Single-cell transcriptomic analysis identifies an immune-prone population in erythroid precursors during human ontogenesis.

Nonimmune cells can have immunomodulatory roles that contribute to healthy development. However, the molecular and cellular mechanisms underlying the immunomodulatory functions of erythroid cells during human ontogenesis remain elusive. Here, integrated, single-cell transcriptomic studies of erythroid cells from the human yolk sac, fetal liver, preterm umbilical cord blood (UCB), term UCB and adult bone marrow (BM) identified classical and immune subsets of erythroid precursors with divergent differentiation trajectories. Immune-erythroid cells were present from the yolk sac to the adult BM throughout human ontogenesis but failed to be generated in vitro from human embryonic stem cells. Compared with classical-erythroid precursors, these immune-erythroid cells possessed dual erythroid and immune regulatory networks, showed immunomodulatory functions and interacted more frequently with various innate and adaptive immune cells. Our findings provide important insights into the nature of immune-erythroid cells and their roles during development and diseases.

Structural basis for the tethered peptide activation of adhesion GPCRs.

Adhesion G-protein-coupled receptors (aGPCRs) are important for organogenesis, neurodevelopment, reproduction and other processes1-6. Many aGPCRs are activated by a conserved internal (tethered) agonist sequence known as the Stachel sequence7-12. Here, we report the cryogenic electron microscopy (cryo-EM) structures of two aGPCRs in complex with Gs: GPR133 and GPR114. The structures indicate that the Stachel sequences of both receptors assume an α-helical-bulge-ß-sheet structure and insert into a binding site formed by the transmembrane domain (TMD). A hydrophobic interaction motif (HIM) within the Stachel sequence mediates most of the intramolecular interactions with the TMD. Combined with the cryo-EM structures, biochemical characterization of the HIM motif provides insight into the cross-reactivity and selectivity of the Stachel sequences. Two interconnected mechanisms, the sensing of Stachel sequences by the conserved 'toggle switch' W6.53 and the constitution of a hydrogen-bond network formed by Q7.49/Y7.49 and the P6.47/V6.47φφG6.50 motif (φ indicates a hydrophobic residue), are important in Stachel sequence-mediated receptor activation and Gs coupling. Notably, this network stabilizes kink formation in TM helices 6 and 7 (TM6 and TM7, respectively). A common Gs-binding interface is observed between the two aGPCRs, and GPR114 has an extended TM7 that forms unique interactions with Gs. Our structures reveal the detailed mechanisms of aGPCR activation by Stachel sequences and their Gs coupling.

ZFHX3 variants cause childhood partial epilepsy and infantile spasms with favourable outcomes.

BACKGROUND: The ZFHX3 gene plays vital roles in embryonic development, cell proliferation, neuronal differentiation and neuronal death. This study aims to explore the relationship between ZFHX3 variants and epilepsy. METHODS: Whole-exome sequencing was performed in a cohort of 378 patients with partial (focal) epilepsy. A Drosophila Zfh2 knockdown model was used to validate the association between ZFHX3 and epilepsy. RESULTS: Compound heterozygous ZFHX3 variants were identified in eight unrelated cases. The burden of ZFHX3 variants was significantly higher in the case cohort, shown by multiple/specific statistical analyses. In Zfh2 knockdown flies, the incidence and duration of seizure-like behaviour were significantly greater than those in the controls. The Zfh2 knockdown flies exhibited more firing in excitatory neurons. All patients presented partial seizures. The five patients with variants in the C-terminus/N-terminus presented mild partial epilepsy. The other three patients included one who experienced frequent non-convulsive status epilepticus and two who had early spasms. These three patients had also neurodevelopmental abnormalities and were diagnosed as developmental epileptic encephalopathy (DEE), but achieved seizure-free after antiepileptic-drug treatment without adrenocorticotropic-hormone/steroids. The analyses of temporal expression (genetic dependent stages) indicated that ZFHX3 orthologous were highly expressed in the embryonic stage and decreased dramatically after birth. CONCLUSION: ZFHX3 is a novel causative gene of childhood partial epilepsy and DEE. The patients of infantile spasms achieved seizure-free after treatment without adrenocorticotropic-hormone/steroids implies a significance of genetic diagnosis in precise treatment. The genetic dependent stage provided an insight into the underlying mechanism of the evolutional course of illness.

Sodium Houttuyfonate Alleviates MCT-induced Pulmonary Hypertension by Regulating Orai1 and Orai2.

Elevated intracellular Ca2+ concentration ([Ca2+]i) is a key trigger for pulmonary arterial smooth muscle cell (PASMC) proliferation and contributes greatly to pulmonary hypertension (PH). Extracellular Ca2+ influx via a store-operated Ca2+ channel (SOCC), termed store-operated Ca2+ entry (SOCE), is a crucial mechanism for [Ca2+]i elevation in PASMCs. Calcium release-activated calcium modulator (Orai) proteins, consisting of three members (Orai1-3), are the main components of SOCC. Sodium houttuyfonate (SH) is a product of the addition reaction of sodium bisulfite and houttuynin and has antibacterial, anti-inflammatory, and other properties. In this study, we assessed the contributions of Orai proteins to MCT-enhanced SOCE, [Ca2+]i, and cell proliferation in PASMCs and determined the effect of SH on MCT-PH and the underlying mechanism, focusing on Orai proteins, SOCE, and [Ca2+]i in PASMCs. Our results showed that 1) Orai1 and Orai2 were selectively upregulated in the distal pulmonary arteries (PAs) and the PASMCs of MCT-PH rats. 2) Knockdown of Orai1 or Orai2 reduced SOCE, [Ca2+]i, and cell proliferation without affecting their expression in PASMCs in MCT-PH rats. 3) SH significantly normalized the characteristic parameters in a dose-dependent manner in the MCT-PH rat model. 4) SH decreased MCT-enhanced SOCE, [Ca2+]i and PASMC proliferation via Orai1 or Orai2. These results indicate that SH likely exerts its protective role in MCT-PH by inhibiting the Orai1,2-SOCE-[Ca2+]i signaling pathway.

CCDC88C variants are associated with focal epilepsy and genotype-phenotype correlation.

CCDC88C gene, which encodes coiled-coil domain containing 88C, is essential for cell communication during neural development. Variants in the CCDC88C caused congenital hydrocephalus, some accompanied by seizures. In patients with epilepsy without acquired etiologies, we performed whole-exome sequencing (trio-based). Two de novo and two biallelic CCDC88C variants were identified in four cases with focal (partial) epilepsy. These variants did not present or had low frequencies in the gnomAD populations and were predicted to be damaging by multiple computational algorithms. Patients with de novo variants presented with adult-onset epilepsy, whereas patients with biallelic variants displayed infant-onset epilepsy. They all responded well to anti-seizure medications and were seizure-free. Further analysis showed that de novo variants were located at crucial domains, whereas one paired biallelic variants were located outside the crucial domains, and the other paired variant had a non-classical splicing and a variant located at crucial domain, suggesting a sub-molecular effect. CCDC88C variants associated with congenital hydrocephalus were all truncated, whereas epilepsy-associated variants were mainly missense, the proportion of which was significantly higher than that of congenital hydrocephalus-associated variants. CCDC88C is potentially associated with focal epilepsy with favorable outcome. The underlying mechanisms of phenotypic variation may correlation between genotype and phenotype.

Two-Phase Electrosynthesis of Dihydroxycoumestans: Discovery of a New Scaffold for Topoisomerase I Poison.

Coumestan represents a biologically relevant structural motif distributed in a number of natural products, and the rapid construction of related derivatives as well as the characterization of targets would accelerate lead compound discovery in medicinal chemistry. In this work, a general and scalable approach to 8,9-dihydroxycoumestans via two-electrode constant current electrolysis was developed. The application of a two-phase (aqueous/organic) system plays a crucial role for success, protecting the sensitive o-benzoquinone intermediates from over-oxidation. Based on the structurally diverse products, a primary SAR study on coumestan scaffold was completed, and compound 3 r exhibited potent antiproliferative activities and a robust topoisomerase I (Top1) inhibitory activity. Further mechanism studies demonstrates that compound 3 r was a novel Top1 poison, which might open an avenue for the development of Top1-targeted antitumor agent.

Different levels of prepulse inhibition among patients with first-episode schizophrenia, bipolar disorder and major depressive disorder.

BACKGROUND: Deficits in prepulse inhibition may be a common feature in first-episode schizophrenia, bipolar disorder (BD) and major depressive disorder (MDD). We sought to explore the levels and viability of prepulse inhibition to differentiate first-episode schizophrenia, BD and MDD in patient populations. METHODS: We tested patients with first-episode schizophrenia, BD or MDD and healthy controls using prepulse inhibition paradigms, namely perceived spatial co-location (PSC-PPI) and perceived spatial separation (PSS-PPI). RESULTS: We included 53 patients with first-episode schizophrenia, 30 with BD and 25 with MDD, as well as 82 healthy controls. The PSS-PPI indicated that the levels of prepulse inhibition were smallest to largest, respectively, in the first-episode schizophrenia, BD, MDD and control groups. Relative to the healthy controls, the prepulse inhibition deficits in the first-episode schizophrenia group were significant (p < 0.001), but the prepulse inhibitions were similar between patients with BD and healthy controls, and between patients with MDD and healthy controls. The receiver operating characteristic curve analysis showed that PSS-PPI (area under the curve [AUC] 0.73, p < 0.001) and latency (AUC 0.72, p < 0.001) were significant for differentiating patients with first-episode schizophrenia or BD from healthy controls. LIMITATIONS: The demographics of the 4 groups were not ideally matched. We did not perform cognitive assessments. The possible confounding effect of medications on prepulse inhibition could not be eliminated. CONCLUSION: The level of prepulse inhibition among patients with first-episode schizophrenia was the lowest, with levels among patients with BD, patients with MDD and healthy controls increasingly higher. The PSS-PPI paradigm was more effective than PSC-PPI to recognize deficits in prepulse inhibition. These results provide a basis for further research on biological indicators that can assist differential diagnoses in psychosis.

N-3 PUFA supplementation alleviates anxiety symptoms by manipulating erythrocyte fatty acid levels in depression.

PURPOSE: Major depressive disorder (MDD) is frequently accompanied by the symptoms of clinical anxiety. Since our previous research has found that n-3 PUFA supplementation alleviates anxiety in MDD, this study was aimed to further explore whether n-3 PUFA supplementation improves anxiety symptoms in depression by directly manipulating fatty acid levels. METHODS: A secondary analysis of biomarker data (erythrocyte fatty acid composition) collected as part of the randomized clinical trial which investigated the adjunctive effect of n-3 PUFAs was conducted on 72 venlafaxine-treated outpatients with first-diagnosed, drug-naïve depression. All participants with longitudinal biomarker data were included in the association analysis to determine how n-3 PUFA supplementation influences fatty acid composition and alleviates anxiety symptoms in depression. RESULTS: Decreases of the C20:3n6 were found in all participants at both follow-up time points (χ2 = 96.36, p = 0.000). The n-3 index (χ2 = 10.59, p = 0.001), EPA (χ2 = 24.31, p = 0.000), and C22:5n3/C20:5n3 ratio (χ2 = 10.71, p = 0.001) were increased, while C22:4n6 (χ2 = 7.703, p = 0.006) was decreased in n-3 PUFA group compared to the placebo group. The improvement in anxiety symptoms positively correlates with the extent of reduction of C16:0, C18:0, and total fatty acid levels as well as D5 desaturase activity (p < 0.05). CONCLUSION: These data suggest that the anxiolytic effect exerted by n-3 PUFAs in first-diagnosed, drug-naïve depression is manipulated by erythrocyte fatty acid levels. Saturated fatty acid levels have an important role in predicting the severity of anxiety symptoms.

Association between obstructive sleep apnea severity and depression risk: a systematic review and dose-response meta-analysis.

Obstructive sleep apnea (OSA) has received considerable attention as a potential risk factor for depressive symptoms. The systematic review was conducted to confirm the dose‒response connection between OSA severity and depression risk. A systematic literature search of English and Chinese articles published in PubMed, EMBASE, Scopus, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and SinoMed databases from their inception to 28 August 2023 was conducted. An evaluation using the Newcastle‒Ottawa Scale was performed. A meta-analysis was used to evaluate the impact of OSA severity. A random-effects dose‒response model was conducted to evaluate the linear and nonlinear dose‒response connections. We evaluated publication bias by funnel plots, and symmetry by Egger's test. We identified 18 cross-sectional researches. 3143 participants which were involved in the dose‒response meta-analysis. Contrasted with mild OSA, individuals with severe OSA had a higher adjusted risk of depression (rate ratio: 1.34, 95% confidence interval = 1.05-1.70), with substantial heterogeneity (I2 = 70.9%, Pheterogeneity<0.001). There is a significant linear connection between OSA severity and depression risk. The depression risk increased by 0.4% for every 1 event per hour increase in the apnea-hypopnea index (AHI). The protocol for this unfunded research was drafted and registered at PROSPERO (ID CRD42023474097).

Evaluation of Clinical Efficacy of Acupuncture and Moxibustion for Asthma: Systematic Review and Meta-Analysis.

Objective: The effectiveness of manual acupuncture for treating bronchial asthma is still debatable and broad, and the effects of different acupuncture points, treatment durations, or illness trajectories have never been rigorously assessed. The objective of this revised systematic review and subgroup meta-analysis of randomized controlled trials (RCTs) is to ascertain the clinical efficacy of manual acupuncture on bronchial asthma and whether these effects varied depending on the acupuncture points, length of treatment, or course of the disease. Materials and methods: PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria were followed for creating a systematic review and meta-analysis. From the beginning through March 25, 2022, six electronic databases were checked. For the treatment of asthma, all RCTs contrasting acupuncture therapy along with conventional treatment against conventional treatment alone were chosen. The information was examined using Review Manager version 5.3 and Comprehensive Meta-Analysis version 3. Clinical efficacy (including the effective rate and the recurrence rate) was the primary outcome, and pulmonary function (including FEV1%, PEF) and The secondary results were T-lymphocyte immunity (containing CD3+, CD4+, and CD8+). Based on the acupuncture points, length of therapy, and nature of the condition, subgroup analyses were carried out. Results: There were a total of 21 RCTs that enrolled 2510 individuals. According to the meta-findings, analysis's manual acupuncture in addition to conventional treatment significantly increased the effective rate when compared to conventional treatment alone [OR = 5.14 95% CI 3.58-7.38, P < .00001], lung functions [FEV1% (MD = 6.18, 95% CI 2.40-9.96, P = .001) and PEF (MD = 0.45 95% CI 0.18-0.73, P = .001)], immune functions [CD3+ T lymphocytes (MD = 7.55 95% CI 6.55-8.56, P < .00001), CD4+ T-lymphocytes (MD = 5.11 95% CI 4.09-6.13, P < .00001), T-lymphocyte CD8+ (MD = -0.37.11 95% CI -3.62--2.51, P < .00001)] and noteworthy reduction in the recurrence rate (OR = 0.19 95% CI 0.10-0.38, P < .00001). Results from the subgroup analysis were consistent. Conclusion: Manual acupuncture combined with Western Medicine is more effective than conventional treatment alone for bronchial asthma. Combination therapy can significantly improve clinical efficacy, lung function, and immune function while reducing the relapse rate. But to further support the results of this investigation, high-quality RCTs with long-term outcomes are still required, taking into account the inherent limitations of the included studies. Registration number: PROSPERO (no. CRD42022357805) (https://www.crd.york.ac.uk/prospero/).

Exosomal Linc00969 induces trastuzumab resistance in breast cancer by increasing HER-2 protein expression and mRNA stability by binding to HUR.

BACKGROUND: Breast cancer (BC) is the most common malignant disease in female patients worldwide. In HER-2+ BC patients, trastuzumab therapy is associated with a better prognosis. However, many HER-2+ BC patients experience recurrence or metastasis because of trastuzumab resistance. The mechanisms underlying trastuzumab resistance remain unclear. Recently, substantial evidence has suggested that exosomes are associated with drug resistance, and lncRNAs have attracted increasing attention due to their potential role in the regulation of trastuzumab resistance. METHODS: We collected the exosomes from the plasma of BC patients with and without trastuzumab resistance, sequenced the whole transcriptomes, identified differentially expressed lncRNAs, and identified lncRNA Linc00969, which was overexpressed in trastuzumab-resistant patients. Then, we established trastuzumab-resistant BC cell lines and explored the role of exosomal Linc00969 in trastuzumab resistance in vitro and in vivo by silencing or overexpressing Linc00969 and performing a series of functional analyses. Furthermore, to explore the mechanism by which exosomal Linc00969 contributes to trastuzumab resistance, we measured changes in HER-2, HUR and autophagy-related protein expression levels after regulating Linc00969 expression. In addition, we investigated the interaction between Linc00969 and HUR via pull-down and RIP assays and the effect of HUR on HER-2 expression and trastuzumab resistance after blocking HUR. RESULTS: We first found that exosomal lncRNA Linc00969 was overexpressed in trastuzumab-resistant BC patients and that exosome-mediated Linc00969 transfer could disseminate trastuzumab resistance in BC. Then, we found that silencing Linc00969 could reduce trastuzumab resistance and that overexpressing Linc00969 could enhance trastuzumab resistance. Furthermore, our results showed that Linc00969 could upregulate HER-2 expression at the protein level and maintain the stability of HER-2 mRNA by binding to HUR. Additionally, we found that exosomal Linc00969 could regulate trastuzumab resistance by inducing autophagy. CONCLUSIONS: In this study, we first identified that exosomal lncRNA Linc00969 could induce trastuzumab resistance by increasing HER-2 protein expression and mRNA stability by binding to HUR, and Linc00969 might also be involved in trastuzumab resistance by inducing autophagy. Our results elucidate a novel mechanism underlying trastuzumab resistance, and Linc00969 might be a new target for improving the treatment of HER-2+ BC patients.

The mitochondria-targeted small molecule SS31 delays progression of behavioral deficits by attenuating ß-amyloid plaque formation and mitochondrial/synaptic deterioration in APP/PS1 mice.

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by progressive cognitive dysfunction and an impaired ability to carry out daily life functions. Mitochondrial dysfunction and ß-amyloid (Aß) deposition are the most common causes of AD. Antioxidants have been shown to delay brain aging and AD development; however, it remains unknown whether the antioxidant peptide SS31 can protect mitochondrial and synaptic function and delay the progression of behavioral deficits in early-stage AD in vivo. Therefore, in this study we compared mitochondrial and synaptic changes, as well as the protective effects of SS31, in APP/PS1 transgenic mice and C57BL/6J control mice. The APP/PS1 transgenic mice exhibited elevated expression of Aß40/Aß42 and mitochondrial fission protein DLP1 and reduced expression of synaptophysin (SYN) and postsynaptic density protein 95 (PSD95) reductions, as well as increased levels of neuronal apoptosis and ROS in the hippocampus, and long-term treatment with SS31 reversed these effects. Furthermore, the cognitive impairments observed in APP/PS1 transgenic mice were reversed by SS31 treatment. Our findings show that SS31 lowers ROS and Aß levels, protecting mitochondrial homeostasis and synaptic integrity, and ultimately improving behavioral deficits in early-stage AD. This suggests that SS31 is a potential pharmacological agent for treating or slowing the progression of AD.

The HDAC2-MTA3 interaction induces nonsmall cell lung cancer cell migration and invasion by targeting c-Myc and cyclin D1.

Genome-wide association studies have identified numerous single-nucleotide polymorphisms (SNPs) associated with lung cancer; however, the functions of histone deacetylase 2 (HDAC2) rs13213007 and HDAC2 in nonsmall cell lung cancer (NSCLC) remain unclear. Here we identified HDAC2 rs13213007 as a risk SNP and showed that HDAC2 was upregulated in both peripheral blood mononuclear cells (PBMCs) and NSCLC tissues with the rs13213007 A/A genotype compared with those with the rs13213007 G/G or G/A genotype. Patient clinical data indicated strong associations between rs13213007 genotype and N classification. Immunohistochemical staining confirmed that higher expression of HDAC2 was associated with NSCLC progression. Furthermore, we generated 293T cells with the rs13213007 A/A genotype using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 gene editing. Chromatin immunoprecipitation sequencing followed by motif analysis showed that HDAC2 can bind to c-Myc in rs13213007 A/A 293T cells. Cell Counting Kit-8, colony formation, wound-healing, and Transwell assays revealed that HDAC2 upregulates c-Myc and cyclin D1 expression and promotes NSCLC cell proliferation, migration, and invasion. Co-immunoprecipitation, quantitative reverse transcription-polymerase chain reaction, and western blot analysis assays showed that MTA3 interacts with HDAC2, decreases HDAC2 expression, and rescues the migration and invasion abilities of NSCLC cells. Taken together, these findings identify HDAC2 as a potential therapeutic biomarker in NSCLC.

Radiation-induced bystander effects impair transplanted human hematopoietic stem cells via oxidative DNA damage.

Total body irradiation (TBI) is commonly used in host conditioning regimens for human hematopoietic stem cell (HSC) transplantation to treat various hematological disorders. Exposure to TBI not only induces acute myelosuppression and immunosuppression, but also injures the various components of the HSC niche in recipients. Our previous study demonstrated that radiation-induced bystander effects (RIBE) of irradiated recipients decreased the long-term repopulating ability of transplanted mouse HSCs. However, RIBE on transplanted human HSCs have not been studied. Here, we report that RIBE impaired the long-term hematopoietic reconstitution of human HSCs as well as the colony-forming ability of human hematopoietic progenitor cells (HPCs). Our further analyses revealed that the RIBE-affected human hematopoietic cells showed enhanced DNA damage responses, cell-cycle arrest, and p53-dependent apoptosis, mainly because of oxidative stress. Moreover, multiple antioxidants could mitigate these bystander effects, though at different efficacies in vitro and in vivo. Taken together, these findings suggest that RIBE impair human HSCs and HPCs by oxidative DNA damage. This study provides definitive evidence for RIBE on transplanted human HSCs and further justifies the necessity of conducting clinical trials to evaluate different antioxidants to improve the efficacy of HSC transplantation for the patients with hematological or nonhematological disorders.

Erythrocyte Membrane Fatty Acid Composition as a Potential Biomarker for Depression.

BACKGROUND: Major depressive disorders is a chronic and severe psychiatric disorder with poor prognosis and quality of life. Abnormal erythrocyte fatty acid (FA) composition in depressed patients were found in our previous study, but the relationship between erythrocyte membrane FA levels and different severity of depressive and anxiety symptoms remains to be explored. METHODS: This cross-sectional study included 139 patients with first-diagnosed, drug-naïve depression and 55 healthy controls whose erythrocyte FA composition was analyzed. Patients with depression were divided into severe depression and mild to moderate depression or depression with severe anxiety and mild to moderate anxiety. Then the differences of FA levels among different groups were analyzed. Finally, the receiver operating characteristic curve analysis was applied to identify potential biomarkers in distinguishing the severity of depressive symptoms. RESULTS: Levels of erythrocyte membrane FAs were elevated among patients with severe depression compared with healthy controls or patients with mild to moderate depression of almost all kinds. While C18:1n9t (elaidic acid), C20:3n6 (eicosatrienoic acid), C20:4n6 (arachidonic acid), C22:5n3 (docosapentaenoic acid), total fatty acids (FAs), and total monounsaturated FAs were elevated in patients with severe anxiety compared with patients with mild to moderate anxiety. Furthermore, the level of arachidonic acid, C22:4n6 (docosatetraenoic acid), elaidic acid, and the combination of all 3 were associated with the severity of depressive symptoms. CONCLUSIONS: The results suggested that erythrocyte membrane FA levels have the potential to be the biological indicator of clinical characteristics for depression, such as depressive symptoms and anxiety. In the future, more research is needed to explore the causal association between FA metabolism and depression.

Association of Socioeconomic Disparities With Nasopharyngeal Carcinoma Survival in an Endemic Area, China.

OBJECTIVES: This retrospective cohort study investigated the association of socioeconomic status with survival outcomes among patients with nasopharyngeal carcinoma in an endemic area of China. METHODS: The primary endpoint was overall survival. Survival outcomes were estimated by the Kaplan-Meier method and compared by the log-rank test, and the multivariate Cox proportional hazards model was used to estimate hazard ratios, 95% CIs, and independent prognostic factors. RESULTS: A total of 11 069 adult patients with NPC were enrolled and included in the analysis. Kaplan-Meier survival analysis revealed that overall survival was significantly different among socioeconomic status. Compared with high socioeconomic status patients, low socioeconomic status patients (HR, 1.190; 95% CI, 1.063-1.333) and medium socioeconomic status patients (HR, 1.111; 95% CI, 1.006-1.226) were associated with increased hazard ratio (HR) of overall survival. CONCLUSION: This analysis highlights patients with nasopharyngeal carcinoma who had high socioeconomic status had better overall survival compared with those who had low and medium socioeconomic status.

Annulative Aminosulfonylation of Unactivated Alkenes for Accessing Pyrazolines via Multicomponent SO2 Insertion.

A direct arylsulfonylation of ß,γ-unsaturated hydrazones method, in which sulfonated pyrazolines are accessed by a three-component reaction of ß,γ-unsaturated hydrazones, DABSO, and aryldiazonium tetrafluoroborates, has been developed without external oxidants or catalysts. This transformation is triggered by the formation of arylsulfonyl radicals in situ from the reaction of aryldiazonium tetrafluoroborates and DABSO, and is enabled by controllable generation of C center radical, in which DABSO was utilized as the sulfone source and an oxidant in this radical-mediated cascaded reaction. A wide range of substrates can be applied in this process to afford pyrazolines in good yield, and it is amenable for gram-scale synthesis.

NKHs27, a sevenband grouper NK-Lysin peptide that possesses immunoregulatory and antimicrobial activity.

As an effective and broad-spectrum antimicrobial peptide, NK-Lysin is attracted more and more attention at present. However, the functions and action mechanism of NK-Lysin peptides are still not comprehensive enough at present. In this study, a sevenband grouper (Hyporthodus septemfasciatus) NK-Lysin peptide, NKHs27, was identified and synthesized, and its biological functions were studied. The results indicated that NKHs27 shares 44.44%∼88.89% overall sequence identities with other teleost NK-Lysin peptides. The following antibacterial activity assay exhibited that NKHs27 was active against both Gram-negative and Gram-positive bacteria, including Staphylococcus aureus, Listonella anguillarum, Vibrio parahaemolyticus and Vibrio vulnificus. Additionally, NKHs27 showed a synergistic effect when it was combined with rifampicin or erythromycin. In the process of interaction with the L. anguillarum cells, NKHs27 changed the cell membrane permeability and retained its morphological integrity, then penetrated into the cytoplasm to act on genomic DNA or total RNA. Then, in vitro studies showed that NKHs27 could enhance the respiratory burst ability of macrophages and upregulate immune-related genes expression in it. Moreover, NKHs27 incubation improved the proliferation of peripheral blood leukocytes significantly. Finally, in vivo studies showed that administration of NKHs27 prior to bacterial infection significantly reduced pathogen dissemination and replication in tissues. In summary, these results provide new insights into the function of NK-Lysin peptides in teleost and support that NKHs27, as a novel broad-spectrum antibacterial peptide, has potential applications in aquaculture against pathogenic infections.

Synthesis of α-allenic aldehydes/ketones from homopropargylic alcohols using a visible-light irradiation system.

A visible-light irradiation tandem oxidative aryl migration/carbonyl formation reaction, mediated by K2S2O8 and visible-light photoredox catalysis, has been discovered. The presented transformation provides a straightforward access to important α-allenic aldehyde/ketone derivatives from readily available homopropargylic alcohol derivatives in a regioselective manner of 1,4-aryl shift concomitant with carbonyl formation. The operational simplicity and broad substrate scope demonstrate the great potential of this method for the synthesis of highly functional α-allenic aldehyde/ketone derivatives.

PhI(OAc)2-mediated aminoacyloxylation of ß,γ-unsaturated hydrazones using Togni reagent II as an acyloxyl precursor.

A metal-free protocol for the direct construction of C(sp2)-N and C-O bonds via a PhI(OAc)2-mediated dehydrogenative aminoacyloxylation of ß,γ-unsaturated hydrazones with Togni reagent II is reported. Initiated by the carboxyl-containing species generated in situ from Togni reagent II, this method offers a new solution for regioselective functionalization at a remote site on ß,γ-unsaturated hydrazones, thus providing a straightforward method for the synthesis of acyloxyl-substituted pyridazines. This reaction features a broad substrate scope and mild conditions.