A tripartite rheostat controls self-regulated host plant resistance to insects.

Plants deploy receptor-like kinases and nucleotide-binding leucine-rich repeat receptors to confer host plant resistance (HPR) to herbivores1. These gene-for-gene interactions between insects and their hosts have been proposed for more than 50 years2. However, the molecular and cellular mechanisms that underlie HPR have been elusive, as the identity and sensing mechanisms of insect avirulence effectors have remained unknown. Here we identify an insect salivary protein perceived by a plant immune receptor. The BPH14-interacting salivary protein (BISP) from the brown planthopper (Nilaparvata lugens Stål) is secreted into rice (Oryza sativa) during feeding. In susceptible plants, BISP targets O. satvia RLCK185 (OsRLCK185; hereafter Os is used to denote O. satvia-related proteins or genes) to suppress basal defences. In resistant plants, the nucleotide-binding leucine-rich repeat receptor BPH14 directly binds BISP to activate HPR. Constitutive activation of Bph14-mediated immunity is detrimental to plant growth and productivity. The fine-tuning of Bph14-mediated HPR is achieved through direct binding of BISP and BPH14 to the selective autophagy cargo receptor OsNBR1, which delivers BISP to OsATG8 for degradation. Autophagy therefore controls BISP levels. In Bph14 plants, autophagy restores cellular homeostasis by downregulating HPR when feeding by brown planthoppers ceases. We identify an insect saliva protein sensed by a plant immune receptor and discover a three-way interaction system that offers opportunities for developing high-yield, insect-resistant crops.

Two C-terminal isoforms of Aplysia tachykinin-related peptide receptors exhibit phosphorylation-dependent and phosphorylation-independent desensitization mechanisms.

Diversity, a hallmark of G protein-coupled receptor (GPCR) signaling, partly stems from alternative splicing of a single gene generating more than one isoform for a receptor. Additionally, receptor responses to ligands can be attenuated by desensitization upon prolonged or repeated ligand exposure. Both phenomena have been demonstrated and exemplified by the deuterostome tachykinin signaling system, although the role of phosphorylation in desensitization remains a subject of debate. Here, we describe the signaling system for tachykinin-related peptides (TKRPs) in a protostome, mollusk Aplysia. We cloned the Aplysia TKRP precursor, which encodes three TKRPs (apTKRP-1, apTKRP-2a, and apTKRP-2b) containing the FXGXR-amide motif. In situ hybridization and immunohistochemistry showed predominant expression of TKRP mRNA and peptide in the cerebral ganglia. TKRPs and their posttranslational modifications were observed in extracts of central nervous system ganglia using mass spectrometry. We identified two Aplysia TKRP receptors (apTKRPRs), named apTKRPR-A and apTKRPR-B. These receptors are two isoforms generated through alternative splicing of the same gene and differ only in their intracellular C termini. Structure-activity relationship analysis of apTKRP-2b revealed that both C-terminal amidation and conserved residues of the ligand are critical for receptor activation. C-terminal truncates and mutants of apTKRPRs suggested that there is a C-terminal phosphorylation-independent desensitization for both receptors. Moreover, apTKRPR-B also exhibits phosphorylation-dependent desensitization through the phosphorylation of C-terminal Ser/Thr residues. This comprehensive characterization of the Aplysia TKRP signaling system underscores the evolutionary conservation of the TKRP and TK signaling systems, while highlighting the intricacies of receptor regulation through alternative splicing and differential desensitization mechanisms.

A Contrast-Enhanced Tri-Modal MRI Technique for High-Performance Hypoxia Imaging of Breast Cancer.

Personalized radiotherapy strategies enabled by the construction of hypoxia-guided biological target volumes (BTVs) can overcome hypoxia-induced radioresistance by delivering high-dose radiotherapy to targeted hypoxic areas of the tumor. However, the construction of hypoxia-guided BTVs is difficult owing to lack of precise visualization of hypoxic areas. This study synthesizes a hypoxia-responsive T1, T2, T2 mapping tri-modal MRI molecular nanoprobe (SPION@ND) and provides precise imaging of hypoxic tumor areas by utilizing the advantageous features of tri-modal magnetic resonance imaging (MRI). SPION@ND exhibits hypoxia-triggered dispersion-aggregation structural transformation. Dispersed SPION@ND can be used for routine clinical BTV construction using T1-contrast MRI. Conversely, aggregated SPION@ND can be used for tumor hypoxia imaging assessment using T2-contrast MRI. Moreover, by introducing T2 mapping, this work designs a novel method (adjustable threshold-based hypoxia assessment) for the precise assessment of tumor hypoxia confidence area and hypoxia level. Eventually this work successfully obtains hypoxia tumor target and accurates hypoxia tumor target, and achieves a one-stop hypoxia-guided BTV construction. Compared to the positron emission tomography-based hypoxia assessment, SPION@ND provides a new method that allows safe and convenient imaging of hypoxic tumor areas in clinical settings.

DLRAPom: a hybrid pipeline of Optimized XGBoost-guided integrative multiomics analysis for identifying targetable disease-related lncRNA-miRNA-mRNA regulatory axes.

The lack of a reliable and easy-to-operate screening pipeline for disease-related noncoding RNA regulatory axis is a problem that needs to be solved urgently. To address this, we designed a hybrid pipeline, disease-related lncRNA-miRNA-mRNA regulatory axis prediction from multiomics (DLRAPom), to identify risk biomarkers and disease-related lncRNA-miRNA-mRNA regulatory axes by adding a novel machine learning model on the basis of conventional analysis and combining experimental validation. The pipeline consists of four parts, including selecting hub biomarkers by conventional bioinformatics analysis, discovering the most essential protein-coding biomarkers by a novel machine learning model, extracting the key lncRNA-miRNA-mRNA axis and validating experimentally. Our study is the first one to propose a new pipeline predicting the interactions between lncRNA and miRNA and mRNA by combining WGCNA and XGBoost. Compared with the methods reported previously, we developed an Optimized XGBoost model to reduce the degree of overfitting in multiomics data, thereby improving the generalization ability of the overall model for the integrated analysis of multiomics data. With applications to gestational diabetes mellitus (GDM), we predicted nine risk protein-coding biomarkers and some potential lncRNA-miRNA-mRNA regulatory axes, which all correlated with GDM. In those regulatory axes, the MALAT1/hsa-miR-144-3p/IRS1 axis was predicted to be the key axis and was identified as being associated with GDM for the first time. In short, as a flexible pipeline, DLRAPom can contribute to molecular pathogenesis research of diseases, effectively predicting potential disease-related noncoding RNA regulatory networks and providing promising candidates for functional research on disease pathogenesis.

DELAYED GREENING 409 encodes a dual-localized pentatricopeptide repeat protein required for chloroplast and mitochondrial development.

In flowering plants, hundreds of RNA editing events occur in the chloroplasts and mitochondria during posttranscriptional processes. Although several pentatricopeptide repeat (PPR) proteins have been shown to form the editosome core, the precise interactions between the different editing factors are still obscure. Here, we isolated an Arabidopsis (Arabidopsis thaliana) PPR protein, designated DELAYED GREENING 409 (DG409), that was dually targeted to chloroplasts and mitochondria. This protein consists of 409 amino acids with 7 PPR motifs but lacks a C-terminal E, E+, or DYW domain. A mild dg409 knockdown mutant displays a sickly phenotype. In this mutant, the young leaves are pale green and turn green at maturity, and the development of chloroplasts and mitochondria is severely disrupted. Complete loss of DG409 function results in defective embryos. Transcriptomic analysis of the dg409 knockdown plants showed some editing defects in genes from both organelles, including CASEINOLYTIC PROTEASE P (clpP)-559, RNA POLYMERASE SUBUNIT ALPHA (rpoA)-200, ACETYL-COA CARBOXYLASE CARBOXYL TRANSFERASE SUBUNIT BETA (accD)-1568, NADH DEHYDROGENASE SUBUNIT 7 (nad7)-1505, and RIBOSOMAL PROTEIN S3 (rps3)-1344. RNA immunoprecipitation showed that DG409 was associated with the targeted transcripts in vivo. Interaction assays revealed that DG409 directly interacted with 2 DYW-type PPR proteins (EARLY CHLOROPLAST BIOGENESIS2 [AtECB2] and DYW DOMAIN PROTEIN2 [DYW2]) and 3 multiple organellar RNA editing factors (MORF2, MORF8, and MORF9). These results indicate that DG409 is involved in RNA editing via protein complexes and is therefore essential for chloroplast and mitochondrial development.

Clinical and Immunological Features of Bronchial Asthma Comorbid Chronic Urticaria: A Retrospective Study.

INTRODUCTION: Asthma and chronic urticaria (CU) are two high prevalent diseases and often coexist. The underlying relationship and potential immunological mechanism between the two diseases are still unclear. The objective of this study was to investigate the clinical and immunological feature of asthma comorbid with CU. METHODS: A retrospective study was conducted. Fifty patients with asthma comorbid CU, 50 patients with asthma, and 50 patients with CU alone were included. Age and sex of the patients enrolled were matched. Data of demographic characteristics, clinical manifestations including disease severity (frequency of symptoms, age of onset, disease duration, symptom score, complication with allergic rhinitis) as well as serum immunological index including total IgE (tIgE), allergen-specific IgE (sIgE), and food-specific IgG4 (FS-IgG4), were collected and analyzed. RESULTS: No significant differences in the frequency of symptoms, age of onset, and disease duration were found among the three groups. The score of asthma control test (ACT) in patients with asthma comorbid CU was significantly lower than that of asthma (p = 0.005); however, compared with patients with CU, the 7-day urticaria activity score (UAS7) of patients with asthma comorbid CU did not show obvious differences. Immunological index showed that the positive rates of tIgE, house dust mite (HDM)-sIgE, and FS-IgG4 were different among the three groups (p < 0.05). Patients with asthma comorbid CU had the highest rate of positive tIgE, moderate and severe positive sIgE to HDM. Egg-specific IgG4 (egg-sIgG4) had the highest positive rate in all groups. Patients of asthma comorbid CU obtained the highest rate of severe positive of egg-sIgG4. CONCLUSION: Our results demonstrated that patients with asthma comorbid CU have lower control level of asthma symptoms, higher tIgE and HDM-sIgE level, and highest rate of severe positive egg-sIgG4. These results indicate that comorbidity of CU in asthma obviously increases the severity of allergens.

T-cell lymphopenia is associated with an increased infecting risk in children after cardiopulmonary bypass.

BACKGROUND: children who undergo CPB operations are at an elevated risk of infection due to immunosuppression. This study aims to investigate the association between lymphopenia following CPB and early postoperative infection in children. METHODS: A retrospective analysis including 41 children under 2 years old underwent CPB. Among them, 9 subjects had an early postoperative infection, and 32 subjects were period-matched without infection. Inflammatory cytokines, serum CRP and PCT values were measured in plasma, additionally, circulating total leucocyte and lymphocyte subpopulations were counted. RESULTS: Infected subjects exhibited significantly higher levels of inflammatory cytokines, including IL-6, IL-8, IL-10, IL-1ß and TNF-α, than non-infected subjects after CPB. Additionally, lower absolute number of lymphocyte and their subpopulations CD3+ T cells, CD4+ T-helper cells and CD8+cytotoxic T-cells, were observed in infected subjects. The impairment of T-cells Immune was found to be associated with higher levels of inflammatory cytokines IL-10. The ROC demonstrated that the absolute number of CD3+ T-cells <1934/ul, CD4+ T helper cells <1203/ul and CD8+cytotoxic T-cells <327/ul were associated with early postoperative infection. CONCLUSION: Higher levels of inflammatory cytokines resulted in T-cells lymphopenia after CPB, which significantly increasing the risk of postoperative infection in infants and young children. IMPACT: Infection complications after cardiopulmonary bypass (CPB) in pediatric CHD patients are serious issues, identifing the infection from after CPB remains a challenging. CPB can release numerous inflammatory cytokines associated with T cells lymphopenia, which increases the risk of postoperative infection after surgery. Monitoring T cells lymphopenia maybe more beneficial to predict early postoperative infection than C-reactive protein and procalcitonin.

Characterizing the post-traumatic growth trajectory in gastric cancer survivors: a population-based longitudinal study.

OBJECTIVES: Post-traumatic growth can improve the quality of life of cancer survivors. The objective of this study was to investigate post-traumatic growth heterogeneity trajectory in perioperative gastric cancer survivors, and to identify characteristics that predict membership for each trajectory. METHODS: Gastric cancer survivors (n = 403) were recruited before surgery, their baseline assessment (including post-traumatic growth and related characteristics) was completed, and post-traumatic growth levels were followed up on the day they left the intensive care unit, at discharge, and 1 month after discharge. Latent growth mixture mode was used to identify the heterogeneous trajectory of post-traumatic growth, and the core predictors of trajectory subtypes were explored using a decision tree model. RESULTS: Three post-traumatic growth development trajectories were identified among gastric cancer survivors: stable high of PTG group (20.6%), fluctuation of PTG group (44.4%), persistent low of PTG group (35.0%). The decision tree model showed anxiety, coping style, and psychological resilience-which was the primary predictor-might be used to predict the PTG trajectory subtypes of gastric cancer survivors. CONCLUSIONS: There was considerable variability in the experience of post-traumatic growth among gastric cancer survivors. Recognition of high-risk gastric cancer survivors who fall into the fluctuation or persistent low of PTG group and provision of psychological resilience-centered support might allow medical professionals to improve patients' post-traumatic growth and mitigate the impact of negative outcomes.

The Clinical Value of Apparent Diffusion Coefficient of Readout Segmentation of Long Variable Echo Trains and Correlation With Ki-67 Expression in Distal Rectal Cancer.

OBJECTIVE: The aim of the study is to explore the clinical value of the apparent diffusion coefficient (ADC) derived from the readout segmentation of long variable echo trains (RESOLVE) technique for identifying clinicopathologic features of distal rectal cancer and correlations between ADC and Ki-67 expression. METHODS: The data of 112 patients with a proven pathology of distal rectal cancer who underwent preoperative magnetic resonance imaging were retrospectively analyzed. The mean ADC value was measured using the "full-layer and center" method. Differences in ADC values and Ki-67 expression in different clinical stages, pathological types, and tumor differentiation were compared using analysis of variance. Correlations between ADC value and clinicopathologic features were assessed using Spearman correlation analysis. RESULTS: Interobserver agreement of confidence levels from 2 radiologists was excellent for ADC measurement ( k =  0.85). Patients with a lower clinical stage, well-differentiated adenocarcinomas, and a higher possibility of mucinous adenocarcinoma exhibited a positive correlation with higher ADC values, but these factors were negatively correlated with Ki-67 expression (all P < 0.05). We found that ADC value was negatively correlated with Ki-67 expression ( r = -0.62, P < 0.001). CONCLUSIONS: The ADC value generated by RESOLVE sequences was significantly associated with clinicopathologic features and Ki-67 expression in patients with distal rectal cancer in this study. Thus, the ADC value could be considered a new noninvasive imaging biomarker that could be helpful in predicting the biological properties of distal rectal cancer.

A versatile Cas12k-based genetic engineering toolkit (C12KGET) for metabolic engineering in genetic manipulation-deprived strains.

The genetic modification of microorganisms is conducive to the selection of high-yield producers of high-value-added chemicals, but a lack of genetic tools hinders the industrialization of most wild species. Therefore, it is crucial to develop host-independent gene editing tools that can be used for genetic manipulation-deprived strains. The Tn7-like transposon from Scytonema hofmanni has been shown to mediate homologous recombination-independent genomic integration after heterologous expression in Escherichia coli, but the integration efficiency of heterologous sequences larger than 5 kb remains suboptimal. Here, we constructed a versatile Cas12k-based genetic engineering toolkit (C12KGET) that can achieve genomic integration of fragments up to 10 kb in size with up to 100% efficiency in challenging strains. Using C12KGET, we achieved the first example of highly efficient genome editing in Sinorhizobium meliloti, which successfully solved the problem that industrial strains are difficult to genetically modify, and increased vitamin B12 production by 25%. In addition, Cas12k can be directly used for transcriptional regulation of genes with up to 92% efficiency due to its naturally inactivated nuclease domain. The C12KGET established in this study is a versatile and efficient marker-free tool for gene integration as well as transcriptional regulation that can be used for challenging strains with underdeveloped genetic toolkits.

Evolving approaches in paediatric thyroid cytopathology: A review.

The guidelines for the workup of thyroid nodules have been established in adult populations and secondarily applied to paediatric populations. In particular, The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is commonly applied to both adult and paediatric thyroid nodules. However, as paediatric nodules have distinct molecular drivers and behavioural trajectories, there is renewed interest in diagnostic and management strategies that are paediatric specific. Here, we review key differences between paediatric and adult thyroid cancer and recent literature evaluating the use of TBSRTC in paediatric populations.

Evaluation and application of American College of Radiology Thyroid Imaging Reporting and Data System for improved malignancy detection in paediatric thyroid nodules.

OBJECTIVE: The American College of Radiology Thyroid Imaging Reporting and Data System (TI-RADS) is a widely used method for the management of adult thyroid nodules. However, its use in paediatric patients is controversial because adult fine needle aspiration biopsy (FNAB) recommendations may lead to delayed diagnoses of cancer in children. The objectives of this study were to evaluate the performance of TI-RADS in paediatric thyroid nodules and to tailor FNAB recommendations for children. METHODS: Consecutive surgically resected paediatric thyroid nodules from two tertiary care centres between 2003 and 2021 were reviewed. Ultrasounds were blindly scored by radiologists according to TI-RADS. Management recommendations based on TI-RADS were evaluated. Various modelling methodologies were used to determine the optimal cutoff for FNAB in children. RESULTS: Of the 96 patients, 79 (82%) were female and the median age at surgery was 16.1 years. Fifty (52%) nodules were malignant on surgical pathology. The area under the receiver operating characteristic curve of TI-RADS for predicting malignancy was 0.78. Adult TI-RADS recommendations would have resulted in 4% of cancerous nodules being lost to follow-up. Modifications to TI-RADS (FNAB of all TR3 nodules ≥1.5 cm, FNAB of TR4 and TR5 nodules ≥0.5 cm, surveillance of nodules ≥1 cm, consider surgery for nodules >4 cm) reduced this missed malignancy rate to 0%. CONCLUSIONS: TI-RADS can risk-stratify paediatric thyroid nodules. However, the system requires modifications to reduce the missed malignancy rate in paediatric thyroid nodules. Our data suggest that lower size thresholds for FNAB are warranted in children.

Investigating the Mechanism of Chinese Medicine Formula AACO Against Chronic Heart Failure by Network Pharmacology Analysis and Experimental Validation.

Background: A traditional Chinese medicine (TCM) formula, containing Astragalus membranaceus (Fisch.) Bunge, Aconitum wilsonii Stapf ex Veitch, Curcuma longa L., and Radix ophiopogonis (AACO), has therapeutic value for the treatment of chronic heart failure (CHF). Objective: This study intends to explore the pharmacological mechanism underlying the activity of the AACO formula against CHF. Materials and Methods: Using the TCM Systems Pharmacology database and Bioinformatics Analysis Tool for Molecular Mechanism of TCM, the active ingredients contained in the herbs of the AACO formula were screened. Meanwhile, the target genes related to these active ingredients were identified and genes correlated with CHF were screened. Protein-protein interaction networks were built to elucidate the relationships between the AACO formula and CHF. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway enrichment analysis were carried out using the DAVID database. A "drug-component-target-disease" network was constructed with Cytoscape 3.7.0. The therapeutic effect of the AACO formula was proven by hemodynamic study, echocardiography evaluation, and histological analysis in transverse aortic constriction-induced CHF mice and was validated in vitro. Results: A total of 105 active ingredients and 1026 related targets were screened and identified, and 240 related targets overlapping with CHF were selected. According to GO analysis, the enriched genes participated in gene expression and cardiac contraction regulation by Ca2+ regulation. From KEGG analysis, the calcium axis was identified as one of the main mechanisms through which the AACO formula exerts an anti-CHF effect. AACO was validated to significantly improve cardiac diastolic and systolic functions in vivo via an increase in the rate of Ca2+ reuptake of the myocardial sarcoplasmic reticulum and improved myocardial contractility in vitro. Conclusions: Network pharmacology is a convenient method to study the complex pharmacological mechanisms of TCM. The calcium axis likely participates in the anti-CHF mechanism of AACO.

Effectiveness of eHealth Interventions in Improving Medication Adherence Among Patients With Cardiovascular Disease: Systematic Review and Meta-Analysis.

BACKGROUND: Nonadherence to medication among patients with cardiovascular diseases undermines the desired therapeutic outcomes. eHealth interventions emerge as promising strategies to effectively tackle this issue. OBJECTIVE: The aim of this study was to conduct a network meta-analysis (NMA) to compare and rank the efficacy of various eHealth interventions in improving medication adherence among patients with cardiovascular diseases (CVDs). METHODS: A systematic search strategy was conducted in PubMed, Embase, Web of Science, Cochrane, China National Knowledge Infrastructure Library (CNKI), China Science and Technology Journal Database (Weipu), and WanFang databases to search for randomized controlled trials (RCTs) published from their inception on January 15, 2024. We carried out a frequentist NMA to compare the efficacy of various eHealth interventions. The quality of the literature was assessed using the risk of bias tool from the Cochrane Handbook (version 2.0), and extracted data were analyzed using Stata16.0 (StataCorp LLC) and RevMan5.4 software (Cochrane Collaboration). The certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. RESULTS: A total of 21 RCTs involving 3904 patients were enrolled. The NMA revealed that combined interventions (standardized mean difference [SMD] 0.89, 95% CI 0.22-1.57), telephone support (SMD 0.68, 95% CI 0.02-1.33), telemonitoring interventions (SMD 0.70, 95% CI 0.02-1.39), and mobile phone app interventions (SMD 0.65, 95% CI 0.01-1.30) were statistically superior to usual care. However, SMS compared to usual care showed no statistical difference. Notably, the combined intervention, with a surface under the cumulative ranking curve of 79.3%, appeared to be the most effective option for patients with CVDs. Regarding systolic blood pressure and diastolic blood pressure outcomes, the combined intervention also had the highest probability of being the best intervention. CONCLUSIONS: The research indicates that the combined intervention (SMS text messaging and telephone support) has the greatest likelihood of being the most effective eHealth intervention to improve medication adherence in patients with CVDs, followed by telemonitoring, telephone support, and app interventions. The results of these network meta-analyses can provide crucial evidence-based support for health care providers to enhance patients' medication adherence. Given the differences in the design and implementation of eHealth interventions, further large-scale, well-designed multicenter trials are needed. TRIAL REGISTRATION: INPLASY 2023120063; https://inplasy.com/inplasy-2023-12-0063/.

Lactobacillus salivarius Ameliorates AFB1-induced hepatotoxicity via PINK1/Parkin-mediated mitophagy in Geese.

Aflatoxin B1 (AFB1) is commonly found in feed ingredients and foods all over the world, posing a significant threat to food safety and public health in animals and humans. Lactobacillus salivarius (L. salivarius) was recorded to improve the intestinal health and performance of chickens. However, whether L. salivarius can alleviate AFB1-induced hepatotoxicity in geese was unknown. A total of 300 Lande geese were randomly assigned to five groups: control group, AFB1 low-dose group (L), L. salivarius+AFB1 low-dose group (LL), AFB1 high dosage groups (H), L. salivarius+AFB1 high dosage groups (LH), respectively. The results showed that the concentrations of ALT, AST, and GGT significantly increased after exposure to AFB1. Similarly, severe damage of hepatic morphology was observed including the hepatic structure injury and inflammatory cell infiltration. The oxidative stress was evidenced by the elevated concentrations of MDA, and decreased activities of GSH-Px, GSH and SOD. The observation of immunofluorescence, real-time PCR, and western blotting showed that the expression of PINK1 and the value of LC3II/LC3I were increased, but that of p62 significantly decreased after AFB1 exposure. Moreover, the supplementation of L. salivarius effectively improved the geese performance, ameliorated AFB1-induced oxidative stress, inhibited mitochondrial mitophagy and enhanced the liver restoration to normal level. The present study demonstrated that L. salivarius ameliorated AFB1-induced the hepatotoxicity by decreasing the oxidative stress, and regulating the expression of PINK1/Parkin-mediated mitophagy in the mitochondria of the geese liver. Furthermore, this investigation suggested that L. salivarius might serve as a novel and safe additive for preventing AFB1 contamination in poultry feed.

Analysis of pathogenic variants in 605 Chinese children with non-syndromic cardiac conotruncal defects based on targeted sequencing.

OBJECTIVE: Deleterious genetic variants comprise one cause of cardiac conotruncal defects (CTDs). Genes associated with CTDs are gradually being identified. In the present study, we aimed to explore the profile of genetic variants of CTD-associated genes in Chinese patients with non-syndromic CTDs. METHODS: Thirty-nine CTD-related genes were selected after reviewing published articles in NCBI, HGMD, OMIM, and HPO. In total, 605 patients with non-syndromic CTDs and 300 healthy controls, all of Han ethnicity, were recruited. High-throughput targeted sequencing was used to detect genetic variants in the protein-coding regions of genes. We performed rigorous variant-level filtrations to identify potentially damaging variants (Dvars) using prediction programs including CADD, SIFT, PolyPhen-2, and MutationTaster. RESULT: Dvars were detected in 66.7% (26/39) of the targeted CTD-associated genes. In total, 11.07% (67/605) of patients with non-syndromic CTDs were found to carry one or more Dvars in targeted CTD-associated genes. Dvars in FOXH1, TBX2, NFATC1, FOXC2, and FOXC1 were common in the CTD cohort (1.5% [9/605], 1.2% [7/605], 1.2% [7/605], 1% [6/605], and 0.5% [3/605], respectively). CONCLUSION: Targeted exon sequencing is a cost-effective approach for the genetic diagnosis of CTDs. Our findings contribute to an understanding of the genetic architecture of non-syndromic CTDs.

AI protein structure prediction-based modeling and mutagenesis of a protostome receptor and peptide ligands reveal key residues for their interaction.

The protostome leucokinin (LK) signaling system, including LK peptides and their G protein-coupled receptors, has been characterized in several species. Despite the progress, molecular mechanisms governing LK peptide-receptor interactions remain to be elucidated. Previously, we identified a precursor protein for Aplysia leucokinin-like peptides (ALKs) that contains the greatest number of amidated peptides among LK precursors in all species identified so far. Here, we identified the first ALK receptor from Aplysia, ALKR. We used cell-based IP1 activation assays to demonstrate that two ALK peptides with the most copies, ALK1 and ALK2, activated ALKR with high potencies. Other endogenous ALK-derived peptides bearing the FXXWX-amide motif also activated ALKR to various degrees. Our examination of cross-species activity of ALKs with the Anopheles LK receptor was consistent with a critical role for the FXXWX-amide motif in receptor activity. Furthermore, we showed, through alanine substitution of ALK1, the highly conserved phenylalanine (F), tryptophan (W), and C-terminal amidation were each essential for receptor activation. Finally, we used an artificial intelligence-based protein structure prediction server (Robetta) and Autodock Vina to predict the ligand-bound conformation of ALKR. Our model predicted several interactions (i.e., hydrophobic interactions, hydrogen bonds, and amide-pi stacking) between ALK peptides and ALKR, and several of our substitution and mutagenesis experiments were consistent with the predicted model. In conclusion, our results provide important information defining possible interactions between ALK peptides and their receptors. The workflow utilized here may be useful for studying other ligand-receptor interactions for a neuropeptide signaling system, particularly in protostomes.

The iron burden of cerebral microbleeds contributes to brain atrophy through the mediating effect of white matter hyperintensity.

The goal of this work was to explore the total iron burden of cerebral microbleeds (CMBs) using a semi-automatic quantitative susceptibility mapping and to establish its effect on brain atrophy through the mediating effect of white matter hyperintensities (WMH). A total of 95 community-dwelling people were enrolled. Quantitative susceptibility mapping (QSM) combined with a dynamic programming algorithm (DPA) was used to measure the characteristics of 1309 CMBs. WMH were evaluated according to the Fazekas scale, and brain atrophy was assessed using a 2D linear measurement method. Histogram analysis was used to explore the distribution of CMBs susceptibility, volume, and total iron burden, while a correlation analysis was used to explore the relationship between volume and susceptibility. Stepwise regression analysis was used to analyze the risk factors for CMBs and their contribution to brain atrophy. Mediation analysis was used to explore the interrelationship between CMBs and brain atrophy. We found that the frequency distribution of susceptibility of the CMBs was Gaussian in nature with a mean of 201 ppb and a standard deviation of 84 ppb; however, the volume and total iron burden of CMBs were more Rician in nature. A weak but significant correlation between the susceptibility and volume of CMBs was found (r = -0.113, P < 0.001). The periventricular WMH (PVWMH) was a risk factor for the presence of CMBs (number: ß = 0.251, P = 0.014; volume: ß = 0.237, P = 0.042; total iron burden: ß = 0.238, P = 0.020) and was a risk factor for brain atrophy (third ventricle width: ß = 0.325, P = 0.001; Evans's index: ß = 0.323, P = 0.001). PVWMH had a significant mediating effect on the correlation between CMBs and brain atrophy. In conclusion, QSM along with the DPA can measure the total iron burden of CMBs. PVWMH might be a risk factor for CMBs and may mediate the effect of CMBs on brain atrophy.

Threshold plasticity of SOI-GST microring resonators.

Spiking Neural Networks, also known as third generation Artificial Neural Networks, have widely attracted more attention because of their advantages of behaving more biologically interpretable and being more suitable for hardware implementation. Apart from using traditional synaptic plasticity, neural networks can also be based on threshold plasticity, achieving similar functionality. This can be implemented using e.g. the Bienenstock, Cooper and Munro rule. This is a classical unsupervised learning mechanism in which the threshold is closely related to the output of the post-synaptic neuron. We show in simulations that the threshold characteristics of the nonlinear effects of a microring resonator integrated with Ge2Sb2Te5 demonstrate some complex dependencies on the intracavity refractive index, attenuation, and wavelength detuning of the incident optical pulse, and exhibit class II excitability. We also show that we are able to modify the threshold power of the microring resonator by the changes of the refractive index and loss of Ge2Sb2Te5, due to transitions between the crystalline and amorphous states. Simulations show that the presented device exhibits both excitatory and inhibitory learning behavior, either lowering or raising the threshold.

Fall-related Injuries and Opioid Administration Among Veterans With Dementia in US Department of Veterans Affairs Community Living Centers.

OBJECTIVES: Opioid use is associated with fall-related injuries (FRI) among older adults, especially those with dementia. We examined FRI following changes in national opioid safety initiatives over 3 regulatory periods [preinitiatives baseline (period 1): October 2012 to June 2013; post-Veteran Affairs (VA) opioid safety initiative (period 2): January 2014 to November 2015; post-VA and CDC opioid prescribing guidelines (period 3): March 2017 to September 2018] among Department of VA Community Living Center (CLC) long-stay residents with dementia. DATA: VA provided and purchased care records, Medicare claims, CLC Minimum Data Set (MDS) assessments. VA bar-code medication administration data, VA outpatient prescription refill data, and Medicare Part D data were used to capture medication from inpatient, outpatient, and Medicare sources. SETTINGS AND PARTICIPANTS: A total of 12,229 long-stay CLC residents with dementia between October 2012 and September 2018. METHODS: We applied Veteran-regulatory period level (1) generalized linear model to examine the unadjusted and adjusted trends of FRI, and (2) difference-in-difference model with propensity score weighting to examine the relationship between opioid safety initiatives and FRI in 3 regulatory periods. We applied propensity score weighting to enable the cohorts in periods 2 and 3 had similar indications for opioid administration as in period 1. RESULTS: FRI prevalence per month among CLC residents with Alzheimer disease and related dementias decreased from 3.1% in period 1 to 1.6% and 1.2% in periods 2 and 3, and the adjusted probability of FRI was 17% and 40% lower in periods 2 and 3 compared with period 1. The any, incident, and continued opioid administration were significantly associated with higher FRI, whereas the differences in FRI probabilities between opioid and nonopioid users had no significant changes over the 3 regulatory periods. CONCLUSIONS: FRI was reduced among CLC residents with Alzheimer disease and related dementias receiving care in VA CLCs over the 3 regulatory periods, but the FRI reduction was not significantly associated with opioid safety initiatives. Other interventions that potentially targeted falls are likely to have helped reduce these fall events. Future studies could examine whether opioid use reduction ultimately benefitted nursing home residents by focusing on other possible outcomes or whether such reduction only resulted in more untreated pain.