity and specificity of 0.75 and 0.87 respectively. CONCLUSIONS: The simplified risk scoring system was able to stratify oral cancer and oral potentially malignant disorders risk with satisfactory sensitivity and specificity and can be applied in risk-based disease screening.

Efficacy of hypermethylated DNA biomarkers in saliva and oral swabs for oral cancer diagnosis: Systematic review and meta-analysis.

OBJECTIVES: This study aims to determine the diagnostic test accuracy (DTA) of hypermethylated DNA biomarkers in saliva and oral swabs for oral squamous cell carcinoma (OSCC) detection from the prevalidation studies available. MATERIALS AND METHODS: Electronic database searching of PubMed, EMBASE, Cochrane Library, Scopus, Web of Science, and LILACS was conducted to identify relevant articles that were published between January 1, 2000, and August 1, 2020. RESULTS: Meta-analysis was conducted based on 11 of 20 studies selected for review. Included studies had high bias concerns on the QUADAS-2 study assessment tool. We found that salivary and oral swab hypermethylation markers had better specificity than sensitivity for oral cancer detection. Summary sensitivity and specificity (95% CI) of hypermethylation panels were 86.2% (60-96.2) and 90.6% (85.9-93.9) while for individual markers, summary sensitivity and specificity (95% CI) were 70% (56.9-80.5) and 91.9% (80.3-96.9), respectively. Respective positive and negative likelihood ratios for combined markers were 9.2 (5.89-14.36) and 0.15 (0.05-0.5), and 8.61 (3.39-21.87) and 0.33 (0.22-0.49) for single-application biomarkers. CONCLUSION: DNA hypermethylation biomarkers especially in combination have acceptable DTA that warrants further optimization with rigorous biomarker evaluation methods for conclusive determination of their efficacy.

A neural-related gene risk score for head and neck squamous cell carcinoma.

OBJECTIVES: This study aimed to establish a neural-related gene risk score (NRGRS) for the prediction of head and neck squamous cell carcinoma prognosis and explore its predictive value on the benefit of immune checkpoint inhibitor therapy. METHODS: Based on the transcriptome data of HNSCC patients (n = 546) from The Cancer Genome Atlas database, 37 neural-related hub genes were identified by weighted gene co-expression network analysis. Four genes (ITGA5, PYGM, GNG7 and ATP2A3) were identified to construct NRGRS using Lasso-Cox regression method based on the derivation cohort and validated in the Gene Expression Omnibus cohort (n = 109). The survival analysis was performed to validate the prognostic value of NRGRS and immune characteristics in NRGRS-defined subgroups were analyzed. RESULTS: NRGRS-high patients had a worse overall survival than NRGRS-low patients. Tumors with high NRGRS were more likely to have high infiltration of naive CD4+ T cells, M0, M2 macrophages and resting mast cells, which illustrated suppressive immunity and less benefit from immunotherapy therapy. CONCLUSION: NRGRS strongly correlates with survival and is a promising biomarker to predict immunotherapy benefits for head and neck cancer patients. This study provides evidence for the potential correlation between neural-related transcriptome alteration and immune activity.

Robust Beamforming Based on Graph Attention Networks for IRS-Assisted Satellite IoT Communications.

Satellite communication is expected to play a vital role in realizing Internet of Remote Things (IoRT) applications. This article considers an intelligent reflecting surface (IRS)-assisted downlink low Earth orbit (LEO) satellite communication network, where IRS provides additional reflective links to enhance the intended signal power. We aim to maximize the sum-rate of all the terrestrial users by jointly optimizing the satellite's precoding matrix and IRS's phase shifts. However, it is difficult to directly acquire the instantaneous channel state information (CSI) and optimal phase shifts of IRS due to the high mobility of LEO and the passive nature of reflective elements. Moreover, most conventional solution algorithms suffer from high computational complexity and are not applicable to these dynamic scenarios. A robust beamforming design based on graph attention networks (RBF-GAT) is proposed to establish a direct mapping from the received pilots and dynamic network topology to the satellite and IRS's beamforming, which is trained offline using the unsupervised learning approach. The simulation results corroborate that the proposed RBF-GAT approach can achieve more than 95% of the performance provided by the upper bound with low complexity.

An LRR-only protein promotes NLP-triggered cell death and disease susceptibility by facilitating oligomerization of NLP in Arabidopsis.

Necrosis- and ethylene-inducing peptide 1 (Nep1)-like proteins (NLPs) constitute a superfamily of proteins toxic to dicot plants, but the molecular basis of this toxicity remains obscure. Using quantitative trait locus (QTL) analysis we investigated the genetic variation underlying ion leakage in Arabidopsis plants elicited with MoNLP1 derived from Magnaporthe oryzae. The QTL conditioning MoNLP1 toxicity was positionally cloned and further characterized to elucidate its mode of action. MoNLP1-triggered cell death varied significantly across > 250 Arabidopsis accessions and three QTLs were identified conferring the observed variation. The QTL on chromosome 4 was uncovered to encode a leucine-rich repeat (LRR)-only protein designated as NTCD4, which shares high sequence identity with a set of nucleotide-binding LRR proteins. NTCD4 was secreted into the apoplast and physically interacted with multiple NLPs. Apoplastic NTCD4 facilitated the oligomerization of NLP, which was closely associated with toxicity in planta. The natural genetic variation causing D3N change in NTCD4 reduced the secretion efficiency of NTCD4 and the infection of Botrytis cinerea on Arabidopsis plants. These observations demonstrate that the plant-derived NTCD4 is recruited by NLPs to promote toxicity via facilitating their oligomerization, which extends our understanding of a key step in the toxic mode of action of NLPs.

Three-Dimensionally Printed Patient-Specific Surgical Plates Increase Accuracy of Oncologic Head and Neck Reconstruction Versus Conventional Surgical Plates: A Comparative Study.

BACKGROUND: Surgeons are pursuing accurate head and neck reconstruction to enhance aesthetic and functional outcomes after oncologic resection. This study aimed to investigate whether accuracy of head and neck reconstruction is improved with the use of three-dimensionally (3D)-printed patient-specific surgical plates compared with conventional plates. METHODS: In this comparative study, patients were prospectively recruited into the study group (3DJP16) with 3D-printed patient-specific surgical plates. The patients in control group with conventional surgical plates were from a historic cohort in the same unit. The primary end point of the study was the accuracy of head and neck reconstruction. The secondary end points were accuracy of osteotomy, intraoperative blood loss, total operative time, and length of hospital stay. RESULTS: The study recruited of 33 patients, including 17 in the study group and 16 in the control group. The patients' baseline characteristics were similar between the two groups. The absolute distance deviation of the maxilla or mandible was 1.5 ± 0.5 mm in the study group and 2.1 ± 0.7 mm in the control group [mean difference, - 0.7 mm; 95% confidence interval (CI) - 1.1 to - 0.3; p = 0.003], showing superior accuracy of reconstruction for the patients with 3D-printed patient-specific surgical plates. Improved accuracy of reconstruction also was detected in terms of bilateral mandibular angles and bone grafts. Concerning the secondary end points, the accuracy of the osteotomy was similar in the two groups. No difference was found regarding intraoperative blood loss, total operative time, or length of hospital stay. CONCLUSIONS: This is the first study to prove that compared with conventional plates, 3D-printed patient-specific surgical plates improve the accuracy of oncologic head and neck reconstruction.

The critical role of calcineurin/NFAT (C/N) pathways and effective antitumor prospect for colorectal cancers.

Transcription factors (TFs) like a nuclear factor of activated T-cells (NFAT) and its controller calcineurin are highly expressed in primary intestinal epithelial cells (IECs) due to delamination, damage by tumor-associated flora and selective activation in the intestinal tract tumor are crucial in the progression and growth of colorectal cancer (CRC). This study sought to summarize the current findings concerning the dysregulated calcineurin/NFAT (C/N) signaling involved in CRC initiation and progression. These signalings include proliferation, T-cell functions, and glycolysis with high lactate production that remodels the acidosis, which genes in tumor cells provide an evolutionary advantage, or even increased their attack phenotype. Moreover, the relationship between C/N and gut microbiome in CRC, especially role of NFAT and toll-like receptor signaling in regulating intestinal microbiota are also discussed. Furthermore, this review will discuss the proteins and genes relating to C/N induced acidosis in CRC, which includes ASIC2 regulated C/N1 and TFs associated with the glycolytic by-product that affect T-cell functions and CRC cell growth. It is revealed that calcineurin or NFAT targeting to antitumor, selective calcineurin inhibition or targets in NFAT signaling may be useful for clinical treatment of CRC. This can further aid in the identification of specific targets via cancer patient-personalized approach. Future studies should be focused on targeting to C/N or TLR signaling by the combination of therapeutic agents to regulate T-cell functions and gut microbiome for activating potent anticancer property with the prospect of potentiating the antitumor therapy for CRC.

Association of lymph node involvement with the prognosis of pathological T1 invasive non-small cell lung cancer.

BACKGROUND: Lymph node involvement could help to predict the prognosis of pathological T1 (pT1, diameters of ≤3 cm) non-small cell lung cancer (NSCLC). This study assessed the clinicopathological factors and associated lymph node involvement in invasive lung adenocarcinoma (IAC) and squamous cell lung cancer (SCC) and the overall and disease-free survival associated with these factors. METHODS: Three hundred and twenty-five patients with pathological T1 NSCLC (253 IAC and 72 SCC) were retrospectively analyzed from a pool of 1094 primary lung cancer patients. The data were assessed using multiple logistic regression, Kaplan-Meier curves and multivariable analyses. RESULTS: Among patients with a ≤30-mm tumor lesion (N = 325), N1 and N2 lymph node involvement was found in 28 (8.6%) and 34 (10.4%) patients, respectively. Lymph node metastasis occurred in 13.0% (33/253) of pT1 IAC patients and 40.3% (29/72) of SCC patients. Carcinoembryonic antigen (CEA) levels, SCC by histology, and tumor lesions larger than 1.0 cm were associated with lymph node involvement (P < 0.0001, <0.0001, and 0.048, respectively). In IAC patients, negative lymph nodes were associated with better overall survival compared with lymph node-positive ones (P = 0.021). No significant difference was observed in SCC patients regardless of lymph node status (P = 0.40). Multivariable Cox analysis revealed that lymph node involvement was an independent prognostic predictor of overall IAC patient survival (P = 0.041), but not of SCC patient survival (P = 0.470). Chemotherapy was administered to 72.2% (52/72) of SCC patients, a significantly higher rate when compared with that of IAC patients (42.3%, 107/253). CONCLUSIONS: Lymph node metastasis was inversely associated with the overall survival of IAP patients, but not with the survival of SCC patients. Patients with pT1 SCC exhibited a significantly higher rate of lymph node involvement when compared with IAC patients. Thus, a systematic lymph node dissection should be performed in pT1 IAC patients, especially in patients with IAC larger than 1.0 cm, for additional treatment selections to improve survival.

Differential expression of miR-125a-5p and let-7e predicts the progression and prognosis of non-small cell lung cancer.

Aberrant expression of various microRNAs (miRNA) has shown diagnostic and prognostic significance in non-small cell lung cancer (NSCLC). qRT-PCR analysis confirmed altered expression of miR-125a-5p, let-7e, miR-30a, miR-30e and miR-30e-3p in 70 paired tissue and serum samples from NSCLC patients. The reduced expression of miR-125a-5p, let-7e and miR-30e was strongly associated with NSCLC dedifferentiation. The lost expression of miR-125a-5p and let-7e was associated with shorter overall survival and let-7e was an independent prognostic factor for NSCLC patients. These five miRNA expressions should be further evaluated as biomarkers for the early detection and prognosis of NSCLC patients.

Circulating methylated MINT2 promoter DNA is a potential poor prognostic factor in gastric cancer.

BACKGROUND AND AIM: Aberrant DNA methylation has been shown to be associated with the growth, development, metastasis, and prognosis of tumors. Methylated DNAs may be suitable biomarkers for cancer patients. Here, we investigated whether circulating methylated MINT2 DNAs represent a potential poor prognostic factor in gastric cancer (GC). METHODS: MINT2 methylation was detected by real-time methylation-specific PCR in tumor tissues, pairing preoperative peritoneal lavage fluid (PPLF) and blood from 92 GC patients. The theory meaning and clinical practicality value of MINT2 methylation in different specimens were analyzed. RESULTS: The methylation status of the MINT2 gene was found to be significantly higher in tumor tissues (44.6%, 41/92) than in adjacent normal tissues (3.3%, 3/92). No MINT2 methylation was found in healthy controls, and partial MINT2 methylation was observed in three (6.25%, 3/48) patients with chronic atrophic gastritis. The frequency of MINT2 methylation in pairing PPLF and blood samples from 92 GC patients was 40.2% (37/92) and 39.1% (36/92), respectively. Methylated MINT2 in tumor tissues, pairing PPLF, and blood samples were very approximate. Aberrant MINT2 methylation in tumor tissues and pairing PPLF or blood samples were closely related to peritoneal dissemination, tumor progression, and poor prognosis (all P < 0.0001). CONCLUSIONS: Aberrant MINT2 methylation in PPLF/blood may predict peritoneal micrometastasis for GC patients, which is a potential poor prognostic factor in GC.

Macrophage polarization regulation shed lights on immunotherapy for CaOx kidney stone disease.

Kidney stone disease (KSD) is a major public health concern associated with high morbidity and recurrence, places a significant burden on the health care system worldwide. Calcium oxalate (CaOx) alone or a mixture of CaOx and calcium phosphate stones accounting for more than 80 % of cases. However, beyond surgical removal, the prevention and reduction of recurrence of CaOx kidney stones have always been a challenge. Given that macrophages are traditional innate immune cells that play critical roles in the clearance of pathogens and the maintenance of tissue homeostasis, which have gained more and more interests in nephrolithiasis. Several studies recently clearly demonstrated that M2-macrophage could reduce the renal calcium oxalate (CaOx) crystal acumination, and provide premise insights and therapeutic options for KSD by modulating the macrophage phenotypes. However, the mechanism of macrophage-polarization regulation and that effects on kidney stone prevention and treatments are far from clear. Here, we comprehensively reviewed the literatures related to cytokines, epigenetic modifications and metabolic reprograming of macrophage in CaOx kidney stone disease, aimed to provide better understandings on macrophage polarization regulation as well as its potential clinical applications in CaOx kidney stone disease treatments and prevention.

Lingual Denervation Improves the Efficacy of Anti-PD-1 Immunotherapy in Oral Squamous Cell Carcinomas by Downregulating TGFß Signaling.

PURPOSE: Intratumoral nerve infiltration relates to tumor progression and poor survival in oral squamous cell carcinoma (OSCC). How neural involvement regulates antitumor immunity has not been well characterized. This study aims to investigate molecular mechanisms of regulating tumor aggressiveness and impairing antitumor immunity by nerve-derived factors. EXPERIMENTAL DESIGN: We performed the surgical lingual denervation in an immunocompetent mouse OSCC model to investigate its effect on tumor growth and the efficacy of anti-PD-1 immunotherapy. A trigeminal ganglion neuron and OSCC cell coculture system was established to investigate the proliferation, migration, and invasion of tumor cells and the PD-L1 expression. Both the neuron-tumor cell coculture in vitro model and the OSCC animal model were explored. RESULTS: Lingual denervation slowed down tumor growth and improved the efficacy of anti-PD-1 treatment in the OSCC model. Coculturing with neurons not only enhanced the proliferation, migration, and invasion but also upregulated TGFß-SMAD2 signaling and PD-L1 expression of tumor cells. Treatment with the TGFß signaling inhibitor galunisertib reversed nerve-derived tumor aggressiveness and downregulated PD-L1 on tumor cells. Similarly, lingual denervation in vivo decreased TGFß and PD-L1 expression and increased CD8+ T-cell infiltration and the expression of IFNγ and TNFα within tumor. CONCLUSIONS: Neural involvement enhanced tumor aggressiveness through upregulating TGFß signaling and PD-L1 expression in OSCC, while denervation of OSCC inhibited tumor growth, downregulated TGFß signaling, enhanced activities of CD8+ T cells, and improved the efficacy of anti-PD-1 immunotherapy. This study will encourage further research focusing on denervation as a potential adjuvant therapeutic approach in OSCC. SIGNIFICANCE: This study revealed the specific mechanisms for nerve-derived cancer progression and impaired antitumor immunity in OSCC, providing a novel insight into the cancer-neuron-immune network as well as pointing the way for new strategies targeting nerve-cancer cross-talk as a potential adjuvant therapeutic approach for OSCC.

Antimicrobial peptide LL37 and regulatory T cell associated with late-onset sepsis in very preterm infants.

Stem cell therapy may prevent late-onset sepsis (LOS) via antimicrobial peptide LL37 secretion and regulatory T cell (Treg) regulation. The early prediction of LOS is still a challenge. This study evaluated whether immunological state of LL37 or Tregs precedes LOS. We firstly analyzed the LL37 level, Treg proportion, and LOS incidence in very preterm infants treated with autologous cord blood mononuclear cells (ACBMNCs) in our previous trial. Then, we constructed a prediction model and built validation cohort. We found ACBMNC intervention reduced the incidence of LOS from 27.3% to 6.9% (p = 0.021). LL37 and Treg abundances were higher in the ACBMNCs group. The nomogram demonstrated that early-life Treg and LL37 characteristics were closely associated with LOS (area under the curve, AUC 0.936), with implications for early prediction and timely clinical management. This composite model was also helpful to evaluate the beneficial effect of ACBMNCs intervention on LOS, thus promoting translational research.

Berberine Enhances Intestinal Mucosal Barrier Function by Promoting Vitamin D Receptor Activity.

OBJECTIVE: To evaluate if berberine can act on vitamin D receptors (VDR) and thereby regulate the expression of tight junction proteins (TJPs) in irritable bowel syndrame-diarrhea-predominant (IBS-D) rats. METHODS: The newborn rats were induced into IBS-D rat model via neonatal maternal separation combined with acetic acid chemical stimulation. After modeling, the model was evaluated and rats were divided into the control group and berberine treatment groups (0.85, 1.7 and 3.4 mg/kg, once a day for 2 weeks). The distal colon was obtained and colonic epithelial cells (CECs) were isolated and cultured after IBS-D model evaluation. The vitamin D receptor response element (VDRE) reporter gene was determined in the CECs of IBS-D rats to analyze the effect of berberine on the VDRE promoter. VDR overexpression or silencing technology was used to analyze whether VDR plays a role in promoting intestinal barrier repair, and to determine which region of VDR plays a role in berberine-regulated intestinal TJPs. RESULTS: The IBS-D rat model was successfully constructed and the symptoms were improved by berberine in a dose-dependent manner (P<0.05). The activity of VDRE promoter was also effectively promoted by berberine (P<0.05). Berberine increased the expression of TJPs in IBS-D CECs (P<0.05). VDR expression was significantly increased after transfection of different domains of VDR when compared to normal control and basic plasmid groups (all P<0.05). RT-qPCR and Western blot results showed that compared with the blank group, expressions of occludin and zonula occludens-1 were significantly higher in VDR containing groups (all P<0.05). Berberine plus pCMV-Myc-VDR-N group exerted the highest expression levels of occludin and zonula occludens-1 (P<0.05). CONCLUSION: Berberine enhances intestinal mucosal barrier function of IBS-D rats by promoting VDR activity, and the main site of action is the N-terminal region of VDR.