The Ca2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum.

Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) signaling adaptor that is essential for the type I interferon response to DNA pathogens. Aberrant activation of STING is linked to the pathology of autoimmune and autoinflammatory diseases. The rate-limiting step for the activation of STING is its translocation from the ER to the ER-Golgi intermediate compartment. Here, we found that deficiency in the Ca2+ sensor stromal interaction molecule 1 (STIM1) caused spontaneous activation of STING and enhanced expression of type I interferons under resting conditions in mice and a patient with combined immunodeficiency. Mechanistically, STIM1 associated with STING to retain it in the ER membrane, and coexpression of full-length STIM1 or a STING-interacting fragment of STIM1 suppressed the function of dominant STING mutants that cause autoinflammatory diseases. Furthermore, deficiency in STIM1 strongly enhanced the expression of type I interferons after viral infection and prevented the lethality of infection with a DNA virus in vivo. This work delineates a STIM1-STING circuit that maintains the resting state of the STING pathway.

Chiral Supramolecular Nanofibers Regulated Tumor-Derived Exosomes Secretion for Constructing an Anti-Tumor Extracellular Microenvironment.

Tumor-derived exosomes (TDEs) induced extracellular microenvironment has recently been validated to be critical for tumor progression and metastasis, however, remodeling it for oncotherapy still remains a major challenge due to difficulty in regulation of TDEs secretion. Herein, the supramolecular chiral nanofibers, composed of L/D -phenylalanine derivates (L/D-Phe) and linear hyaluronic acid (HA), are successfully employed to construct TDEs induced anti-tumor extracellular microenvironment. The left-handed L-Phe @HA nanofibers significantly inhibit TDEs secretion into extracellular microenvironment, which results in suppression of tumor proliferation and metastasis in vitro and vivo. Biological assays and theoretical modeling reveal that these results are mainly attributed to strong adsorption of the key exosomes transporters (Ras-related protein Rab-27A and synaptosome-associated protein 23) on left-handed L-Phe @HA nanofibers via enhanced stereoselective interaction, leading to degradation and phosphorylated dropping of exosomes transporters. Subsequently, transfer function of exosomes transporters is limited, which causes remarkable inhibition of TDEs secretion. These findings provide a promising novel insight of chiral functional materials to establish an anti-tumor extracellular microenvironment via regulation of TDEs secretion.

Mice harboring a R133L heterozygous mutation in LMNA exhibited ectopic lipid accumulation, aging, and mitochondrial dysfunction in adipose tissue.

The LMNA gene encodes for the nuclear envelope proteins lamin A and C (lamin A/C). A novel R133L heterozygous mutation in the LMNA gene causes atypical progeria syndrome (APS). However, the underlying mechanism remains unclear. Here, we used transgenic mice (LmnaR133L/+ mice) that expressed a heterozygous LMNA R133L mutation and 3T3-L1 cell lines with stable overexpression of LMNA R133L (by lentiviral transduction) as in vivo and in vitro models to investigate the mechanisms of LMNA R133L mutations that mediate the APS phenotype. We found that a heterozygous R133L mutation in LMNA induced most of the metabolic disturbances seen in patients with this mutation, including ectopic lipid accumulation, limited subcutaneous adipose tissue (SAT) expansion, and insulin resistance. Mitochondrial dysfunction and senescence promote ectopic lipid accumulation and insulin resistance. In addition, the FLAG-mediated pull-down capture followed by mass spectrometry assay showed that p160 Myb-binding protein (P160 MBP; Mybbp1 a $$ a $$ ), the critical transcriptional repressor of PGC-1α, was bound to lamin A/C. Increased Mybbp1 a $$ a $$ levels in tissues and greater Mybbp1 a $$ a $$ -lamin A/C binding in nuclear inhibit PGC-1α activity and promotes mitochondrial dysfunction. Our findings confirm that the novel R133L heterozygous mutation in the LMNA gene caused APS are associated with marked mitochondrial respiratory chain impairment, which were induced by decreased PGC-1α levels correlating with increased Mybbp1a levels in nuclear, and a senescence phenotype of the subcutaneous fat.

Mass Flow and Metabolic Pathway of Nonaeration Greywater Treatment in an Oxygenic Microalgal-Bacterial Biofilm.

A symbiotic microalgal-bacterial biofilm can enable efficient carbon (C) and nitrogen (N) removal during aeration-free wastewater treatment. However, the contributions of microalgae and bacteria to C and N removal remain unexplored. Here, we developed a baffled oxygenic microalgal-bacterial biofilm reactor (MBBfR) for the nonaerated treatment of greywater. A hydraulic retention time (HRT) of 6 h gave the highest biomass concentration and biofilm thickness as well as the maximum removal of chemical oxygen demand (94.8%), linear alkylbenzenesulfonates (LAS, 99.7%), and total nitrogen (97.4%). An HRT of 4 h caused a decline in all of the performance metrics due to LAS biotoxicity. Most of C (92.6%) and N (95.7%) removals were ultimately associated with newly synthesized biomass, with only minor fractions transformed into CO2 (2.2%) and N2 (1.7%) on the function of multifarious-related enzymes in the symbiotic biofilm. Specifically, microalgae photosynthesis contributed to the removal of C and N at 75.3 and 79.0%, respectively, which accounted for 17.3% (C) and 16.7% (N) by bacteria assimilation. Oxygen produced by microalgae favored the efficient organics mineralization and CO2 supply by bacteria. The symbiotic biofilm system achieved stable and efficient removal of C and N during greywater treatment, thus providing a novel technology to achieve low-energy-input wastewater treatment, reuse, and resource recovery.

Ca2+ Signaling Augmented by ORAI1 Trafficking Regulates the Pathogenic State of Effector T Cells.

Activation of the Ca2+ release-activated Ca2+ (CRAC) channel is crucial for T cell functions. It was recently shown that naked cuticle homolog 2 (NKD2), a signaling adaptor molecule, orchestrates trafficking of ORAI1, a pore subunit of the CRAC channels, to the plasma membrane for sustained activation of the CRAC channels. However, the physiological role of sustained Ca2+ entry via ORAI1 trafficking remains poorly understood. Using NKD2 as a molecular handle, we show that ORAI1 trafficking is crucial for sustained Ca2+ entry and cytokine production, especially in inflammatory Th1 and Th17 cells. We find that murine T cells cultured under pathogenic Th17-polarizing conditions have higher Ca2+ levels that are NKD2-dependent than those under nonpathogenic conditions. In vivo, deletion of Nkd2 alleviated clinical symptoms of experimental autoimmune encephalomyelitis in mice by selectively decreasing effector T cell responses in the CNS. Furthermore, we observed a strong correlation between NKD2 expression and proinflammatory cytokine production in effector T cells. Taken together, our findings suggest that the pathogenic effector T cell response demands sustained Ca2+ entry supported by ORAI1 trafficking.

ORAI1 Limits SARS-CoV-2 Infection by Regulating Tonic Type I IFN Signaling.

ORAI1 and stromal interaction molecule 1 (STIM1) are the critical mediators of store-operated Ca2+ entry by acting as the pore subunit and an endoplasmic reticulum-resident signaling molecule, respectively. In addition to Ca2+ signaling, STIM1 is also involved in regulation of the type I IFN (IFN-I) response. To examine their potential role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we generated ORAI1 and STIM1 knockout human HEK293-angiotensin-converting enzyme 2 cells and checked their responses. STIM1 knockout cells showed strong resistance to SARS-CoV-2 infection as a result of enhanced IFN-I response. On the contrary, ORAI1 deletion induced high susceptibility to SARS-CoV-2 infection. Mechanistically, ORAI1 knockout cells showed reduced homeostatic cytoplasmic Ca2+ concentration and severe impairment in tonic IFN-I signaling. Transcriptome analysis showed downregulation of multiple antiviral signaling pathways in ORAI1 knockout cells, likely because of reduced expression of the Ca2+-dependent transcription factors of the AP-1 family and MEF2C Accordingly, modulation of homeostatic Ca2+ concentration by pretreatment with ORAI1 blocker or agonist could influence baseline IFNB expression and resistance to SARS-CoV-2 infection in a human lung epithelial cell line. Our results identify a novel role of ORAI1-mediated Ca2+ signaling in regulating the tonic IFN-I levels, which determine host resistance to SARS-CoV-2 infection.

Global research trends in tongue cancer from 2000 to 2022: bibliometric and visualized analysis.

OBJECTIVES: This study conducts a systematic bibliometric analysis of tongue cancer publications to identify key topics, hotspots, and research distribution. METHODS: We analyzed tongue cancer publications in the Web of Science core collection database, assessing their quantity and quality. We investigated contributors, including countries, affiliations, journals, authors, and categories, within collaborative networks. Additionally, we synthesized key research findings using various analytical techniques, such as alluvial flow, burstness analysis, cluster analysis, co-occurrence network of associations, and network layer overlay. RESULTS: From 2000 to 2022, this bibliometric study covers 2205 articles and reviews across 617 journals, involving 72 countries, 2233 institutions, and 11,266 authors. It shows consistent growth, particularly in 2016. Key contributors include China (499 publications), Karolinska Institute (84 publications), Oral Oncology (144 publications), and Tuula Salo (47 publications). Other notable contributors are the USA (16,747 citations), the National Cancer Institute (NCI) (2597 citations), and the Memorial Sloan-Kettering Cancer Center (MSK) (2231 citations). Additionally, there are significant teams led by Tuula Salo and Dalianis. We have identified six primary clusters: #0 apoptosis, #1 depth of invasion, #2 radiotherapy, #3 hpv, #4 tongue cancer, #5 oral cancer. The top ten highly cited documents primarily pertain to epidemiology, prognostic indicators in early-stage oral tongue cancer, and HPV. Additionally, we observed 16 reference clusters, with depth of invasion (#3), young patients (#4), and tumor budding (#6) gaining prominence since 2012, indicating sustained research interests. CONCLUSIONS: This analysis emphasizes the increasing scholarly interest in tongue cancer research. The bibliometric evaluation highlights pivotal recent research themes such as HPV, depth of invasion, tumor budding, and surgical margins. CLINICAL RELEVANCE: The bibliometric analysis highlights the key topics and studies which have shaped the understanding and management of tongue cancer.

The association of Cortisol, Testosterone, and Cortisol/Testosterone Ratio with Stroke: a cross-sectional study.

AIMS: We aimed to investigate the association between serum cortisol, testosterone, and cortisol/testosterone (C/T) ratio and stroke. MATERIALS AND METHODS: A total of 6157 subjects were included in this study. The serum levels of cortisol and testosterone were determined by liquid chromatography-tandem mass spectrometry method. The relationships of serum cortisol, testosterone, and C/T ratio levels with the odds ratios (ORs) of stroke were calculated using logistic regression analysis. The dose-response associations between serum cortisol, testosterone, and C/T ratio levels with stroke estimated by restricted cubic splines. RESULTS: After adjusting for multiple variables, serum testosterone levels were negactively associated with stroke in males (per 1 unit, odds ratio (OR)=0.83, 95% confidence interval (CI): 0.70, 0.97). The serum C/T ratio is positively associated with stroke in both males and females (OR=1.16, 95% CI:1.04,1.34 in males and OR=1.15, 95% CI:1.02,1.31 in females). Restricted cubic splines showed a significant linear dose-response relationship between testosterone and C/T ratio and stroke in males (P for overall association <0.05, P for nonlinearity >0.05). CONCLUSION: Our study findings show that serum testosterone levels are negatively correlated with stroke in males; meanwhile, serum C/T ratio is positively correlated with stroke in both males and females.

Effects of Hydrophobic Biochar-Modified Landfill Soil Cover on Methane Oxidation.

Landfill cover soils play an important role in mitigating landfill methane (CH4) emissions. Incorporating biochar into the soil has proven effective in reducing CH4 emissions. However, the role of hydrophobic biochar in this context remains underexplored. This study investigated the CH4 removal efficiency of a biochar-modified landfill soil cover column (RB) and hydrophobic biochar-modified landfill soil cover column (RH) under varying CH4 influx gas concentrations (25 and 35%), simulated CH4 inflow rates (10, 15, and 20 ml/min), and temperatures (20, 25, 30, 35, and 40 °C). RH consistently outperformed RB in terms of CH4 removal efficiency under these experimental conditions. The optimal conditions for CH4 degradation by both RB and RH were observed at a CH4 influx gas concentration of 35%, a simulated CH4 inflow rate of 10 ml/min, and a temperature of ~30 °C. RH achieved a CH4 removal rate of up to 99.96%. In summary, the addition of hydrophobic biochar enhanced the air permeability and hydrophobicity of landfill cover soils, providing a promising alternative to conventional cover soils for reducing CH4 emissions from landfills.

Anti-Alzheimers molecular mechanism of icariin: insights from gut microbiota, metabolomics, and network pharmacology.

BACKGROUND: Icariin (ICA), an active ingredient extracted from Epimedium species, has shown promising results in the treatment of Alzheimer's disease (AD), although its potential therapeutic mechanism remains largely unknown. This study aimed to investigate the therapeutic effects and the underlying mechanisms of ICA on AD by an integrated analysis of gut microbiota, metabolomics, and network pharmacology (NP). METHODS: The cognitive impairment of mice was measured using the Morris Water Maze test and the pathological changes were assessed using hematoxylin and eosin staining. 16S rRNA sequencing and multi-metabolomics were performed to analyze the alterations in the gut microbiota and fecal/serum metabolism. Meanwhile, NP was used to determine the putative molecular regulation mechanism of ICA in AD treatment. RESULTS: Our results revealed that ICA intervention significantly improved cognitive dysfunction in APP/PS1 mice and typical AD pathologies in the hippocampus of the APP/PS1 mice. Moreover, the gut microbiota analysis showed that ICA administration reversed AD-induced gut microbiota dysbiosis in APP/PS1 mice by elevating the abundance of Akkermansia and reducing the abundance of Alistipe. Furthermore, the metabolomic analysis revealed that ICA reversed the AD-induced metabolic disorder via regulating the glycerophospholipid and sphingolipid metabolism, and correlation analysis revealed that glycerophospholipid and sphingolipid were closely related to Alistipe and Akkermansia. Moreover, NP indicated that ICA might regulate the sphingolipid signaling pathway via the PRKCA/TNF/TP53/AKT1/RELA/NFKB1 axis for the treatment of AD. CONCLUSION: These findings indicated that ICA may serve as a promising therapeutic approach for AD and that the ICA-mediated protective effects were associated with the amelioration of microbiota disturbance and metabolic disorder.

Assembly of Helical Nanostructures: Solvent-Induced Morphology Transition and Its Effect on Cell Adhesion.

Being able to precisely manipulate both the morphology and chiroptical signals of supramolecular assemblies will help to better understand the natural biological self-assembly mechanism. Two simple l/d-phenylalanine-based derivatives (L/DPFM) have been designed, and their solvent-dependent morphology evolutions are illustrated. It was found that, as the content of H2 O in aqueous ethanol solutions was increased, LPFM self-assembles first into right-handed nanofibers, then flat fibrous structures, and finally inversed left-handed nanofibers. Assemblies in ethanol and H2 O exhibit opposite conformations and circular dichroism (CD) signals even though they are constructed from the same molecules. Thus, the morphology-dependent cell adhesion and proliferation behaviors are further characterized. Left-handed nanofibers are found to be more favorable for cell adhesion than right-handed nanostructures. Quantitative AFM analysis showed that the L929 cell adhesion force on left-handed LPFM fibers is much higher than that on structures with inversed handedness. Moreover, the value of cell Young's modulus is lower for left-handed nanofibrous films, which indicates better flexibility. The difference in cell-substrate interactions might lead to different effects on cell behavior.

Effect of Albumin Corona Conformation on In Vitro and In Vivo Profiles of Intravenously Administered Nanoparticles.

Under physiological conditions, nanoparticles (NPs) inevitably interact with proteins, resulting in extensive protein adsorption and the formation of a protein corona. Recent studies have shown that the different surface properties of NPs lead to varying degrees of conformational changes of adsorbed proteins. However, the impact of corona protein conformation on the in vitro and in vivo profiles of NPs remain largely unexplored. Herein, d-α-tocopherol polyethylene glycol 1000 succinate-based NPs with natural human serum albumin (HSAN) corona or thermally denatured HSA (HSAD) corona were synthesized following a previously established method. We then conducted a systematic study of the protein conformation as well as adsorption behaviors. Additionally, the impact of protein corona conformation on the NPs profiles in vitro and in vivo were elucidated to gain insight into its biological behaviors as a targeted delivery system for renal tubule diseases. Overall, NPs modified by HSAN corona showed improved serum stability, greater cell uptake efficiency, better renal tubular targetability, and therapeutic efficacy on acute kidney injury in rats than NPs modified by HSAD corona. Hence, the conformation of protein adsorbed on the surface of NPs may impact the in vitro and in vivo profiles of NPs.

pH-dependent microbial niches succession and antibiotic resistance genes distribution in an oxygen-based membrane biofilm reactor treating greywater.

System pH is found to crucially affect biofilm growth and microorganisms' activity in the biofilm-based wastewater treatment system. This study investigated the pH-dependent pollutants removal, microbial niches succession and antibiotic resistance genes (ARGs) accumulation in an oxygen-based membrane biofilm reactor treating greywater. Results indicated that neutral conditions achieved the highest biofilm concentration and living cells, which enabled the highest pollutants removal rates; multifarious functional groups in biofilm enabled pollutants adsorption, which favored its continuous bio-removal. Microbial communities under acidic condition (pH = 5.0) were significantly different with that under other conditions (p < 0.05). The neutral and alkaline niches (pH = 7.0 and 9.0) were predominant by organics biodegradation and nitrogen reduction bacteria (e.g. Sphingobacteriales, Pseudomonas, Flavobacterium and Phenylobacterium), but which were significantly dropped under acidic conditions, leading to the declined reactor performance. ARGs in biofilm (predominant by korB, intI-1, sul1 and sul2) were much higher than that in the cell-free liquid and the target ARGs accumulation (korB, intI-1, blaCTX-M, qnrS) had nearly linear positive relationships (R2 > 0.95, P < 0.01) with biofilm-attached linear alkylbenzene sulfonate (LAS). LAS stimulate ARGs proliferation in functional microorganisms (korB, sul-1 and intI-1 were significantly associated with related microbial genus) and biofilm played a key role in ARGs dissemination. The relatively low ARGs in both biofilm and effluent under neutral conditions suggested that pH controlling can be an effective strategy to inhibit ARGs dissemination and proliferation in the system.

First Report of Soft Rot Caused by Pectobacterium polaris on Lettuce in China.

Lettuce (Lactuca sativa) is a leafy vegetable that belongs to the family Asteraceae. It is widely cultivated and consumed around the world. In May 2022, lettuce plants (cv. 204) showing soft rot symptoms were observed in greenhouses in Fuhai District (25°18'N, 103°6'E), Kunming City, Yunnan Province, China. The disease incidence in three greenhouses (0.3 ha in size) was between 10% to 15%. The lower parts of the outer leaves showed brown and water-soaked symptoms, but at the same time the roots were asymptomatic. Sclerotinia species can cause soft decay on lettuce leaves, known as lettuce drop, which can produce symptoms partially resembling those of bacterial soft rot (Subbarao 1998). The absence of white mycelium or black sclerotia on the leaf surfaces of diseased plants indicated that Sclerotinia species were not responsible for the disease. Instead, it is more likely that bacterial pathogens were the cause. Fourteen diseased plants were sampled from three greenhouses, and potential pathogens were isolated from the leaf tissues of six plant individuals. Leaf samples were cut into pieces ca. 0.5 cm in length. The pieces were then surface-sterilized by dipping in 75% ethanol for 60 sec, followed by three successive rinses using sterile distilled water. The tissues were immersed in 250 µl of 0.9% saline in 2 mL microcentrifuge tubes and gently pressed down with grinding pestles for 10 sec. The tubes were let stand still for 20 min. Aliquots (20 µl) 100-fold dilutions of the tissue suspensions were plated onto Luria-Bertani (LB) plates and incubated at 28°C for 24 h. Three single colonies were picked from each LB plate and restreaked five times for purity. After purification, eighteen strains were obtained, and nine of these were identified by 16S rDNA sequencing using the universal primer pair 27F/1492R (Weisburg et al. 1991). Six out of nine strains (6/9) belonged to the genus Pectobacterium (OP968950-OP968952, OQ568892- OQ568894), two strains (2/9) belonged to the genus Pantoea (OQ568895 and OQ568896), and one strain (1/9) belonged to Pseudomonas sp. (OQ568897). Since the Pectobacterium strains shared identical 16S rDNA sequence, strains CM22112 (OP968950), CM22113 (OP968951) and CM22132 (OP968952) were selected as representative strains for further testing. The 16S rDNA sequences of Pectobacterium strains were 100% identical to that of the P. polaris strain NIBIO 1392 (NR_159086.1). To identify the strains to the species level, multilocus sequence analysis (MLSA) was performed using sequences of six housekeeping genes acnA, gapA, icdA, mdh, proA and rpoS (OP972517-OP972534) (Ma et al. 2007; Waleron et al. 2008). Phylogenetic analysis showed that the strains clustered with P. polaris type strain NIBIO1006T (Dees et al. 2017). They were all capable of utilizing citrate, which is an important biochemical feature in distinguishing P. polaris from its most closely related sister species P. parvum (Pasanen et al. 2020). Lettuce plants (cv. 204), at the rosette stage, were inoculated with the strains CM22112 and CM22132 by injecting 100 µl of bacterial suspensions (107 CFU·mL-1) into the lower parts of the leaf; for the controls, 100 µl of saline was used instead. Inoculated plants were incubated at room temperature (23°C) and 90% relative humidity. Five days after inoculation, only the bacteria-inoculated lettuce showed severe soft rot symptoms. Similar results were observed in two independent experiments. Bacterial colonies were obtained from the infected lettuce leaves, which showed identical sequences to P. polaris strains CM22112 and CM22132. Therefore, these strains fulfilled Koch's postulates for lettuce soft rot. P. polaris is prevalent on potato in many countries (Dees et al. 2017). To our knowledge, this is the first report of P. polaris causing soft rot on lettuce in China. This disease could seriously affect the appearance and saleability of lettuce. Further research on the epidemiology and management strategies of the disease is needed.

A membrane-protected micro-solid-phase extraction method based on molecular imprinting and its application to the determination of local anesthetics in cosmetics.

As local anesthetics that are illegally added to cosmetics are harmful to consumer health, it is necessary to establish an efficient method for detecting these substances. Herein, a molecularly imprinted polymer (bupivacaine) was prepared by bulk polymerization and packed into a hollow fiber for use as an extraction phase to fabricate a membrane-protected micro-solid-phase extraction device. The optimal values of the influencing parameters for the microextraction process were as follows: a sample solution pH of 9.0, a loading and washing time of 2 h, and an elution time of 32 min. A gas chromatography-mass spectrometry method was established for the determination of local anesthetics and coupled with the microextraction method to successfully detect local anesthetics in cosmetic samples. The calibration curve for the proposed method was linear in the range of 0.4-50 mg/L and showed a good correlation coefficient (r2 ). The limits of detection for local anesthetics were in the range of 0.01-0.71 mg/L. The molecularly imprinted polymer exhibited good imprinting and selectivity, the micro-solid-phase extraction device was simple and inexpensive and fabrication was reproducible. The combination of molecular imprinting technology, membrane separation, and micro-solid-phase extraction methods used in this study can potentially be applied to pretreat local anesthetics in cosmetic samples.

Effect of Dichotomous Conchal Cartilage Transplantation on Correction of Unilateral Cleft Lip Nasal Deformity.

BACKGROUND: Autologous conchal cartilage is becoming increasingly popular as a source of material for secondary reconstruction. The aim of this study was to verify the effect of dichotomous autologous conchal cartilage transplantation in the treatment of unilateral cleft lip nasal deformity. METHODS: Eighteen patients (10 males and 8 females) with unilateral cleft lip nasal deformity treated from August 2018 to August 2019 were selected for the study. The cut C-shaped conchal cartilage was trimmed into a strip shape and a shield shape and transplanted into the alar cartilage and the tip of the nose, respectively. The effect of the operation was evaluated in terms of patient satisfaction, two-dimensional linear quantitative results, and three-dimensional spatial differences after the operation. RESULTS: During follow-up from 6 months to 2 years, the nasal appearance of 18 patients was significantly improved. The postoperative patient satisfaction survey revealed more than 93% satisfaction for each research index. Two-dimensional linear quantitative analysis revealed that the height of the nasal columella and nostril was significantly increased and that the nasal base and breadth were significantly decreased after the operation. Evaluation of the three-dimensional spatial difference between the unaffected side and the affected side before and after the operation revealed a significant decrease in the difference in the soft tissue volume between the unaffected side and the affected side (P < 0.05). CONCLUSIONS: Dichotomous autologous conchal cartilage transplantation is an ideal method for the treatment of unilateral cleft lip nasal deformity.

Transthyretin contributes to insulin resistance and diminishes exercise-induced insulin sensitivity in obese mice by inhibiting AMPK activity in skeletal muscle.

Exercise improves obesity-induced insulin resistance and metabolic disorders via mechanisms that remain unclear. Here, we show that the levels of the hepatokine transthyretin (TTR) in circulation are elevated in insulin-resistant individuals including high-fat diet (HFD)-induced obese mice, db/db mice, and patients with metabolic syndrome. Liver Ttr mRNA and circulating TTR levels were reduced in mice by treadmill training, as was the TTR levels in quadriceps femoris muscle; however, AMP-activated protein kinase (AMPK) signaling activity was enhanced. Transgenic overexpression of TTR or injection of purified TTR triggered insulin resistance in mice fed on regular chow (RC). Furthermore, TTR overexpression reduced the beneficial effects of exercise on insulin sensitivity in HFD-fed mice. TTR was internalized by muscle cells via the membrane receptor Grp78 and the internalization into the quadriceps femoris was reduced by treadmill training. The TTR/Grp78 combination in C2C12 cells was increased, whereas the AMPK activity of C2C12 cells was decreased as the TTR concentration rose. In addition, Grp78 silencing prevented the TTR internalization and reversed its inhibitory effect on AMPK activity in C2C12 cells. Our study suggests that elevated circulating TTR may contribute to insulin resistance and counteract the exercise-induced insulin sensitivity improvement; the TTR suppression might be an adaptive response to exercise through enhancing AMPK activity in skeletal muscles.NEW & NOTEWORTHY Exercise improves obesity-induced insulin resistance via mechanisms that remain unclear. The novel findings of the study are that circulating TTR (a hepatokine) level is decreased by exercise, and the elevated circulating TTR, as was the elevated transthyretin internalization mediated by Grp78, counteracts the exercise-induced insulin sensitivity by downregulating AMPK activity in skeletal muscle of obese mice. These data suggest that TTR suppression might be an adaptive response to exercise through the crosstalk between liver and muscle.

T cell factor 1 initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-gamma.

The differentiation of activated CD4(+) T cells into the T helper type 1 (T(H)1) or T(H)2 fate is regulated by cytokines and the transcription factors T-bet and GATA-3. Whereas interleukin 12 (IL-12) produced by antigen-presenting cells initiates the T(H)1 fate, signals that initiate the T(H)2 fate are not completely characterized. Here we show that early GATA-3 expression, required for T(H)2 differentiation, was induced by T cell factor 1 (TCF-1) and its cofactor beta-catenin, mainly from the proximal Gata3 promoter upstream of exon 1b. This activity was induced after T cell antigen receptor (TCR) stimulation and was independent of IL-4 receptor signaling through the transcription factor STAT6. Furthermore, TCF-1 blocked T(H)1 fate by negatively regulating interferon-gamma (IFN-gamma) expression independently of beta-catenin. Thus, TCF-1 initiates T(H)2 differentiation of activated CD4(+) T cells by promoting GATA-3 expression and suppressing IFN-gamma expression.

Heterogeneity and Diversity of mcr-8 Genetic Context in Chicken-Associated Klebsiella pneumoniae.

Increasing mobile colistin resistance, mediated by the mcr gene family, in Enterobacteriaceae has become a global concern. Among the 10 reported mcr genes, mcr-8 was first identified in Klebsiella pneumoniae, which could cause severe infections with high mortality. Information about the prevalence and genetic context of mcr-8 is still lacking. In this study, we found that mcr-8 was present in 9.83% of K. pneumoniae isolates of chicken origin. S1 nuclease pulsed-field gel electrophoresis (S1-PFGE) and Southern blotting showed that the mcr-8 gene was located on a plasmid in all of the isolates. The genetic context of the plasmids exhibited considerable diversity from the whole-genome sequence through Illumina and MinION long-read sequencing. Mutations in two-component systems may function synergistically with mcr-8, resulting in extremely high resistance to colistin. In addition to colistin resistance, these plasmids also contained genes conferring resistance to beta-lactams, tetracycline, aminoglycosides, sulfonamides, macrolides, chloramphenicol, and florfenicol. Therefore, these findings indicate that the genetic context of mcr-8 is heterogeneous and diverse and that mcr-8 and certain chromosomal mechanisms jointly contribute to high-level colistin resistance in K. pneumoniae strains, which provides new insights into the resistance mechanisms of K. pneumoniae.

Multimode waveguide crossing with ultralow loss and low imbalance.

The mode-division-multiplexing (MDM) technology has become an alternative solution to further increase the link capacity in optical communication systems. Ultralow loss waveguide crossings for multimode waveguides are requisite in on-chip MDM systems. We propose and demonstrate an ultralow loss silicon multimode waveguide crossing using a combination of fully etched and shallowly etched waveguides in the multimode-interference coupler region to reduce the imbalance for two transverse electric polarized (TE) modes. By engineering the geometries and the proportion of the two waveguides, the self-imaging positions for different modes can coincide exactly. Simulated results show that the insertion losses are 0.043 and 0.084 dB for the fundamental TE (TE0) mode and the first-order TE (TE1) mode at 1550 nm, while the experimental values are 0.1 and 0.12 dB, respectively. The measured crosstalk is less than -30 dB for both modes within a 75 nm wavelength span.