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The hybrid electrolyzer coupled glycerol oxidation (GOR) with hydrogen evolution reaction (HER) is fascinating to simultaneously generate H2 and high value-added chemicals with low energy input, yet facing a challenge. Herein, Cu-based metal-organic frameworks (Cu-MOFs) are reported as model catalysts for both HER and GOR through doping of atomically dispersed precious and nonprecious metals. Remarkably, the HER activity of Ru-doped Cu-MOF outperformed a Pt/C catalyst, with its Faradaic efficiency for formate formation at 90% at a low potential of 1.40 V. Furthermore, the hybrid electrolyzer only needed 1.36 V to achieve 10 mA cm-2, 340 mV lower than that for splitting pure water. Theoretical calculations demonstrated that electronic interactions between the host and guest (doped) metals shifted downward the d-band centers (εd) of MOFs. This consequently lowered water adsorption and dissociation energy barriers and optimized hydrogen adsorption energy, leading to significantly enhanced HER activities. Meanwhile, the downshift of εd centers reduced energy barriers for rate-limiting step and the formation energy of OH*, synergistically enhancing the activity of MOFs for GOR. These findings offered an effective means for simultaneous productions of hydrogen fuel and high value-added chemicals using one hybrid electrolyzer with low energy input.
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Lithium metal batteries utilizing lithium metal as the anode can achieve a greater energy density. However, it remains challenging to improve low-temperature performance and fast-charging features. Herein, we introduce an electrolyte solvation chemistry strategy to regulate the properties of ethylene carbonate (EC)-based electrolytes through intermolecular interactions, utilizing weakly solvated fluoroethylene carbonate (FEC) to replace EC, and incorporating the low-melting-point solvent 1,2-difluorobenzene (2FB) as a diluent. We identified that the intermolecular interaction between 2FB and solvent can facilitate Li+ desolvation and lower the freezing point of the electrolyte effectively. The resulting electrolyte enables the LiNi0.8Co0.1Mn0.1O2||Li cell to operate at -30 °C for more than 100 cycles while delivering a high capacity of 154 mAh g-1 at 5.0C. We present a solvation structure and interfacial model to analyze the behavior of the formulated electrolyte composition, establishing a relationship with cell performance and also providing insights for the electrolyte design under extreme conditions.
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Gracilariaceae is a group of marine large red algae and main source of agar with important economic and ecological value. The codon usage patterns of chloroplast genomes in 36 species from Graciliaceae show that GC range from 0.284 to 0.335, the average GC3 range from 0.135 to 0.243 and the value of ENC range from 35.098 to 42.327, which indicates these genomes are rich in AT and prefer to use codons ending with AT in these species. Nc plot, PR2 plot, neutrality plot analyses and correlation analysis indicate that these biases may be caused by multiple factors, such as natural selection and mutation pressure, but prolonged natural selection is the main driving force influencing codon usage preference. The cluster analysis and phylogenetic analysis show that the differentiation relationship of them is different and indicate that codons with weak or unbiased preferences may also play an irreplaceable role in these species' evolution. In addition, we identified 26 common high-frequency codons and 8-18 optimal codons all ending in A/U in these 36 species. Our results will not only contribute to carrying out transgenic work in Gracilariaceae species to maximize the protein yield in the future, but also lay a theoretical foundation for further exploring systematic classification of them.
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Uso do Códon , Genoma de Cloroplastos , Filogenia , Códon/genética , Proteínas/genéticaRESUMO
The Bi0.5 Sb1.5 Te3 (BST) thin film shows great promise in harvesting low-grade heat energy due to its excellent thermoelectric performance at room temperature. In order to further enhance its thermoelectric performance, specifically the power factor and output power, new approaches are highly desirable beyond the common "composition-structure-performance" paradigm. This study introduces ferroelectric polarization engineering as a novel strategy to achieve these goals. A Pb(Zr0.52 Ti0.48 )O3 /Bi0.5 Sb1.5 Te3 (PZT/BST) hybrid film is fabricated via magnetron sputtering. Density functional theory calculations demonstrate PZT polarization's influence on charge redistribution and interlayer charge transfer at the PZT/BST interface, facilitating adjustable carrier transport behavior and power factor of the BST film. As a result, a 26.7% enhancement of the power factor, from unpolarized 12.0 to 15.2 µW cm-1 K-2 , is reached by 2 kV out-of-plane downward polarization of PZT. Furthermore, a five-leg generator constructed using this PZT/BST hybrid film exhibits a maximum output power density of 13.06 W m-2 at ΔT = 39 K, which is 20.8% higher than that of the unpolarized one (10.81 W m-2 ). The research presents a new approach to enhance thermoelectric thin films' power factor and output performance by introducing ferroelectric polarization engineering.
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BACKGROUND: Evidence has shown that the individual metrics in Life's Essential 8 (LE8), an updated cardiovascular health (CVH) concept proposed by the American Heart Association, play a role in the development of inflammatory bowel disease (IBD). However, epidemiological evidence on the overall LE8 on IBD risk remains limited. We aimed to assess the longitudinal associations of LE8-defined CVH and the risks of IBD and its subtypes, ulcerative colitis (UC) and Crohn's disease (CD). We also tested whether genetic susceptibility could modify these associations. METHODS: A total of 260,836 participants from the UK Biobank were included. LE8 scores were determined by 8 metrics (physical activity, diet, nicotine exposure, sleep, body mass index, blood pressure, blood glucose, and blood lipids), and were divided into three levels: low CVH (0-49), moderate CVH (50-79), and high CVH (80-100). Cox proportional hazards models were used to calculate the hazard ratios (HRs) and confidence intervals (CIs) of the risk of IBD in relation to CVH status. RESULTS: Over a median follow-up 12.3 years, we documented 1,500 IBD cases (including 1,070 UC and 502 CD). Compared to participants with low CVH, the HRs (95% CIs) of those with high CVH for IBD, UC, and CD were 0.67 (0.52, 0.83), 0.70 (0.52, 0.93), and 0.55 (0.38, 0.80), respectively. These associations were not modified by genetic susceptibility (all P for interactions > 0.05). The lowest HR (UC: 0.30, 95% CI: 0.20-0.45; CD: 0.33, 95% CI: 0.20-0.57) was observed in participants with both high CVH and low genetic risk. CONCLUSIONS: Better CVH, defined by LE8, was associated with significantly lower risks of IBD, UC, and CD, irrespective of genetic predisposition. Our results underscore the importance of adherence to LE8 guidelines for maintaining CVH as a potential strategy in the prevention of IBD.
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Doença de Crohn , Dieta , Predisposição Genética para Doença , Doenças Inflamatórias Intestinais , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Fatores de Risco , Reino Unido , Adulto , Doenças Inflamatórias Intestinais/genética , Doença de Crohn/genética , Exercício Físico , Idoso , Índice de Massa Corporal , Colite Ulcerativa/genética , Estudos de Coortes , Modelos de Riscos Proporcionais , Estudos Longitudinais , Pressão Sanguínea , Sono , Glicemia/metabolismoRESUMO
OBJECTIVE: A variety of unhealthy sleep behaviors have been shown to be associated with an increased risk of urologic cancers. However, little is known about the association between the overall sleep patterns and urologic cancers. To prospectively investigate the associations between a healthy sleep pattern and the risks of urologic cancers, including bladder cancer (BCa) and renal cell carcinoma (RCC). METHODS: In this prospective cohort study, 377,144 participants free of cancer at baseline were recruited from the UK Biobank. Data on sleep behaviors were collected through questionnaires at recruitment. The incident urologic cancer cases were determined through linkage to national cancer and death registries. We established a healthy sleep score according to five sleep traits (sleep duration, chronotype, insomnia, snoring, and daytime sleepiness). Cox proportional hazard regression models were used to calculate the adjusted hazard ratios and 95% confidence intervals to assess the relationship between the healthy sleep score and the risk of urologic cancers. RESULTS: During a median of ≥9 years of follow-up, we identified 1986 incident urologic cancer cases, including 1272 BCa cases and 706 RCC cases. Compared with the participants with a poor sleep pattern (score of 0-2), the multivariable-adjusted hazard ratio and 95% confidence interval were 0.85 (0.75 to 0.96) for urologic cancers, 0.80 (0.68 to 0.93) for BCa, and 0.91 (0.74, 1.12) for RCC, respectively, for those with the healthier sleep pattern (score of 4-5). CONCLUSION: Our results indicate that a healthy sleep pattern is associated with lower risks of urologic cancers.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Estudos Prospectivos , Carcinoma de Células Renais/complicações , Sono , Ronco/complicações , Neoplasias Renais/epidemiologia , Neoplasias Renais/complicações , Fatores de RiscoRESUMO
Breast milk iodine concentration (BMIC) is a promising indicator of iodine status in lactating women. However, there are limited data on its usefulness to reflect maternal iodine deficiency. Therefore, the aim of our study was to assess iodine concentration in breast milk and urine samples in exclusively breast-feeding women. Eligible pregnant women undergoing routine antenatal care in a large hospital in Shaanxi Province, China, were followed up from the third trimester of pregnancy until the first week of lactation. Urine samples (20 ml) were collected during pregnancy and lactation. Iodine concentration in samples was measured based on Sandell-Kolthoff reaction. Breast milk samples (5 ml) were provided during lactation. A receiver operating curve (ROC) was constructed to determine the diagnostic performance of BMIC. An iodine-specific FFQ was completed twice during pregnancy and lactation. A total of 200 women completed the study. The overall median BMIC was 89 µg/l, indicating iodine sufficiency (i.e. BMIC reference range between 60 and 465 µg/l). Women reported similar median urinary iodine concentration (UIC) during pregnancy and lactation (112 and 113 µg/l, respectively), but their iodine status differed - mild-to-moderate iodine deficiency during pregnancy and iodine sufficiency during lactation. The ROC for BMIC using UIC as a reference standard was 0·755 (95 % CI: 0·644, 0·866). In conclusion, this study demonstrated that women were iodine sufficient in the first week of lactation as assessed by UIC, which was consistent with BMIC. These findings suggested that BMIC is a useful biomarker to assess iodine status in lactating women.
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Iodo , Leite Humano , Feminino , Humanos , Gravidez , Leite Humano/química , Lactação , Iodo/análise , Aleitamento Materno , Biomarcadores , Estado NutricionalRESUMO
Cognitive impairment is recognized as a risk factor for suicide in schizophrenia (SZ) patients. Despite empathy being an important aspect of social cognition, the association between suicidal behavior and empathy has received little attention. We aimed to compare empathy and neurocognition in SZ patients with and without suicide attempts (SAs), and to explore the relationship between empathy, neurocognition, and clinical symptoms in SZ patients with and without SAs. Data on SAs and socio-demographic characteristics were collected from 628 chronic SZ patients. The patients' symptomatology was measured by the Positive and Negative Syndrome Scale (PANSS). Empathy and neurocognition were assessed with the Interpersonal Reactivity Index (IRI) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), respectively. Patients with SAs performed better on all IRI domains (except for Perspective Taking) and total scores. Regression results showed that negative symptoms, positive symptoms, and duration of illness were independently associated with IRI total score in patients without SAs (adjusted R2 = 0.048). In patients without SAs, negative symptoms, general psychopathology, education, age, and sex were independently associated with RBANS total score (adjusted R2 = 0.265), while in patients with SAs, education, PANSS total score, and age at onset were independently associated with RBANS total score (adjusted R2 = 0.456). Our results show that SZ patients with SAs may have better empathic performance than patients without SAs. In chronic SZ patients, negative and positive symptoms may have different effects on cognition in the SAs and non-SAs groups.
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OBJECTIVE: To study how Pneumoperitoneum under Trendelenburg position for robot-assisted laparoscopic surgery impact the perioperative respiratory parameters, diagrammatic function, etc. METHODS: Patients undergoing robot-assisted laparoscopic surgery in the Trendelenburg position and patients undergoing general surgery in the supine position were selected. The subjects were divided into two groups according to the type of surgery: robot-assisted surgery group and general surgery group. â Respiratory parameters such as lung compliance, oxygenation index, and airway pressure were recorded at 5 min after intubation, 1 and 2 h after pneumoperitoneum. â¡ Diaphragm excursion (DE) and diaphragm thickening fraction (DTF) were recorded before entering the operating room (T1), immediately after extubation (T2), 10 min after extubation (T3), and upon leaving the postanesthesia care unit (T4). ⢠Peripheral venous blood (5 ml) was collected before surgery and 30 min after extubation and was analyzed by enzyme-linked immunosorbent assay to determine the serum concentration of Clara cell secretory protein 16 (CC16) and surfactant protein D (SP-D). RESULT: â Compared with the general surgery group (N = 42), the robot-assisted surgery group (N = 46) presented a significantly higher airway pressure and lower lung compliance during the surgery(P < 0.001). â¡ In the robot-assisted surgery group, the DE significantly decreased after surgery (P < 0.001), which persisted until patients were discharged from the PACU (P < 0.001), whereas the DTF only showed a transient decrease postoperatively (P < 0.001) and returned to its preoperative levels at discharge (P = 0.115). In the general surgery group, the DE showed a transient decrease after surgery(P = 0.011) which recovered to the preoperative levels at discharge (P = 1). No significant difference in the DTF was observed among T1, T2, T3, and T4. ⢠Both the general and robot-assisted surgery reduced the postoperative serum levels of SP-D (P < 0.05), while the robot-assisted surgery increased the postoperative levels of CC16 (P < 0.001). CONCLUSION: Robot-assisted laparoscopic surgery significantly impairs postoperative diaphragm function, which does not recover to preoperative levels at PACU discharge. Elevated levels of serum CC16 after surgery suggest potential lung injury. The adverse effects may be attributed to the prolonged Trendelenburg position and pneumoperitoneum during laparoscopic surgery.
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Laparoscopia , Pneumoperitônio , Procedimentos Cirúrgicos Robóticos , Robótica , Humanos , Diafragma , Decúbito Inclinado com Rebaixamento da Cabeça , Proteína D Associada a Surfactante Pulmonar , RespiraçãoRESUMO
The rational design, activity prediction, and adaptive application of biological elements (bio-elements) are crucial research fields in synthetic biology. Currently, a major challenge in the field is efficiently designing desired bio-elements and accurately predicting their activity using vast datasets. The advancement of artificial intelligence (AI) technology has enabled machine learning and deep learning algorithms to excel in uncovering patterns in bio-element data and predicting their performance. This review explores the application of AI algorithms in the rational design of bio-elements, activity prediction, and the regulation of transcription-factor-based biosensor response performance using AI-designed elements. We discuss the advantages, adaptability, and biological challenges addressed by the AI algorithms in various applications, highlighting their powerful potential in analyzing biological data. Furthermore, we propose innovative solutions to the challenges faced by AI algorithms in the field and suggest future research directions. By consolidating current research and demonstrating the practical applications and future potential of AI in synthetic biology, this review provides valuable insights for advancing both academic research and practical applications in biotechnology.
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Algoritmos , Inteligência Artificial , Técnicas Biossensoriais , Fatores de Transcrição , Técnicas Biossensoriais/métodos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Biologia Sintética/métodos , Humanos , Aprendizado Profundo , Aprendizado de MáquinaRESUMO
The median urinary iodine concentration (UIC) of school-aged children has been commonly used as a surrogate to assess iodine status of a population including pregnant women. However, pregnant women have higher iodine requirements than children due to increased production of thyroid hormones. The aim of the study was to evaluate the iodine status of pregnant women and children as well as their household salt iodine concentration (SIC) in Quzhou, Zhejiang Province, China. Eligible pregnant women and children from all six counties of Quzhou in 2021 were recruited into the study. They were asked to complete a socio-demographic questionnaire and provide both a spot urine and a household table salt sample for the determination of UIC and SIC. A total of 629 pregnant women (mean age and gestation weeks of 29.6 years and 21.6 weeks, respectively) and 1273 school-aged children (mean age of 9 years and 49.8% of them were females) were included in the study. The overall median UIC of pregnant women and children in our sample was 127 (82, 193) µg/L and 222 (147, 327) µg/L, respectively, indicating sufficient iodine status in children but a risk of mild-to-moderate iodine deficiency in pregnant women. Distribution of iodine nutrition in children varied significantly according to their sex and age (P < 0.05). The rate of adequately household iodised salt samples (18-33 mg/kg) provided by pregnant women and children was 92.4% and 90.6%, respectively. In conclusion, our results indicated a risk of insufficient iodine status in pregnant population of China, but iodine sufficiency in school-aged children. Our data also suggested that median UIC of children may not be used as a surrogate to assess iodine status in pregnant women.
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Iodo , Cloreto de Sódio na Dieta , Humanos , Iodo/deficiência , Iodo/urina , Iodo/análise , Feminino , Gravidez , China/epidemiologia , Criança , Masculino , Adulto , Cloreto de Sódio na Dieta/análise , Estado NutricionalRESUMO
Renal transplantation is the only efficacious treatment for end-stage kidney disease. However, some people have developed renal insufficiency after transplantation, the mechanisms of which have not been well clarified. Previous studies have focused on patient factors, while the effect of gene expression in the donor kidney on post-transplant renal function has been less studied. Donor kidney clinical data and mRNA expression status were extracted from the GEO database (GSE147451). Weight gene co-expression network analysis (WGCNA) and differential gene enrichment analysis were performed. For external validation, we collected data from 122 patients who accepted renal transplantation at several hospitals and measured the level of target genes by qPCR. This study included 192 patients from the GEO data set, and 13 co-expressed genes were confirmed by WGCNA and differential gene enrichment analysis. Then, the PPI network contained 17 edges as well as 12 nodes, and four central genes (PRKDC, RFC5, RFC3 and RBM14) were identified. We found by collecting data from 122 patients who underwent renal transplantation in several hospitals and by multivariate logistic regression that acute graft-versus-host disease postoperative infection, PRKDC [Hazard Ratio (HR) = 4.44; 95% CI = [1.60, 13.68]; p = 0.006] mRNA level correlated with the renal function after transplantation. The prediction model constructed had good predictive accuracy (C-index = 0.886). Elevated levels of donor kidney PRKDC are associated with renal dysfunction after transplantation. The prediction model of renal function status for post-transplant recipients based on PRKDC has good predictive accuracy and clinical application.
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Doença Enxerto-Hospedeiro , Falência Renal Crônica , Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Regulação para Cima , Sobrevivência de Enxerto , Falência Renal Crônica/genética , Falência Renal Crônica/cirurgia , Proteína Quinase Ativada por DNARESUMO
Rhodophyta are among the closest known relatives of green plants. Studying the codons of their genomes can help us understand the codon usage pattern and characteristics of the ancestor of green plants. By studying the codon usage pattern of all available red algae, it was found that although there are some differences among species, high-bias genes in most red algae prefer codons ending with GC. Correlation analysis, Nc-GC3s plots, parity rule 2 plots, neutrality plot analysis, differential protein region analysis and comparison of the nucleotide content of introns and flanking sequences showed that the bias phenomenon is likely to be influenced by local mutation pressure and natural selection, the latter of which is the dominant factor in terms of translation accuracy and efficiency. It is worth noting that selection on translation accuracy could even be detected in the low-bias genes of individual species. In addition, we identified 15 common optimal codons in seven red algae except for G. sulphuraria for the first time, most of which were found to be complementary and bound to the tRNA genes with the highest copy number. Interestingly, tRNA modification was found for the highly degenerate amino acids of all multicellular red algae and individual unicellular red algae, which indicates that highly biased genes tend to use modified tRNA in translation. Our research not only lays a foundation for exploring the characteristics of codon usage of the red algae as green plant ancestors, but will also facilitate the design and performance of transgenic work in some economic red algae in the future.
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Uso do Códon , Magnoliopsida , Feminino , Gravidez , Humanos , Aminoácidos , Íntrons , MutaçãoRESUMO
The clinical outcome of resectable non-small-cell lung cancer (NSCLC) patients receiving neoadjuvant chemoimmunotherapy is good but varies greatly. In addition, the pathological response after neoadjuvant chemoimmunotherapy is significantly associated with survival outcomes. The aim of this retrospective study was to identify which population of patients with locally advanced and oligometastatic NSCLC has a favorable pathological response after neoadjuvant chemoimmunotherapy. NSCLC patients treated with neoadjuvant chemoimmunotherapy were enrolled between February 2018 and April 2022. Data on clinicopathological features were collected and evaluated. Multiplex immunofluorescence was performed on pre-treatment puncture specimens and surgically resected specimens. In total, 29 patients with stages III and IV locally advanced or oligometastatic NSCLC who received neoadjuvant chemoimmunotherapy and R0 resection were enrolled. The results showed that 55% (16/29) of patients had a major pathological response (MPR) and 41% (12/29) of patients had a complete pathological response (pCR). In the stroma area of the pre-treatment specimen, the higher infiltration of CD3+ PD-L1+ tumor-infiltrating lymphocytes (TILs) and the lower infiltration of CD4+ and CD4+ FOXP3+ TILs were more likely to appear in patients with pCR. However, in the tumor area, the higher infiltration of CD8+ TILs was more likely to appear in patients with non-MPR. In the post-treatment specimen, we found increased infiltration of CD3+ CD8+ , CD8+ GZMB+ , and CD8+ CD69+ TILs and decreased infiltration of PD-1+ TILs both in the stroma and tumor areas. Neoadjuvant chemoimmunotherapy achieved an MPR rate of 55% and induced greater immune infiltration. In addition, we observed that the baseline TILs and their spatial distribution correlate to the pathological response.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia Neoadjuvante , Estudos Retrospectivos , Microambiente Tumoral , Linfócitos do Interstício Tumoral , Antígeno B7-H1RESUMO
Cu2 SnS3 is a promising thermoelectric candidate for power generation at medium temperature due to its low-cost and environmental-benign features. However, the high electrical resistivity due to low hole concentration severely restricts its final thermoelectric performance. Here, analog alloying with CuInSe2 is first adopted to optimize the electrical resistivity by promoting the formation of Sn vacancies and the precipitation of In, and optimize lattice thermal conductivity through the formation of stacking faults and nanotwins. Such analog alloying enables a greatly enhanced power factor of 8.03 µW cm-1 K-2 and a largely reduced lattice thermal conductivity of 0.38 W m-1 K-1 for Cu2 SnS3 - 9 mol.% CuInSe2 . Eventually, a peak ZT as high as 1.14 at 773 K is achieved for Cu2 SnS3 - 9 mol.% CuInSe2 , which is one of the highest ZT among the researches on Cu2 SnS3 -based thermoelectric materials. The work implies analog alloying with CuInSe2 is a very effective route to unleash superior thermoelectric performance of Cu2 SnS3 .
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In Streptomyces rimosus M527, the oxytetracycline (OTC) biosynthetic gene cluster is not expressed under laboratory conditions. In this study a reported-guided mutant selection (RGMS) procedure was used to activate the cluster. The double-reporter plasmid pAGT was constructed in which gusA encoding a ß-glucuronidase and tsr encoding a thiostrepton resistance methyltransferase were placed under the control of the native promoter of oxyA gene (PoxyA ). Plasmid pAGT was introduced and integrated into the chromosome of S. rimosus M527 by conjugation, yielding initial strain M527-pAGT. Subsequently, mutants of M527-pAGT were generated by using ribosome engineering technology. The mutants harboring activated OTC gene cluster were selected based on visual observation of GUS activity and thiostrepton resistance. Finally, mutant M527-pAGT-R7 was selected producing OTC in a concentration of 235.2 mg/L. In this mutant transcriptional levels of oxysr genes especial oxyAsr gene were increased compared to wild-type strain S. rimosus M527. The mutant M527-pAGT-R7 showed antagonistic activities against Gram-negative and Gram-positive strains. All data indicate that the OTC gene cluster was successfully activated using the RGMS method.
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Oxitetraciclina , Streptomyces rimosus , Streptomyces rimosus/genética , Tioestreptona , Família Multigênica , Regiões Promotoras GenéticasRESUMO
Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination, are still lacking. Notably, cerebellar microglial activation appears to be a common feature in different types of ataxic patients and rodent models. However, direct evidence that cerebellar microglial activation in vivo is sufficient to induce ataxia is still lacking. Here, by employing chemogenetic approaches to manipulate cerebellar microglia selectively and directly, we found that specific chemogenetic activation of microglia in the cerebellar vermis directly leads to ataxia symptoms in wild-type mice and aggravated ataxic motor deficits in 3-acetylpyridine (3-AP) mice, a classic mouse model of cerebellar ataxia. Mechanistically, cerebellar microglial proinflammatory activation induced by either chemogenetic M3D(Gq) stimulation or 3-AP modeling hyperexcites Purkinje cells (PCs), which consequently triggers ataxia. Blockade of microglia-derived TNF-α, one of the most important proinflammatory cytokines, attenuates the hyperactivity of PCs driven by microglia. Moreover, chemogenetic inhibition of cerebellar microglial activation or suppression of cerebellar microglial activation by PLX3397 and minocycline reduces the production of proinflammatory cytokines, including TNF-α, to effectively restore the overactivation of PCs and alleviate motor deficits in 3-AP mice. These results suggest that cerebellar microglial activation may aggravate the neuroinflammatory response and subsequently induce dysfunction of PCs, which in turn triggers ataxic motor deficits. Our findings thus reveal a causal relationship between proinflammatory activation of cerebellar microglia and ataxic motor symptoms, which may offer novel evidence for therapeutic intervention for cerebellar ataxias by targeting microglia and microglia-derived inflammatory mediators.
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Ataxia Cerebelar , Camundongos , Animais , Ataxia Cerebelar/induzido quimicamente , Células de Purkinje/fisiologia , Microglia , Fator de Necrose Tumoral alfa/farmacologia , Cerebelo , CitocinasRESUMO
BACKGROUND: Streoptomyces rimosus M527 is a producer of the polyene macrolide rimocidin which shows activity against various plant pathogenic fungi. Notably, the regulatory mechanisms underlying rimocidin biosynthesis are yet to be elucidated. RESULTS: In this study, using domain structure and amino acid alignment and phylogenetic tree construction, rimR2, which located in the rimocidin biosynthetic gene cluster, was first found and identified as a larger ATP-binding regulators of the LuxR family (LAL) subfamily regulator. The rimR2 deletion and complementation assays were conducted to explore its role. Mutant M527-ΔrimR2 lost its ability to produce rimocidin. Complementation of M527-ΔrimR2 restored rimocidin production. The five recombinant strains, M527-ER, M527-KR, M527-21R, M527-57R, and M527-NR, were constructed by overexpressing rimR2 gene using the promoters permE*, kasOp*, SPL21, SPL57, and its native promoter, respectively, to improve rimocidin production. M527-KR, M527-NR, and M527-ER exhibited 81.8%, 68.1%, and 54.5% more rimocidin production, respectively, than the wild-type (WT) strain, while recombinant strains M527-21R and M527-57R exhibited no obvious differences in rimocidin production compared with the WT strain. RT-PCR assays revealed that the transcriptional levels of the rim genes were consistent with the changes in rimocidin production in the recombinant strains. Using electrophoretic mobility shift assays, we confirmed that RimR2 can bind to the promoter regions of rimA and rimC. CONCLUSION: A LAL regulator RimR2 was identified as a positive specific-pathway regulator of rimocidin biosynthesis in M527. RimR2 regulates the rimocidin biosynthesis by influencing the transcriptional levels of rim genes and binding to the promoter regions of rimA and rimC.
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Polienos , Streptomyces rimosus , Proteínas de Bactérias/metabolismo , Regulação Bacteriana da Expressão Gênica , Filogenia , Polienos/metabolismo , Streptomyces rimosus/metabolismoRESUMO
INTRODUCTION: Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with heart failure and stroke, leading sometimes to death. But the pathogenesis of AF remains unclear. Numerous studies have investigated whether the connexin 40 (Cx40) polymorphisms influences the risk of AF, but the results are controversial. METHODS: We searched English and Chinese databases and calculated the odds ratio (OR) and 95% confidence interval (CI) to examine the existence of genetic associations between the Cx40 polymorphisms and the risk of AF. All relevant studies were screened and meta-analyzed using Review Manager 5.0. RESULTS: A total of 12 studies, including 10 studies for -44 polymorphism (rs35594137) and 4 studies for -26 polymorphism (rs10465885), were identified for the meta-analysis. For -44 polymorphism, the results showed a significantly increased risk of AF in the five genetic models in the overall analysis. Furthermore, in subgroup analysis, increased AF risks were also observed in Asian and non-Asian populations. For -26 polymorphism, the overall OR revealed an increased risk of AF in dominant model. In subgroup analysis, increased AF risk was only found in recessive genetic model of the Asian population. CONCLUSIONS: The Cx40 polymorphisms were positively associated with AF in both populations, especially on -44 polymorphism.
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Fibrilação Atrial , Conexinas , Humanos , Fibrilação Atrial/complicações , Conexinas/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteína alfa-5 de Junções ComunicantesRESUMO
BACKGROUND AND AIMS: Skeletal muscle strength decline is strongly associated with inflammation. While previous research has confirmed that diet can modulate chronic inflammation, little is known about the relationship between an anti-inflammatory dietary pattern and muscle strength. The aim of this study was to investigate the association between an anti-inflammatory dietary pattern and handgrip strength decline in a large-scale adult population. METHODS: During a median follow-up period of 3 years, this prospective cohort study was carried out between 2013 and 2018 and included 2840 participants (60.2% men). Dietary intake was assessed using a validated food frequency questionnaire at baseline, and handgrip strength was measured annually with a handheld digital dynamometer. The dietary inflammatory potential score was calculated using white blood cell count and hypersensitive C-reactive protein as inflammatory markers, and was determined using reduced rank regression and stepwise linear regression. Multivariable linear regression models were used to estimate the association between the dietary inflammatory potential score and the annualized change in handgrip strength and weight-adjusted handgrip strength. RESULTS: After adjusting for multiple confounding factors, significant associations between the dietary inflammatory potential score and the annualized change in handgrip strength and weight-adjusted handgrip strength in women, with values of - 0.8322 kg (95% confidence interval [CI] - 1.6405, - 0.0238; P < 0.0408) and - 0.0171 kg/kg (95% CI - 0.0310, - 0.0032; P < 0.0158), respectively. However, no significant differences were observed between the dietary inflammatory potential score and the annualized change in handgrip strength and weight-adjusted handgrip strength in men, with values of 0.1578 kg (95% CI - 0.6107, 0.9261; P < 0.6874) and - 0.0014 kg/kg (95% CI - 0.0115, 0.0088; P < 0.7933), respectively. CONCLUSION: Our findings suggest that consuming an anti-inflammatory dietary pattern could be a protective strategy against the decline in skeletal muscle strength in women.