Differential assembly diversifies GABAA receptor structures and signalling.

Type A γ-aminobutyric acid receptors (GABAARs) are pentameric ligand-gated chloride channels that mediate fast inhibitory signalling in neural circuits1,2 and can be modulated by essential medicines including general anaesthetics and benzodiazepines3. Human GABAAR subunits are encoded by 19 paralogous genes that can, in theory, give rise to 495,235 receptor types. However, the principles that govern the formation of pentamers, the permutational landscape of receptors that may emerge from a subunit set and the effect that this has on GABAergic signalling remain largely unknown. Here we use cryogenic electron microscopy to determine the structures of extrasynaptic GABAARs assembled from α4, ß3 and δ subunits, and their counterparts incorporating γ2 instead of δ subunits. In each case, we identified two receptor subtypes with distinct stoichiometries and arrangements, all four differing from those previously observed for synaptic, α1-containing receptors4-7. This, in turn, affects receptor responses to physiological and synthetic modulators by creating or eliminating ligand-binding sites at subunit interfaces. We provide structural and functional evidence that selected GABAAR arrangements can act as coincidence detectors, simultaneously responding to two neurotransmitters: GABA and histamine. Using assembly simulations and single-cell RNA sequencing data8,9, we calculated the upper bounds for receptor diversity in recombinant systems and in vivo. We propose that differential assembly is a pervasive mechanism for regulating the physiology and pharmacology of GABAARs.

Genome-wide identification, characterization and expression of C2H2 zinc finger gene family in Opisthopappus species under salt stress.

BACKGROUND: The C2H2 zinc finger protein family plays important roles in plants. However, precisely how C2H2s function in Opisthopappus (Opisthopappus taihangensis and Opisthopappus longilobus) remains unclear. RESULTS: In this study, a total of 69 OpC2H2 zinc finger protein genes were identified and clustered into five Groups. Seven tandem and ten fragment repeats were found in OpC2H2s, which underwent robust purifying selection. Of the identified motifs, motif 1 was present in all OpC2H2s and conserved at important binding sites. Most OpC2H2s possessed few introns and exons that could rapidly activate and react when faced with stress. The OpC2H2 promoter sequences mainly contained diverse regulatory elements, such as ARE, ABRE, and LTR. Under salt stress, two up-regulated OpC2H2s (OpC2H2-1 and OpC2H2-14) genes and one down-regulated OpC2H2 gene (OpC2H2-7) might serve as key transcription factors through the ABA and JA signaling pathways to regulate the growth and development of Opisthopappus species. CONCLUSION: The above results not only help to understand the function of C2H2 gene family but also drive progress in genetic improvement for the salt tolerance of Opisthopappus species.

Labeling and Diagnostic Value of miRNA-28-3p in Patients with Nasopharyngeal Carcinoma.

Objective: To explore how miRNA-28-3p targets BIN1 and affects the biological behavior of nasopharyngeal carcinoma cells, and to evaluate its potential as a predictive biomarker for NPC. Methods: We studied 100 nasopharyngeal carcinoma patients who underwent surgery between January 2021 and January 2022. Tissues from tumors and adjacent normal areas were analyzed. Participants were categorized into two groups: one with nasopharyngeal carcinoma and another with adjacent normal tissue. Additionally, the nasopharyngeal carcinoma cell line CNE-2 was divided into three groups: an untreated control, a negative control with NC plasmid, and a test group treated with a miRNA-28-3p inhibitor. Key techniques included PCR, Western blotting, CCK-8, flow cytometry, focusing on the interactions between miRNA-28-3p and BIN1 and their predictive significance for NPC. Results: miRNA-28-3p levels were significantly higher in nasopharyngeal carcinoma tissues compared to adjacent normal tissues (P < .05). The predictive performance of miRNA-28-3p for NPC featured an AUC > 0.75 with sensitivity and specificity both exceeding 70% (P < .001). In nasopharyngeal carcinoma cells, miRNA-28-3p levels were significantly elevated compared to normal cells (P < .05). Transfection with the miRNA-28-3p inhibitor increased apoptosis and BIN1 protein levels while reducing cell proliferation, invasion, and migration significantly (P < .05). Conclusion: miRNA-28-3p is overexpressed in nasopharyngeal carcinoma and inhibits tumor cell proliferation, migration, and invasion, while promoting apoptosis by targeting BIN1. The level of miRNA-28-3p expression serves as a sensitive indicator for predicting nasopharyngeal carcinoma, affirming its potential as a diagnostic biomarker and underscoring the significance of these findings in enhancing understanding and clinical management of NPC.

Responsive Alternative Splicing Events of Opisthopappus Species against Salt Stress.

Salt stress profoundly affects plant growth, prompting intricate molecular responses, such as alternative splicing (AS), for environmental adaptation. However, the response of AS events to salt stress in Opisthopappus (Opisthopappus taihangensis and Opisthopappus longilobus) remains unclear, which is a Taihang Mountain cliff-dwelling species. Using RNA-seq data, differentially expressed genes (DEGs) were identified under time and concentration gradients of salt stress. Two types of AS, skipped exon (SE) and mutually exclusive exons (MXE), were found. Differentially alternative splicing (DAS) genes in both species were significantly enriched in "protein phosphorylation", "starch and sucrose metabolism", and "plant hormone signal transduction" pathways. Meanwhile, distinct GO terms and KEGG pathways of DAS occurred between two species. Only a small subset of DAS genes overlapped with DEGs under salt stress. Although both species likely adopted protein phosphorylation to enhance salt stress tolerance, they exhibited distinct responses. The results indicated that the salt stress mechanisms of both Opisthopappus species exhibited similarities and differences in response to salt stress, which suggested that adaptive divergence might have occurred between them. This study initially provides a comprehensive description of salt responsive AS events in Opisthopappus and conveys some insights into the molecular mechanisms behind species tolerance on the Taihang Mountains.

Adaptive evolution characteristics of mitochondrial genomes in genus Aparapotamon (Brachyura, Potamidae) of freshwater crabs.

BACKGROUND: Aparapotamon, a freshwater crab genus endemic to China, includes 13 species. The distribution of Aparapotamon spans the first and second tiers of China's terrain ladder, showing great altitudinal differences. To study the molecular mechanisms of adaptive evolution in Aparapotamon, we performed evolutionary analyses, including morphological, geographical, and phylogenetic analyses and divergence time estimation. We sequenced the mitogenomes of Aparapotamon binchuanense and Aparapotamon huizeense for the first time and resequenced three other mitogenomes of Aparapotamon grahami and Aparapotamon gracilipedum. These sequences were combined with NCBI sequences to perform comparative mitogenome analysis of all 13 Aparapotamon species, revealing mitogenome arrangement and the characteristics of protein-coding and tRNA genes. RESULTS: A new species classification scheme of the genus Aparapotamon has been detected and verified by different aspects, including geographical, morphological, phylogenetics and comparative mitogenome analyses. Imprints from adaptive evolution were discovered in the mitochondrial genomes of group A, including the same codon loss at position 416 of the ND6 gene and the unique arrangement pattern of the tRNA-Ile gene. Multiple tRNA genes conserved or involved in adaptive evolution were detected. Two genes associated with altitudinal adaptation, ATP8 and ND6, which experienced positive selection, were identified for the first time in freshwater crabs. CONCLUSIONS: Geological movements of the Qinghai-Tibet Plateau and Hengduan Mountains likely strongly impacted the speciation and differentiation of the four Aparapotamon groups. After some group A species dispersed from the Hengduan Mountain Range, new evolutionary characteristics emerged in their mitochondrial genomes, facilitating adaptation to the low-altitude environment of China's second terrain tier. Ultimately, group A species spread to high latitudes along the upper reaches of the Yangtze River, showing faster evolutionary rates, higher species diversity and the widest distribution.

Real-world clinical analysis in 190 advanced NSCLC patients with uncommon EGFR mutations: A multi-center study.

Differently from epidermal growth factor receptor (EGFR) 19Del and L858R mutations, the panoramic description of uncommon EGFR mutations is far from mature. Our understanding of its population characteristics, treatment response, and drug resistance mechanisms needs urgent expansion and deepening. Our study enrolled 437 patients with non-small-cell lung cancer from four clinical centers and who had uncommon EGFR mutations. The clinical characteristics of all patients and the treatment outcomes of 190 advanced patients who received pharmacotherapy were analyzed. Moreover, the acquired resistance mechanisms were explored based on 53 tissue or liquid re-biopsy data in 45 patients. Patients with EGFR 20ins had a shorter survival time compared with patients with non-20ins mutations. In total, 149 cases had received EGFR-tyrosine kinase inhibitors (TKI); afatinib was significantly superior to other EGFR-TKIs both in ORR and mPFS in all uncommon mutations and especially in the L861Q group. The most common acquired drug resistance mechanism was MET amplification, followed by EGFR T790M, which was significantly different from common EGFR mutations.

FOXN4 affects myocardial ischemia-reperfusion injury through HIF-1α/MMP2-mediated ferroptosis of cardiomyocytes.

Myocardial ischemia-reperfusion injury (MIRI) is an important factor leading to myocardial injury and necrosis, and can induce ischemic heart disease. Forkhead box protein N4 (FOXN4) belongs to the gene family of Fork head domain (Fox) transcription factors and plays an important role in heart formation and function. However, whether FOXN4 is involved in MIRI progression is unknown. In this study, we investigated the clinicopathological significance and potential mechanisms of FOXN4 in MIRI. The expressions of FOXN4 and MMP2 were measured by quantitative reverse transcriptase polymerase chain reaction, apoptosis was detected by flow cytometry, and cell viability was detected by examining EdU incorporation into DNA. The signaling pathway related proteins FOXN4, MMP2, HIF-1α, apoptosis-related proteins Bcl-2 and Bax, and ferroptosis-related proteins TFR1 and IREB2 were detected by western blot, the levels of malondialdehyde (MDA), Fe2+, reactive oxygen species (ROS), and glutathione were detected by commercially available kits, and the cardiac histopathology after MIRI was evaluated by hematoxylin and eosin staining. We found that knockdown of FOXN4 alleviated oxidative stress, inhibited ROS production, and inhibited ferroptosis in MIR-injured tissues and cardiomyocytes. In addition, knockdown of FOXN4 inhibited myocardial injury, improved myocardial cell viability, restored myocardial function, and alleviated MIRI. We interrogated the mechanism and found that FOXN4 can enhance its binding to HIF-1α, up-regulate the expression of MMP2, and mediate ferroptosis to regulate the functional activity of cardiomyocytes to affect the progression of MIRI. This study provides new insights into the role of FOXN4 in MIRI progression and suggests that FOXN4 may represent a potential therapeutic target in MIRI progression by regulating the active function of cardiomyocytes through HIF-1α/MMP2-mediated ferroptosis.

A combined passivator of zeolite and calcium magnesium phosphate fertilizer: Passivation behavior and mechanism for Cd (II) in composting.

Passivation of heavy metals is one of the most efficient techniques to improve the quality of compost. Many studies confirmed the passivation effect of passivators (e.g., zeolite and calcium magnesium phosphate fertilizer) on cadmium (Cd), but passivators with single component could not effectively passivate Cd in the long-term operation of composting. In the present study, a combined passivator of zeolite and calcium magnesium phosphate fertilizer (ZCP) was used to explore its impacts of adding at different composting periods (heating period, thermophilic period, cooling period) on the Cd control, compost quality (e.g., temperature, moisture content and humification), microbial community structure as well as the compost available forms of Cd and addition strategy of ZCP. Results showed that Cd passivation rate could be increased by 35.70-47.92% under all treatments in comparison to the control treatment. By altering bacterial community structure, reducing Cd bioavailability and improving the chemical properties of the compost, the combined inorganic passivator could achieve high efficiency for Cd passivation. To sum up, the addition of ZCP at different composting periods has effects on the process and quality of composting, which could provide ideas for the optimization of the passivators addition strategy.

A qualitative analysis of stress experiences and coping strategies in adolescents with Crohn's disease.

BACKGROUND: In this study, we investigated the coping mechanisms and stress perceptions of adolescent patients with Crohn's disease. METHODS: Using semi-structured face-to-face interviews, we conducted an extensive qualitative study of the disease perceptions, stress experiences, and corresponding coping mechanisms in adolescent patients with Crohn's disease. We used Colaizzi content analysis to synthesize the themes. RESULTS: The two main themes in this study were inappropriate coping mechanisms and physical and psychological stress. The primary initiators of physical and psychological stress in adolescents with Crohn's disease were weak disease perception, symptom distress, negative emotions, lack of support, and multiple stressors. The decrease in self-management and self-control induced by the initiators led to changes in cognition, emotions, and attitudes, which subsequently led to poor coping behavior. CONCLUSION: Adolescents with Crohn's disease can better combat the condition by implementing appropriate coping strategies. Their mental health should be given attention, and a multidisciplinary team should be assembled to provide them with supportive care.

Risk factors for antibiotic resistance and mortality in patients with bloodstream infection of Escherichia coli.

This study aimed to investigate the risk factors for bloodstream infection (BSI) caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli) and related mortality. The clinical data of 388 patients with E. coli BSI were analyzed. Blood cultures were performed and the antimicrobial susceptibility profiles of the resulting isolates were determined. Four single-nucleotide polymorphisms (rs231775, rs12343816, rs16944, and rs2233406) were genotyped using real-time PCR. ESBL were detected by disk diffusion confirmatory testing. Univariate and multivariate regression analyses were applied to identify the risk factors for ESBL-producing isolates and the BSI-induced mortality. The prevalence of ESBL-producing E. coli in BSI patients was 40.98%. E. coli isolates were commonly susceptible to carbapenem and ß-lactam/ß-lactamase inhibitor combinations. The major ESBL genes were CTX-M-14, CTX-M-55, CTX-M-15, and CTX-M-27. The proportion of CTX-M-15 was significantly higher in patients over 70 years and those receiving stomach tube catheterization. Nosocomial infection, biliary tract infection, stomach tube catheterization, and previous cephalosporin administration were independent risk factors for ESBL-producing isolates. ESBL positivity, nosocomial infection, and cancer were independent risk factors of mortality. Two genetic polymorphisms associated with inflammation activation, rs231775 A allele and rs2233406 T allele, significantly increased the mortality risk of E. coli BSI with a risk ratio (95% CI) of 1.93 (1.05-3.55) and 4.38 (2.07-9.29), respectively. For patients with nosocomial infection, biliary tract infection, and cancer, the monitor of BSI and antibiotic susceptibility should be enhanced. The invasive procedures should be minimized. rs231775 and rs2233406 are promising prognostic markers for E. coli BSI patients.

Photoaffinity labeling identifies an intersubunit steroid-binding site in heteromeric GABA type A (GABAA) receptors.

Allopregnanolone (3α5α-P), pregnanolone, and their synthetic derivatives are potent positive allosteric modulators (PAMs) of GABAA receptors (GABAARs) with in vivo anesthetic, anxiolytic, and anti-convulsant effects. Mutational analysis, photoaffinity labeling, and structural studies have provided evidence for intersubunit and intrasubunit steroid-binding sites in the GABAAR transmembrane domain, but revealed only little definition of their binding properties. Here, we identified steroid-binding sites in purified human α1ß3 and α1ß3γ2 GABAARs by photoaffinity labeling with [3H]21-[4-(3-(trifluoromethyl)-3H-diazirine-3-yl)benzoxy]allopregnanolone ([3H]21-pTFDBzox-AP), a potent GABAAR PAM. Protein microsequencing established 3α5α-P inhibitable photolabeling of amino acids near the cytoplasmic end of the ß subunit M4 (ß3Pro-415, ß3Leu-417, and ß3Thr-418) and M3 (ß3Arg-309) helices located at the base of a pocket in the ß+-α- subunit interface that extends to the level of αGln-242, a steroid sensitivity determinant in the αM1 helix. Competition photolabeling established that this site binds with high affinity a structurally diverse group of 3α-OH steroids that act as anesthetics, anti-epileptics, and anti-depressants. The presence of a 3α-OH was crucial: 3-acetylated, 3-deoxy, and 3-oxo analogs of 3α5α-P, as well as 3ß-OH analogs that are GABAAR antagonists, bound with at least 1000-fold lower affinity than 3α5α-P. Similarly, for GABAAR PAMs with the C-20 carbonyl of 3α5α-P or pregnanolone reduced to a hydroxyl, binding affinity is reduced by 1,000-fold, whereas binding is retained after deoxygenation at the C-20 position. These results provide a first insight into the structure-activity relationship at the GABAAR ß+-α- subunit interface steroid-binding site and identify several steroid PAMs that act via other sites.

Development and validation of a nomogram for assessing survival in extensive-stage small-cell lung cancer patients with superior vena cava syndrome referred for thoracic radiotherapy: a comparison of upfront vs. consolidative approaches.

PURPOSE: This study sought to design and validate a nomogram capable of predicting outcomes in extensive-stage small-cell lung cancer (ES-SCLC) patients with superior vena cava syndrome (SVCS) based upon the timing of their radiotherapy treatment. METHODS: We retrospectively analyzed data from 175 ES-SCLC patients with SCVS, comparing outcomes between those that underwent upfront thoracic radiotherapy (initial radiotherapy with simultaneous chemotherapy) and those that underwent consolidative thoracic radiotherapy (following 4-6 cycles of chemotherapy). Significant predictors of patient outcomes were identified using a Cox proportional hazard model and were used to construct our nomogram. This model was subsequently validated using receiver operating characteristic (ROC) curves, concordance index (C-index) values, and a risk classification system in order to evaluate its discriminative and predictive accuracy. RESULTS: The overall survival (OS) of ES-SCLC patients with SVCS that underwent chemotherapy (CT), consolidative thoracic radiotherapy (cc-TRT), and upfront thoracic radiotherapy (cu-TRT) was 8.2, 11.7, and 14.9 months, respectively (p < 0.001), with respective progression-free survival (PFS) durations of 3.3, 5.0, and 7.3 months (p < 0.001). A multivariate regression analysis revealed age, gender, ECOG performance status, sites of tumor metastasis, and treatment approach to all be independent predictors of survival outcomes. A nomogram was therefore developed incorporating these factors. C­index values upon internal and external validation of this nomogram were 0.7625 and 0.7959, respectively, and ROC and calibration curves revealed this model to be accurate and consistent. CONCLUSIONS: We found that upfront thoracic radiotherapy in combination with chemotherapy may be associated with a positive impact on outcomes in ES-SCLC patients with SVCS.

Factors Influencing Nurses' Work Interruption in Wuhan Isolation Wards During the COVID-19 Pandemic.

BACKGROUND Through January 2021, the novel coronavirus (COVID-19) continued to create significant pressure on medical staff who have worked to treat patients with the disease and control its spread. This study aimed to increase understanding of the situation and influencing factors of nurses' work interruption in Wuhan's isolation ward during the COVID-19 pandemic. MATERIAL AND METHODS A self-designed general situation questionnaire and work interruption questionnaire were used to survey 160 nurses from Beijing, Chongqing, and Jilin who worked during the COVID-19 pandemic in Wuhan in March 2020. The questionnaire could only be answered once by each nurse via a WeChat account. The submitted answers were verified by 2 researchers. RESULTS The results showed that the rate of interruption of work among nurses in the isolation ward was 25%, and the rate of nurses experiencing a negative experience was 96.9%. The results of univariate analysis showed that the following factors were related to the work interruption of the nurses in the isolation ward (all P<0.05): emergency public incident training; emergency public incident treatment experience; knowledge of COVID-19 pneumonia; hours worked per shift in the quarantine area; and negative physiologic experience. Logistic regression analysis showed that negative experience, hours worked per shift, and emergency public incident training were the independent factors influencing work interruption among nurses in the isolation wards. CONCLUSIONS The incidence of interruption of work among nurses in the isolation ward was 25%. Negative experiences, long working hours per shift, and lack of emergency public incident training made the nurses more prone to work interruption.

Acute severe radiation pneumonitis among non-small cell lung cancer (NSCLC) patients with moderate pulmonary dysfunction receiving definitive concurrent chemoradiotherapy: Impact of pre-treatment pulmonary function parameters.

PURPOSE: Severe acute radiation pneumonitis (SARP) is a life-threatening complication of thoracic radiotherapy. Pre-treatment pulmonary function (PF) may influence its incidence. We have previously reported on the incidence of SARP among patients with moderate pulmonary dysfunction who received definitive concurrent chemoradiotherapy (dCCRT) for non-small cell lung cancer (NSCLC). METHODS: The clinical outcomes, dose-volume histograms (DVH), and PF parameters of 122 patients (forced expiratory volume in 1 s [FEV1%]: 60-69%) receiving dCCRT between 2013 and 2019 were recorded. SARP was defined as grade ≥3 RP occurring during or within 3 months after CCRT. Logistic regression, receiver operating characteristics curves (ROC), and hazard ratio (HR) analyses were performed to evaluate the predictive value of each factor for SARP. RESULTS: Univariate and multivariate analysis indicated that the ratio of carbon monoxide diffusing capacity (DLCO%; odds ratio [OR]: 0.934, 95% confidence interval [CI] 0.896-0.974, p = 0.001) and mean lung dose (MLD; OR: 1.002, 95% CI 1.001-1.003, p = 0.002) were independent predictors of SARP. The ROC AUC of combined DLCO%/MLD was 0.775 (95% confidence interval [CI]: 0.688-0.861, p = 0.001), with a sensitivity and specificity of 0.871 and 0.637, respectively; this was superior to DLCO% (0.656) or MLD (0.667) alone. Compared to the MLD-low/DLCO%-high group, the MLD-high/DLCO%-low group had the highest risk for SARP, with an HR of 9.346 (95% CI: 2.133-40.941, p = 0.003). CONCLUSION: The DLCO% and MLD may predict the risk for SARP among patients with pre-treatment moderate pulmonary dysfunction who receive dCCRT for NSCLC. Prospective studies are needed to validate our findings.

Competitive Antagonism of Etomidate Action by Diazepam: In Vitro GABAA Receptor and In Vivo Zebrafish Studies.

BACKGROUND: Recent cryo-electron microscopic imaging studies have shown that in addition to binding to the classical extracellular benzodiazepine binding site of the α1ß3γ2L γ-aminobutyric acid type A (GABAA) receptor, diazepam also binds to etomidate binding sites located in the transmembrane receptor domain. Because such binding is characterized by low modulatory efficacy, the authors hypothesized that diazepam would act in vitro and in vivo as a competitive etomidate antagonist. METHODS: The concentration-dependent actions of diazepam on 20 µM etomidate-activated and 6 µM GABA-activated currents were defined (in the absence and presence of flumazenil) in oocyte-expressed α1ß3γ2L GABAA receptors using voltage clamp electrophysiology. The ability of diazepam to inhibit receptor labeling of purified α1ß3γ2L GABAA receptors by [H]azietomidate was assessed in photoaffinity labeling protection studies. The impact of diazepam (in the absence and presence of flumazenil) on the anesthetic potencies of etomidate and ketamine was compared in a zebrafish model. RESULTS: At nanomolar concentrations, diazepam comparably potentiated etomidate-activated and GABA-activated GABAA receptor peak current amplitudes in a flumazenil-reversible manner. The half-maximal potentiating concentrations were 39 nM (95% CI, 27 to 55 nM) and 26 nM (95% CI, 16 to 41 nM), respectively. However, at micromolar concentrations, diazepam reduced etomidate-activated, but not GABA-activated, GABAA receptor peak current amplitudes in a concentration-dependent manner with a half-maximal inhibitory concentration of 9.6 µM (95% CI, 7.6 to 12 µM). Diazepam (12.5 to 50 µM) also right-shifted the etomidate-concentration response curve for direct activation without reducing the maximal response and inhibited receptor photoaffinity labeling by [H]azietomidate. When administered with flumazenil, 50 µM diazepam shifted the etomidate (but not the ketamine) concentration-response curve for anesthesia rightward, increasing the etomidate EC50 by 18-fold. CONCLUSIONS: At micromolar concentrations and in the presence of flumazenil to inhibit allosteric modulation via the classical benzodiazepine binding site of the GABAA receptor, diazepam acts as an in vitro and in vivo competitive etomidate antagonist.

Decomposing differences in depressive symptoms between older rural-to-urban migrant workers and their counterparts in mainland China.

BACKGROUND: There has been an increase in older rural-to-urban migrant workers (aged 50 and above) in mainland China, little known about their depressive symptoms. The aim of this study was to identify depressive symptoms among older rural-to-urban migrant workers, as well as explored the factors leading to differences in depressive symptoms between older rural-to-urban migrant workers and their rural counterparts (older rural dwellers) and urban counterparts (older urban residents) in mainland China. The results provided a comprehensive understanding of the depressive symptoms of older rural-to-urban migrant workers, and had great significance for improving the depressive symptoms for this vulnerable group. METHODS: Data were derived from the China Health and Retirement Longitudinal Study (CHARLS) conducted in 2015, and coarsened exact matching (CEM) method was employed to control confounding factors. This study employed a Chinese version 10-item short form of the Center for Epidemiologic Studies-Depression Scale (CES-D 10) to measure depressive symptoms, and used the Social-Ecological Model as a framework to explore influential factors related to depressive symptoms. Specifically, the approach of Fairlie's decomposition was used to parse out differences into observed and unobserved components. RESULTS: After matching, our findings indicated that the prevalence of depressive symptoms in older rural-to-urban migrant workers was lower than older rural dwellers; and the prevalence of depressive symptoms in older rural-to-urban migrant workers was higher than older urban residents. Fairlie's decomposition analysis indicated that type of in-house shower, sleeping time at night and ill in the last month were proved to be major contributors to the differences in depressive symptoms between older rural-to-urban migrant workers and older rural dwellers; self-reported health and sleeping time at night were proved to be major contributors to the differences in depressive symptoms between older rural-to-urban migrant workers and older urban residents. CONCLUSIONS: Differences in depressive symptoms between older rural-to-urban migrant workers and their rural and urban counterparts did exist. Our findings contributed to a more reliable understanding in depressive symptoms among older rural-to-urban migrant workers. Our findings would be of referential significance for improving older rural-to-urban migrant workers' depressive symptoms.

Differential Sensitivity of Target Genes to Translational Repression by miR-17~92.

MicroRNAs (miRNAs) are thought to exert their functions by modulating the expression of hundreds of target genes and each to a small degree, but it remains unclear how small changes in hundreds of target genes are translated into the specific function of a miRNA. Here, we conducted an integrated analysis of transcriptome and translatome of primary B cells from mutant mice expressing miR-17~92 at three different levels to address this issue. We found that target genes exhibit differential sensitivity to miRNA suppression and that only a small fraction of target genes are actually suppressed by a given concentration of miRNA under physiological conditions. Transgenic expression and deletion of the same miRNA gene regulate largely distinct sets of target genes. miR-17~92 controls target gene expression mainly through translational repression and 5'UTR plays an important role in regulating target gene sensitivity to miRNA suppression. These findings provide molecular insights into a model in which miRNAs exert their specific functions through a small number of key target genes.

Identifying Drugs that Bind Selectively to Intersubunit General Anesthetic Sites in the α1ß3γ2 GABAAR Transmembrane Domain.

GABAA receptors (GABAARs) are targets for important classes of clinical agents (e.g., anxiolytics, anticonvulsants, and general anesthetics) that act as positive allosteric modulators (PAMs). Previously, using photoreactive analogs of etomidate ([3H]azietomidate) and mephobarbital [[3H]1-methyl-5-allyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid ([3H]R-mTFD-MPAB)], we identified two homologous but pharmacologically distinct classes of general anesthetic binding sites in the α1ß3γ2 GABAAR transmembrane domain at ß +-α - (ß + sites) and α +-ß -/γ +-ß - (ß - sites) subunit interfaces. We now use competition photolabeling with [3H]azietomidate and [3H]R-mTFD-MPAB to identify para-substituted propofol analogs and other drugs that bind selectively to intersubunit anesthetic sites. Propofol and 4-chloro-propofol bind with 5-fold selectivity to ß +, while derivatives with bulkier lipophilic substitutions [4-(tert-butyl)-propofol and 4-(hydroxyl(phenyl)methyl)-propofol] bind with ∼10-fold higher affinity to ß - sites. Similar to R-mTFD-MPAB and propofol, these drugs bind in the presence of GABA with similar affinity to the α +-ß - and γ +-ß - sites. However, we discovered four compounds that bind with different affinities to the two ß - interface sites. Two of these bind with higher affinity to one of the ß - sites than to the ß + sites. We deduce that 4-benzoyl-propofol binds with >100-fold higher affinity to the γ +-ß - site than to the α +-ß - or ß +-α - sites, whereas loreclezole, an anticonvulsant, binds with 5- and 100-fold higher affinity to the α +-ß - site than to the ß + and γ +-ß - sites. These studies provide a first identification of PAMs that bind selectively to a single intersubunit site in the GABAAR transmembrane domain, a property that may facilitate the development of subtype selective GABAAR PAMs.

Effects of leaf colorness, pigment contents and allelochemicals on the orientation of the Asian citrus psyllid among four Rutaceae host plants.

BACKGROUND: Asian citrus psyllid (ACP) is the primary vector responsible for the transmission of the phloem-limited bacteria Candidatus Liberibacter spp., associated with huanglongbing (HLB), which causes great loss to the citrus industry. Although the roles of leaf color and volatile compounds in the orientation of ACP have been proven, the quantification of color and allelochemicals in the host plant are kept unclear, especially in wild citrus germplasms. RESULTS: Chongyi wild mandarin significantly attracted more ACP than wild Hong Kong kumquat, 'Gannan zao' navel orange and orange jasmine did in the four-choice and olfactometer assays. The color parameters of the tender leaves from Chongyi wild mandarin and 'Gannan zao' were similar. The yellow color in both of them was less saturated than that of the other two plants species, but Chongyi wild mandarin had significant lower carotenoid content (P < 0.05). Notably metabolic profiling differences were observed among the healthy tender shoots from the four tested plants via UPLC-QQQ-MS and GC-MS analyses. Comparing with the other three plant species, 66 and 50 metabolites with significantly different contents in Chongyi wild mandarin were selected as UPLC-identified and GC-identified metabolites of interest (P < 0.05), respectively. Flavonoids accounted for a large group of secondary metabolites of interest, which may function as stimulants or repellents of ACP. Higher content of salicylic acid o-hexoside and lower content of (+)-jasmonic acid in Chongyi wild mandarin may lead to higher amount of methyl salicylate (an ACP attractant) and lower amount of trans-ocimene (an attractant to herbivores' natural enemies) as well as the suppression of JA-mediated wounding response. This kind of synergistic or antagonistic effect among the metabolites differentially accumulated in Chongyi wild mandarin made it a more attractive host plant to ACP. CONCLUSIONS: Less saturated yellow color, high amount of attractants, low amount of repellents and insensitivity of JA-mediated wounding response are the four possible reasons why Chongyi wild mandarin attracted more ACP. This work may shed light on the olfactory and visual response of ACP to wild citrus germplasm hosts, and suggest the feasibility of developing ACP attractants or repellents patterned on potential metabolites.

A Novel Nomogram and Risk Classification System Predicting the Cancer-Specific Survival of Patients with Initially Diagnosed Metastatic Esophageal Cancer: A SEER-Based Study.

BACKGROUND: Metastatic esophageal cancer (mEC) is the end stage of esophageal cancer. We aimed to construct a predictive model predicting the cancer-specific survival (CSS) of mEC patients. METHODS: Data from 1917 patients with initially diagnosed mEC were extracted from the Surveillance, Epidemiology, and End Results database between 2010 and 2015. Patients were randomly divided into the training and validation cohorts (7:3). Cox regression was conducted to select the predictors of CSS. The validation of the nomogram was performed using concordance index (C-index), calibration curves, and decision curve analyses (DCAs). RESULTS: Cancer-specific death occurred in 1559/1917 (81.3%) cases. Multivariate Cox regression indicated that factors including age, sex, grade at diagnosis, number of metastatic organs at diagnosis, pathological type, local treatment, and chemotherapy were independent predictors of CSS. Based on these factors, a predictive model was built and virtualized by nomogram. The C-index of the nomogram was 0.762. The calibration curves showed good consistency of CSS between the actual observation and the nomogram prediction, and the DCA showed great clinical usefulness of the nomogram. A risk classification system was built that could perfectly classify mEC patients into three risk groups. In the total cohort, the median CSS of patients in the low-, intermediate- and high-risk groups was 11.0 months (95% confidence interval [CI] 10.1-11.9), 8.0 months (95% CI 7.3-8.7), and 2.0 months (95% CI 1.8-2.2), respectively. CONCLUSIONS: We constructed a nomogram and a corresponding risk classification system predicting the CSS of patients with initially diagnosed mEC. These tools can assist in patient counseling and guiding treatment decision making.