metaProbiotics: a tool for mining probiotic from metagenomic binning data based on a language model.

Beneficial bacteria remain largely unexplored. Lacking systematic methods, understanding probiotic community traits becomes challenging, leading to various conclusions about their probiotic effects among different publications. We developed language model-based metaProbiotics to rapidly detect probiotic bins from metagenomes, demonstrating superior performance in simulated benchmark datasets. Testing on gut metagenomes from probiotic-treated individuals, it revealed the probioticity of intervention strains-derived bins and other probiotic-associated bins beyond the training data, such as a plasmid-like bin. Analyses of these bins revealed various probiotic mechanisms and bai operon as probiotic Ruminococcaceae's potential marker. In different health-disease cohorts, these bins were more common in healthy individuals, signifying their probiotic role, but relevant health predictions based on the abundance profiles of these bins faced cross-disease challenges. To better understand the heterogeneous nature of probiotics, we used metaProbiotics to construct a comprehensive probiotic genome set from global gut metagenomic data. Module analysis of this set shows that diseased individuals often lack certain probiotic gene modules, with significant variation of the missing modules across different diseases. Additionally, different gene modules on the same probiotic have heterogeneous effects on various diseases. We thus believe that gene function integrity of the probiotic community is more crucial in maintaining gut homeostasis than merely increasing specific gene abundance, and adding probiotics indiscriminately might not boost health. We expect that the innovative language model-based metaProbiotics tool will promote novel probiotic discovery using large-scale metagenomic data and facilitate systematic research on bacterial probiotic effects. The metaProbiotics program can be freely downloaded at https://github.com/zhenchengfang/metaProbiotics.

Urolithin A attenuates hexavalent chromium-induced small intestinal injury by modulating PP2A/Hippo/YAP1 pathway.

Hexavalent chromium (Cr(VI)) exposure has been linked with gastrointestinal toxicity, whereas the molecular pathways and key targets remain elusive. Computational toxicology analysis predicted the correlation between protein phosphatase 2A (PP2A) and genes regarding Cr(VI)-induced intestinal injury. Here, we generated a mouse model with intestinal epithelium-specific knock out of Ppp2r1a (encoding PP2A Aα subunit) to investigate the mechanisms underlying Cr(VI)-induced small intestinal toxicity. Heterozygous (HE) mice and matched WT littermates were administrated with Cr(VI) at 0, 5, 20, and 80 mg/l for 28 successive days. Cr(VI) treatment led to crypt hyperplasia, epithelial cell apoptosis, and intestinal barrier dysfunction, accompanied by the decline of goblet cell counts and Occludin expression in WT mice. Notably, these effects were aggravated in HE mice, indicating that PP2A Aα deficiency conferred mice with susceptibility to Cr(VI)-induced intestinal injury. The combination of data analysis and biological experiments revealed Cr(VI) exposure could decrease YAP1 phosphorylation at Ser127 but increase protein expression and activity, together with elevated transcriptional coactivator with PDZ-binding motif protein driving epithelial crypt cells proliferation following damage, suggesting the involvement of Hippo/YAP1 signaling pathway in Cr(VI)-induced intestinal toxicity. Nevertheless, the enhanced phosphorylation of YAP1 in HE mice resulted in proliferation/repair defects in intestinal epithelium, thereby exacerbating Cr(VI)-induced gut barrier dysfunction. Notably, by molecular docking and further studies, we identified urolithin A, a microbial metabolite, attenuated Cr(VI)-induced disruption of intestinal barrier function, partly by modulating YAP1 expression and activity. Our findings reveal the novel molecular pathways participated in Cr(VI)-caused small intestinal injury and urolithin A could potentially protect against environmental hazards-induced intestinal diseases.

Integrated metagenomic and metabolomic analysis reveals distinctive stage-specific gut-microbiome-derived metabolites in intracranial aneurysms.

OBJECTIVE: Our study aimed to explore the influence of gut microbiota and their metabolites on intracranial aneurysms (IA) progression and pinpoint-related metabolic biomarkers derived from the gut microbiome. DESIGN: We recruited 358 patients with unruptured IA (UIA) and 161 with ruptured IA (RIA) from two distinct geographical regions for conducting an integrated analysis of plasma metabolomics and faecal metagenomics. Machine learning algorithms were employed to develop a classifier model, subsequently validated in an independent cohort. Mouse models of IA were established to verify the potential role of the specific metabolite identified. RESULTS: Distinct shifts in taxonomic and functional profiles of gut microbiota and their related metabolites were observed in different IA stages. Notably, tryptophan metabolites, particularly indoxyl sulfate (IS), were significantly higher in plasma of RIA. Meanwhile, upregulated tryptophanase expression and indole-producing microbiota were observed in gut microbiome of RIA. A model harnessing gut-microbiome-derived tryptophan metabolites demonstrated remarkable efficacy in distinguishing RIA from UIA patients in the validation cohort (AUC=0.97). Gut microbiota depletion by antibiotics decreased plasma IS concentration, reduced IA formation and rupture in mice, and downregulated matrix metalloproteinase-9 expression in aneurysmal walls with elastin degradation reduction. Supplement of IS reversed the effect of gut microbiota depletion. CONCLUSION: Our investigation highlights the potential of gut-microbiome-derived tryptophan metabolites as biomarkers for distinguishing RIA from UIA patients. The findings suggest a novel pathogenic role for gut-microbiome-derived IS in elastin degradation in the IA wall leading to the rupture of IA.

Combined analysis of the effects of hypoxia and oxidative stress on DNA methylation and the transcriptome in HTR-8/SVneo trophoblast cells.

The alterations in DNA methylation and transcriptome in trophoblast cells under conditions of low oxygen and oxidative stress have major implications for pregnancy-related disorders. However, the exact mechanism is still not fully understood. In this study, we established models of hypoxia (H group) and oxidative stress (HR group) using HTR-8/SVneo trophoblast cells and performed combined analysis of genome-wide DNA methylation changes using reduced representation bisulphite sequencing and transcriptome expression changes using RNA sequencing. Our findings revealed that the H group exhibited a higher number of differentially methylated genes and differentially expressed genes than the HR group. In the H group, only 0.90% of all differentially expressed genes displayed simultaneous changes in DNA methylation and transcriptome expression. After the threshold was expanded, this number increased to 6.29% in the HR group. Notably, both the H group and HR group exhibited concurrent alterations in DNA methylation and transcriptome expression within Axon guidance and MAPK signalling pathway. Among the top 25 differentially methylated KEGG pathways in the promoter region, 11 pathways were commonly enriched in H group and HR group, accounting for 44.00%. Among the top 25 KEGG pathways in transcriptome with significant differences between the H group and HR group, 10 pathways were consistent, accounting for 40.00%. By integrating our previous data on DNA methylation from preeclamptic placental tissues, we identified that the ANKRD37 and PFKFB3 genes may contribute to the pathogenesis of preeclampsia through DNA methylation-mediated transcriptome expression under hypoxic conditions.

Clinical characteristics of post-stroke basal ganglia aphasia and the study of language-related white matter tracts based on diffusion spectrum imaging.

BACKGROUND: Stroke often damages the basal ganglia, leading to atypical and transient aphasia, indicating that post-stroke basal ganglia aphasia (PSBGA) may be related to different anatomical structural damage and functional remodeling rehabilitation mechanisms. The basal ganglia contain dense white matter tracts (WMTs). Hence, damage to the functional tract may be an essential anatomical structural basis for the development of PSBGA. METHODS: We first analyzed the clinical characteristics of PSBGA in 28 patients and 15 healthy controls (HCs) using the Western Aphasia Battery and neuropsychological test batteries. Moreover, we investigated white matter injury during the acute stage using diffusion magnetic resonance imaging scans for differential tractography. Finally, we used multiple regression models in correlation tractography to analyze the relationship between various language functions and quantitative anisotropy (QA) of WMTs. RESULTS: Compared with HCs, patients with PSBGA showed lower scores for fluency, comprehension (auditory word recognition and sequential commands), naming (object naming and word fluency), reading comprehension of sentences, Mini-Mental State Examination, and Montreal Cognitive Assessment, along with increased scores in Hamilton Anxiety Scale-17 and Hamilton Depression Scale-17 within 7 days after stroke onset (P < 0.05). Differential tractography revealed that patients with PSBGA had damaged fibers, including in the body fibers of the corpus callosum, left cingulum bundles, left parietal aslant tracts, bilateral superior longitudinal fasciculus II, bilateral thalamic radiation tracts, left fornix, corpus callosum tapetum, and forceps major, compared with HCs (FDR < 0.02). Correlation tractography highlighted that better comprehension was correlated with a higher QA of the left inferior fronto-occipital fasciculus (IFOF), corpus callosum forceps minor, and left extreme capsule (FDR < 0.0083). Naming was positively associated with the QA of the left IFOF, forceps minor, left arcuate fasciculus, and uncinate fasciculus (UF) (FDR < 0.0083). Word fluency of naming was also positively associated with the QA of the forceps minor, left IFOF, and thalamic radiation tracts (FDR < 0.0083). Furthermore, reading was positively correlated with the QA of the forceps minor, left IFOF, and UF (FDR < 0.0083). CONCLUSION: PSBGA is primarily characterized by significantly impaired word fluency of naming and preserved repetition abilities, as well as emotional and cognitive dysfunction. Damaged limbic pathways, dorsally located tracts in the left hemisphere, and left basal ganglia pathways are involved in PSBGA pathogenesis. The results of connectometry analysis further refine the current functional localization model of higher-order neural networks associated with language functions.

The effect of repetitive magnetic stimulation on neuronal apoptosis and PI3K/Akt protein expression in rats with incomplete spinal cord injury.

The pathological and physiological process of spinal cord injury is complex, and there is currently no effective treatment method. Magnetic stimulation is an emerging electromagnetic therapy method in recent years, and studies have shown its potential to reduce cell apoptosis. This study used an improved Allen's method to replicate an incomplete spinal cord injury rat model, and repetitive magnetic stimulation (rMS) intervention was performed on the rats for 21 days. The research plan consists of two parts. The first part aims to observe the effects of rMS on motor function and neuronal cell apoptosis in rats. The Basso-Beattie-Bresnahan (BBB) score results indicate that rMS promotes the recovery of motor function in rats; H&E staining showed that rMS improved spinal cord structural damage and inflammatory infiltration; TUNEL and NeuN staining suggest that rMS can reduce cell apoptosis and promote neuronal cell survival. The second part aims to explore the mechanism of action of rMS. Immunofluorescence staining showed that after rMS intervention, the positive counts of PI3K and Akt increased, whereas the positive counts of caspase-3 decreased. Western blot showed that after rMS intervention, the expression of phospho-phosphatidylinositol-3 kinase (p-PI3K)/PI3K, phospho (p)-Akt/Akt, and Bcl-2 increased, whereas the expression of Bcl-2-associated X protein (Bax) and caspase-3 decreased. In summary, rMS can significantly reduce cell apoptosis in the damaged spinal cord and promote neuronal cell survival. Its mechanism of action may be related to promoting the expression of PI3K/Akt pathway proteins, upregulating the antiapoptotic protein Bcl-2, downregulating the proapoptotic protein Bax, and thereby inhibiting the expression of apoptotic protein caspase-3. NEW & NOTEWORTHY Spinal cord injury is a serious disabling central nervous system disease. Recently, research on magnetic stimulation therapy for spinal cord injury has been increasing, and its potential has gradually attracted the attention of experts. This study found that repetitive magnetic stimulation (rMS) can improve motor function and reduce neuronal apoptosis in spinal cord injury rats. The mechanism may be related to increasing the expression of phosphatidylinositol-3 kinase (PI3K)/Akt protein, thereby inhibiting cell apoptosis and promoting neuronal survival.

Gut microbiota-mediated ursodeoxycholic acids regulate the inflammation of microglia through TGR5 signaling after MCAO.

Ischemic stroke has been demonstrated to cause an imbalance of gut microbiota. However, the change in gut microbiota-mediated bile acids (BAs) metabolites remains unclear. Here, we observed a decrease in gut microbiota-mediated BAs, especially ursodeoxycholic acid (UDCA), in the serum of stroke patients as well as in the intestine, serum and brain of stroke mice. Restoration of UDCA could decrease the area of infarction and improve the neurological function and cognitive function in mice in association with inhibition of NLRP3-related pro-inflammatory cytokines through TGR5/PKA pathway. Furthermore, knocking out TGR5 and inhibiting PKA activity reduce the protective effect of UDCA. Taken together, our results suggest that microbiota-mediated UDCA plays an important role in alleviating inflammatory responses and might be a promising therapeutic target in ischemic stroke.

One-Pot Reaction Sequence: N-Acylation/Pictet-Spengler Reaction/Intramolecular [4 + 2] Cycloaddition/Aromatization in the Synthesis of ß-Carboline Alkaloid Analogues.

One-pot synthesis of tetrahydro-ß-carbolines, fused with an isoindole core, was proposed starting from maleic anhydride and azomethines easily available from tryptamines and 3-(hetaryl)acroleins. This sequence includes four key steps: an acylation of the aldimine with maleic anhydride, a Pictet-Spengler cyclization, an intramolecular Diels-Alder reaction, and a concluding [1,3]-H shift. As a result, six- or seven-nuclear alkaloid-like heterocyclic systems, containing a benzo[1,2]indolizino[8,7-b]indole fragment annulated with furan, thiophene, or pyrrole, are formed in a diastereoselective manner.

Association between leisure sedentary behaviors and hypertension risk: A prospective cohort study and two-sample Mendelian randomization analysis in Europeans.

OBJECTIVE: This study aimed to investigate the potential causal relationship between domain-specific sedentary behaviors (including television watching, computer use, and driving) and hypertension risk in European populations. METHODS: Initially, we conducted a multivariable Cox regression analysis to evaluate the associations between domain-specific sedentary behaviors and the risk of developing hypertension using data from 261,829 hypertension-free participants in the UK Biobank. To validate the findings of observational analysis, we employed two-sample univariable mendelian randomization (UVMR) analysis utilizing summary statistics from genome-wide association study conducted on European populations. We then performed multivariable mendelian randomization (MVMR) analysis to account for the influence of the risk factors for hypertension. RESULTS: In this prospective observational analysis, individuals who spent >3 h per day watching television had significantly higher risk of developing hypertension (HR = 1.24, 95% CI: 1.20-1.29, P < 0.001) compared to those who watched television for 0-1 h per day. The mendelian randomization analysis provided consistent evidence for a causal relationship between prolonged television watching time and hypertension risk (OR = 1.45, 95% CI: 1.25-1.69, P < 0.001; all PMVMR < 0.05) in both UVMR and MVMR results. No significant associations were found between computer use, driving behaviors and the risk of hypertension in either the observational or UVMR/MVMR analyses. CONCLUSIONS: These findings provide evidence for a causal effect specifically linking higher television watching time to an increased risk of hypertension and indicate the potential effectiveness of reducing television viewing time as a preventive measure to mitigate the risk of hypertension.

An RNAi screen of RNA helicases identifies eIF4A3 as a regulator of embryonic stem cell identity.

RNA helicases are involved in multiple steps of RNA metabolism to direct their roles in gene expression, yet their functions in pluripotency control remain largely unexplored. Starting from an RNA interference (RNAi) screen of RNA helicases, we identified that eIF4A3, a DEAD-box (Ddx) helicase component of the exon junction complex (EJC), is essential for the maintenance of embryonic stem cells (ESCs). Mechanistically, we show that eIF4A3 post-transcriptionally controls the pluripotency-related cell cycle regulators and that its depletion causes the loss of pluripotency via cell cycle dysregulation. Specifically, eIF4A3 is required for the efficient nuclear export of Ccnb1 mRNA, which encodes Cyclin B1, a key component of the pluripotency-promoting pathway during the cell cycle progression of ESCs. Our results reveal a previously unappreciated role for eIF4A3 and its associated EJC in maintaining stem cell pluripotency through post-transcriptional control of the cell cycle.

Blood culture quality and turnaround time of clinical microbiology laboratories in Chinese Teaching Hospitals: A multicenter study.

PURPOSE: Blood culture (BC) remains the gold standard for the diagnosis of bloodstream infections. Improving the quality of clinical BC samples, optimizing BC performance, and accelerating antimicrobial susceptibility test (AST) results are essential for the early detection of bloodstream infections and specific treatments. METHODS: We conducted a retrospective multicenter study using 450,845 BC specimens from clinical laboratories obtained from 19 teaching hospitals between 1 January 2021 and 31 December 2021. We evaluated key performance indicators (KPIs), turnaround times (TATs), and frequency distributions of processing in BC specimens. We also evaluated the AST results of clinically significant isolates for four different laboratory workflow styles. RESULTS: Across the 10 common bacterial isolates (n = 16,865) and yeast isolates (n = 1011), the overall median (interquartile range) TATs of AST results were 2.67 (2.05-3.31) and 3.73 (2.98-4.64) days, respectively. The specimen collections mainly occurred between 06:00 and 24:00, and specimen reception and loadings mainly between 08:00 and 24:00. Based on the laboratory workflows of the BCs, 16 of the 19 hospitals were divided into four groups. Time to results (TTRs) from specimen collection to the AST reports were 2.35 (1.95-3.06), 2.61 (1.98-3.32), 2.99 (2.60-3.87), and 3.25 (2.80-3.98) days for groups I, II, III, and IV, respectively. CONCLUSION: This study shows the related BC KPIs and workflows in different Chinese hospitals, suggesting that laboratory workflow optimization can play important roles in shortening time to AST reports and initiation of appropriate timely treatment.

Novel tripeptide RKH derived from Akkermansia muciniphila protects against lethal sepsis.

OBJECTIVE: The pathogenesis of sepsis is complex, and the sepsis-induced systemic proinflammatory phase is one of the key drivers of organ failure and consequent mortality. Akkermansia muciniphila (AKK) is recognised as a functional probiotic strain that exerts beneficial effects on the progression of many diseases; however, whether AKK participates in sepsis pathogenesis is still unclear. Here, we evaluated the potential contribution of AKK to lethal sepsis development. DESIGN: Relative abundance of gut microbial AKK in septic patients was evaluated. Cecal ligation and puncture (CLP) surgery and lipopolysaccharide (LPS) injection were employed to establish sepsis in mice. Non-targeted and targeted metabolomics analysis were used for metabolites analysis. RESULTS: We first found that the relative abundance of gut microbial AKK in septic patients was significantly reduced compared with that in non-septic controls. Live AKK supplementation, as well as supplementation with its culture supernatant, remarkably reduced sepsis-induced mortality in sepsis models. Metabolomics analysis and germ-free mouse validation experiments revealed that live AKK was able to generate a novel tripeptide Arg-Lys-His (RKH). RKH exerted protective effects against sepsis-induced death and organ damage. Furthermore, RKH markedly reduced sepsis-induced inflammatory cell activation and proinflammatory factor overproduction. A mechanistic study revealed that RKH could directly bind to Toll-like receptor 4 (TLR4) and block TLR4 signal transduction in immune cells. Finally, we validated the preventive effects of RKH against sepsis-induced systemic inflammation and organ damage in a piglet model. CONCLUSION: We revealed that a novel tripeptide, RKH, derived from live AKK, may act as a novel endogenous antagonist for TLR4. RKH may serve as a novel potential therapeutic approach to combat lethal sepsis after successfully translating its efficacy into clinical practice.

Early-life exposure to the Great Chinese Famine and gut microbiome disruption across adulthood for type 2 diabetes: three population-based cohort studies.

BACKGROUND: The early life stage is critical for the gut microbiota establishment and development. We aimed to investigate the lifelong impact of famine exposure during early life on the adult gut microbial ecosystem and examine the association of famine-induced disturbance in gut microbiota with type 2 diabetes. METHODS: We profiled the gut microbial composition among 11,513 adults (18-97 years) from three independent cohorts and examined the association of famine exposure during early life with alterations of adult gut microbial diversity and composition. We performed co-abundance network analyses to identify keystone taxa in the three cohorts and constructed an index with the shared keystone taxa across the three cohorts. Among each cohort, we used linear regression to examine the association of famine exposure during early life with the keystone taxa index and assessed the correlation between the keystone taxa index and type 2 diabetes using logistic regression adjusted for potential confounders. We combined the effect estimates from the three cohorts using random-effects meta-analysis. RESULTS: Compared with the no-exposed control group (born during 1962-1964), participants who were exposed to the famine during the first 1000 days of life (born in 1959) had consistently lower gut microbial alpha diversity and alterations in the gut microbial community during adulthood across the three cohorts. Compared with the no-exposed control group, participants who were exposed to famine during the first 1000 days of life were associated with consistently lower levels of keystone taxa index in the three cohorts (pooled beta - 0.29, 95% CI - 0.43, - 0.15). Per 1-standard deviation increment in the keystone taxa index was associated with a 13% lower risk of type 2 diabetes (pooled odds ratio 0.87, 95% CI 0.80, 0.93), with consistent results across three individual cohorts. CONCLUSIONS: These findings reveal a potential role of the gut microbiota in the developmental origins of health and disease (DOHaD) hypothesis, deepening our understanding about the etiology of type 2 diabetes.

Association between oral microbial dysbiosis and poor functional outcomes in stroke-associated pneumonia patients.

BACKGROUND: Despite advances in our understanding of the critical role of the microbiota in stroke patients, the oral microbiome has rarely been reported to be associated with stroke-associated pneumonia (SAP). We sought to profile the oral microbial composition of SAP patients and to determine whether microbiome temporal instability and special taxa are associated with pneumonia progression and functional outcomes. METHODS: This is a prospective, observational, single-center cohort study that examined patients with acute ischemic stroke (AIS) who were admitted within 24 h of experiencing a stroke event. The patients were divided into three groups based on the occurrence of pneumonia and the use of mechanical ventilation: nonpneumonia group, SAP group, and ventilator-associated pneumonia (VAP) group. We collected oral swabs at different time points post-admission and analyzed the microbiota using 16 S rRNA high-throughput sequencing. The microbiota was then compared among the three groups. RESULTS: In total, 104 nonpneumonia, 50 SAP and 10 VAP patients were included in the analysis. We found that SAP and VAP patients exhibited significant dynamic differences in the diversity and composition of the oral microbiota and that the magnitude of this dysbiosis and instability increased during hospitalization. Then, by controlling the potential effect of all latent confounding variables, we assessed the changes associated with pneumonia after stroke and explored patients with a lower abundance of Streptococcus were more likely to suffer from SAP. The logistic regression analysis revealed that an increase in specific taxa in the phylum Actinobacteriota was linked to a higher risk of poor outcomes. A model for SAP patients based on oral microbiota could accurately predict 30-day clinical outcomes after stroke onset. CONCLUSIONS: We concluded that specific oral microbiota signatures could be used to predict illness development and clinical outcomes in SAP patients. We proposed the potential of the oral microbiota as a non-invasive diagnostic biomarker in the clinical management of SAP patients. CLINICAL TRIAL REGISTRATION: NCT04688138. Registered 29/12/2020, https://clinicaltrials.gov/ct2/show/NCT04688138 .

Stretchable Semi-Interpenetrating Carboxymethyl Guar Gum-Based Composite Hydrogel for Moisture-Proof Wearable Strain Sensor.

Wearable strain sensors of conductive hydrogels have very broad application prospects in electronic skins and human-machine interfaces. However, conductive hydrogels suffer from unstable signal transmission due to environmental humidity and inherent shortcomings of their materials. Herein, we introduce a novel moisture-proof conductive hydrogel with high toughness (2.89 MJ m-3), mechanical strength (1.00 MPa), and high moisture-proof sensing performance by using dopamine-functionalized gold nanoparticles as conductive fillers into carboxymethyl guar gum and acrylamide. Moreover, the hydrogel can realize real-time monitoring of major and subtle human movements with good sensitivity and repeatability. In addition, the hydrogel-assembled strain sensor exhibits stable sensing signals after being left for 1 h, and the relative resistance change rate under different strains (25-300%) shows no obvious noise signal up to 99% relative humidity. Notably, the wearable strain sensing is suitable for wearable sensor devices with high relative humidity.

Enhancement of recombinant human interleukin-22 production by fusing with human serum albumin and supplementing N-acetylcysteine in Pichia Pastoris.

Interleukin-22 (IL-22) plays an important role in the treatment of organ failure, which can induce anti-apoptotic and proliferative signaling pathways; Nevertheless, the practical utilization of IL-22 is hindered by the restricted efficacy of its production. Pichia pastoris presents a viable platform for both industrial and pharmaceutical applications. In this study, we successfully generated a fusion protein consisting of truncated human serum albumin and human IL-22 (HSA-hIL-22) using P. pastoris, and examined the impact of antioxidants on HSA-hIL-22 production. We have achieved the production of HSA-hIL-22 in the culture medium at a yield of approximately 2.25 mg/ml. Moreover, 0-40 mM ascorbic acid supplementation did not significantly affect HSA-hIL-22 production or the growth rate of the recombinant strain. However, 80 mM ascorbic acid treatment had a detrimental effect on the expression of HSA-hIL-22. In addition, 5-10 mM N-acetyl-l-cysteine (NAC) resulted in an increase of HSA-hIL-22 production, accompanied by a reduction in the growth rate of the recombinant strain. Conversely, 20-80 mM NAC supplementation inhibited the growth of the recombinant strains and reduced intact HSA-hIL-22 production. However, neither NAC nor ascorbic acid exhibited any effect on superoxide dismutase (SOD) and malondialdehyde (MDA) levels, except that NAC increased GSH content. Furthermore, our findings indicate that recombinant HSA-hIL-22, which demonstrated the ability to stimulate the proliferation of HepG2 cells, possesses bioactivity. In addition, NAC did not affect HSA-hIL-22 bioactivity. In conclusion, our study demonstrates that NAC supplementation can enhance the secretion of functional HSA-hIL-22 proteins produced in P. pastoris without compromising their activity.

Bifunctional Thiourea-Catalyzed Enantioselective Aza-Friedel-Crafts Reaction of 3-Aminobenzofurans with Isatin-Derived Ketimines.

A quinine-derived thiourea-promoted enantioselective aza-Friedel-Crafts reaction of 3-aminobenzofurans with isatin-derived ketimines is developed, providing a variety of 3-benzofuran-3-amino-2-oxindoles bearing a quaternary stereocenter with good to excellent yields (72-95%) and moderate to excellent enantioselectivities (48-97%). The synthetic potential of this concise and efficient protocol is revealed by gram-scale preparation and further transformation of the adduct to an optically pure spirocyclic oxindole.

Clinical characteristics and prognostic risk factors of candidemia in non-neutropenic patients: a retrospective cohort study.

This study aimed to determine the clinical characteristics and the prognostic risk factors in non-neutropenic patients with candidemia. Data were retrospectively collected through the medical record information system. Non-neutropenic patients with candidemia were relatively aged, with a more than one-third rate of in-hospitalization mortality. In multivariate analysis, APACHE II score (adjusted odds ratio [aOR], 1.138; 95% confidence interval [CI], 1.067-1.213), septic shock (aOR, 5.704; 95% CI, 2.639-12.326) and RRT (aOR, 16.152; 95% CI, 2.628-99.275) (all P < 0.01) were independent related with non-survivors. In conclusion, non-neutropenic patients with candidemia have a high in-hospitalization mortality, and APACHE II, septic shock, and RRT are independently factors.

Solvent-promoted photochemical carbonylation of benzylic C-H bonds under iron catalysis.

This paper describes the iron-catalyzed photochemical carbonylation of benzylic C-H bonds resulting in the synthesis of various aryl ketones. Using 5 W blue LED irradiation, the reactions proceed smoothly in the presence of 2 mol% of FeBr3 in MeOH at 35 °C. The catalytic system could be extended for the oxidation of silane, thioether, and phosphine into silenol, sulphoxide, and phosphoxide, respectively. A mechanistic study suggests that a hydrogen bond-stabilized iron-hydroperoxo species is the reactive intermediate. It is shown that the reaction proceeds via a four-electron-transfer pathway, and a benzylic cation seems to be the crucial reactive species. The method is applied for the synthesis of pomalyst, haloperidol, melperone, and lenperone.

A Novel Near-Infrared Ratiometric Fluorescence Probe for Hg2+ Based on Quinoline-Fused Rhodamine Dye.

As one of the most toxic metals, Mercury ions cause serious environmental pollution and threaten the health of living organisms. Hence, we designed and synthesised a new near-infrared (NIR) ratiometric fluorescent probe toward monitoring of Hg2+ based on quinoline-fused rhodamine dye. Owing to the specific spirolactam ring-opening reaction, the probe exhibits a ratiometric fluorescent change after treatment of Hg2+ with increased emission in NIR and significantly reduced emission in visible region. The specific response mechanism and dual-channel fluorescence change allow the probe to have remarkable detection selectivity, fast response and high detection sensitivity. Moreover, with the properties of excellent cell permeability and low cytotoxicity, probe can be applied as detection tool for mercury ions with dual-channel ratiometric fluorescence imaging in living cell.