The increase of long noncoding RNA Fendrr in hepatocytes contributes to liver fibrosis by promoting IL-6 production.

Liver fibrosis/cirrhosis is a pathological state caused by excessive extracellular matrix deposition. Sustained activation of hepatic stellate cells (HSC) is the predominant cause of liver fibrosis, but the detailed mechanism is far from clear. In this study, we found that long noncoding RNA Fendrr is exclusively increased in hepatocytes in the murine model of CCl4- and bile duct ligation-induced liver fibrosis, as well as in the biopsies of liver cirrhosis patients. In vivo, ectopic expression of Fendrr aggravated the severity of CCl4-induced liver fibrosis in mice. In contrast, inhibiting Fendrr blockaded the activation of HSC and ameliorated CCl4-induced liver fibrosis. Our mechanistic study showed that Fendrr binds to STAT2 and enhances its enrichment in the nucleus, which then promote the expression of interleukin 6 (IL-6), and, ultimately, activates HSC in a paracrine manner. Accordingly, disrupting the interaction between Fendrr and STAT2 by ectopic expression of a STAT2 mutant attenuated the profibrotic response inspired by Fendrr in the CCl4-induced liver fibrosis. Notably, the increase of Fendrr in patient fibrotic liver is positively correlated with the severity of fibrosis and the expression of IL-6. Meanwhile, hepatic IL-6 positively correlates with the extent of liver fibrosis and HSC activation as well, thus suggesting a causative role of Fendrr in HSC activation and liver fibrosis. In conclusion, these observations identify an important regulatory cross talk between hepatocyte Fendrr and HSC activation in the progression of liver fibrosis, which might represent a potential strategy for therapeutic intervention.

Long noncoding RNA AI662270 promotes kidney fibrosis through enhancing METTL3-mediated m6 A modification of CTGF mRNA.

The sustained release of profibrotic cytokines, mainly transforming growth factor-ß (TGF-ß), leads to the occurrence of kidney fibrosis and chronic kidney disease (CKD). Connective tissue growth factor (CTGF) appears to be an alternative target to TGF-ß for antifibrotic therapy in CKD. In this study, we found that long noncoding RNA AI662270 was significantly increased in various renal fibrosis models. In vivo, ectopic expression of AI662270 alone was sufficient to activate interstitial fibroblasts and drive kidney fibrosis, whereas inhibition of AI662270 blocked the activation of interstitial fibroblasts and ameliorated kidney fibrosis in various murine models. Mechanistic studies revealed that overexpression of AI662270 significantly increased CTGF product, which was required for the role of AI662270 in driving kidney fibrosis. Furthermore, AI662270 binds to the CTGF promoter and directly interacts with METTL3, the methyltransferase of RNA N6 -methyladenosine (m6 A) modification. Functionally, AI662270-mediated recruitment of METTL3 increased the m6 A methylation of CTGF mRNA and consequently enhanced CTGF mRNA stability. In conclusion, our results support that AI662270 promotes CTGF expression at the posttranscriptional stage by recruiting METTL3 to the CTGF promoter and depositing m6 A modifications on the nascent mRNA, thereby, uncovering a novel regulatory mechanism of CTGF in the pathogenesis of kidney fibrosis.

Sulforaphane Attenuates AOM/DSS-Induced Colorectal Tumorigenesis in Mice via Inhibition of Intestinal Inflammation.

Sulforaphane (SFN) is a compound derived from cruciferous plants. It has received considerable attention in recent years due to its effectiveness in cancer prevention and anti-inflammatory properties. The purpose of this study was to evaluate the antitumor potential of sulforaphane on colitis-associated carcinogenesis (CAC) through the establishment of a mouse model with AOM/DSS. First, AOM/DSS and DSS-induced model were established and administered SFN for 10 wk, and then the severity of colitis-associated colon cancer was examined macroscopically and histologically. Subsequently, immune cells and cytokines in the tumor microenvironment (TME) were quantified. Finally, the influence of sulforaphane was also investigated using different colon cell lines. We found that sulforaphane treatment decreased tumor volume, myeloid-derived suppressor cells (MDSC) expansion, the expression of the proinflammatory cytokine IL-1ß, and the level of IL-10 in serum. Also, it enhanced the antitumor activities of CD8+ T cells and significantly reduced tumorigenesis as induced by AOM/DSS. SFN also attenuated intestinal inflammation in DSS-induced chronic colitis by reshaping the inflammatory microenvironment. This work demonstrates that sulforaphane suppresses carcinogenesis-associated intestinal inflammation and prevents AOM/DSS-induced intestinal tumorigenesis and progression.

HBB contributes to individualized aconitine-induced cardiotoxicity in mice via interfering with ABHD5/AMPK/HDAC4 axis.

The root of Aconitum carmichaelii Debx. (Fuzi) is an herbal medicine used in China that exerts significant efficacy in rescuing patients from severe diseases. A key toxic compound in Fuzi, aconitine (AC), could trigger unpredictable cardiotoxicities with high-individualization, thus hinders safe application of Fuzi. In this study we investigated the individual differences of AC-induced cardiotoxicities, the biomarkers and underlying mechanisms. Diversity Outbred (DO) mice were used as a genetically heterogeneous model for mimicking individualization clinically. The mice were orally administered AC (0.3, 0.6, 0.9 mg· kg-1 ·d-1) for 7 d. We found that AC-triggered cardiotoxicities in DO mice shared similar characteristics to those observed in clinic patients. Most importantly, significant individual differences were found in DO mice (variation coefficients: 34.08%-53.17%). RNA-sequencing in AC-tolerant and AC-sensitive mice revealed that hemoglobin subunit beta (HBB), a toxic-responsive protein in blood with 89% homology to human, was specifically enriched in AC-sensitive mice. Moreover, we found that HBB overexpression could significantly exacerbate AC-induced cardiotoxicity while HBB knockdown markedly attenuated cell death of cardiomyocytes. We revealed that AC could trigger hemolysis, and specifically bind to HBB in cell-free hemoglobin (cf-Hb), which could excessively promote NO scavenge and decrease cardioprotective S-nitrosylation. Meanwhile, AC bound to HBB enhanced the binding of HBB to ABHD5 and AMPK, which correspondingly decreased HDAC-NT generation and led to cardiomyocytes death. This study not only demonstrates HBB achievement a novel target of AC in blood, but provides the first clue for HBB as a novel biomarker in determining the individual differences of Fuzi-triggered cardiotoxicity.

CT enterography-based radiomics combined with body composition to predict infliximab treatment failure in Crohn's disease.

PURPOSE: Accurately predicting the treatment response in patients with Crohn's disease (CD) receiving infliximab therapy is crucial for clinical decision-making. We aimed to construct a prediction model incorporating radiomics and body composition features derived from computed tomography (CT) enterography for identifying individuals at high risk for infliximab treatment failure. METHODS: This retrospective study included 137 patients with CD between 2015 and 2021, who were divided into a training cohort and a validation cohort with a ratio of 7:3. Patients underwent CT enterography examinations within 1 month before infliximab initiation. Radiomic features of the intestinal segments involved were extracted, and body composition features were measured at the level of the L3 lumbar vertebra. A model that combined radiomics with body composition was constructed. The primary outcome was the occurrence of infliximab treatment failure within 1 year. The model performance was evaluated using discrimination, calibration, and decision curves. RESULTS: Fifty-two patients (38.0%) showed infliximab treatment failure. Eight significant radiomic features were used to develop the radiomics model. The model incorporating radiomics model score, skeletal muscle index (SMI), and creeping fat showed good discrimination for predicting infliximab treatment failure, with an area under the curve (AUC) of 0.88 (95% CI 0.81, 0.95) in the training cohort and 0.83 (95% CI 0.66, 1.00) in the validation cohort. The favorable clinical application was observed using decision curve analysis. CONCLUSIONS: We constructed a comprehensive model incorporating radiomics and muscle volume, which could potentially be used to facilitate the individualized prediction of infliximab treatment response in patients with CD.

Trifluoromethyl Rhodium-Carbynoid in [2+1+2] Cycloadditions.

Trifluoromethyl cationic carbyne (CF3 C+ :) possessing dual carbene-carbocation behavior emulated as trifluoromethyl metal-carbynoid (CF3 C+ =M) has not been explored yet, and its reaction characteristics are unknown. Herein, a novel α-diazotrifluoroethyl sulfonium salt was prepared and used in Rh-catalyzed three-component [2+1+2] cycloadditions for the first time with commercially available N-fused heteroarenes and nitriles, yielding a series of imidazo[1,5-a] N-heterocycles that are of interest in medicinal chemistry, in which the insertion of trifluoromethyl Rh-carbynoid (CF3 C+ =Rh) into C=N bonds of N-fused heteroarenes was involved. This strategy demonstrates synthetic applications in late-stage modification of pharmaceuticals, construction of CD3 -containing N-heterocycles, gram-scale experiments, and synthesis of phosphodiesterase 10A inhibitor analog. These highly valuable and modifiable imidazo[1,5-a] N-heterocycles exhibit good antitumor activity in vitro, thus demonstrating their potential applications in medicinal chemistry.

A predictive paradigm for COVID-19 prognosis based on the longitudinal measure of biomarkers.

Novel coronavirus disease 2019 (COVID-19) is an emerging, rapidly evolving crisis, and the ability to predict prognosis for individual COVID-19 patient is important for guiding treatment. Laboratory examinations were repeatedly measured during hospitalization for COVID-19 patients, which provide the possibility for the individualized early prediction of prognosis. However, previous studies mainly focused on risk prediction based on laboratory measurements at one time point, ignoring disease progression and changes of biomarkers over time. By using historical regression trees (HTREEs), a novel machine learning method, and joint modeling technique, we modeled the longitudinal trajectories of laboratory biomarkers and made dynamically predictions on individual prognosis for 1997 COVID-19 patients. In the discovery phase, based on 358 COVID-19 patients admitted between 10 January and 18 February 2020 from Tongji Hospital, HTREE model identified a set of important variables including 14 prognostic biomarkers. With the trajectories of those biomarkers through 5-day, 10-day and 15-day, the joint model had a good performance in discriminating the survived and deceased COVID-19 patients (mean AUCs of 88.81, 84.81 and 85.62% for the discovery set). The predictive model was successfully validated in two independent datasets (mean AUCs of 87.61, 87.55 and 87.03% for validation the first dataset including 112 patients, 94.97, 95.78 and 94.63% for the second validation dataset including 1527 patients, respectively). In conclusion, our study identified important biomarkers associated with the prognosis of COVID-19 patients, characterized the time-to-event process and obtained dynamic predictions at the individual level.

Tubule-derived INHBB promotes interstitial fibroblast activation and renal fibrosis.

Upstream stimuli for myofibroblast activation are of considerable interest for understanding the mechanisms underlying renal fibrosis. Activin B, a member of the TGF-ß family, exists as a homodimer of inhibin subunit beta B (INHBB), but its role in renal fibrosis remains unknown. We found that INHBB expression was significantly increased in various renal fibrosis models and human chronic kidney disease specimens with renal fibrosis. Notably, the increase of INHBB occurred mainly in the tubular epithelial cells (TECs). In vivo, inhibiting INHBB blocked the activation of interstitial fibroblasts and ameliorated the renal fibrosis induced by unilateral ureteral obstruction or ischemia-reperfusion injury, while ectopic expression of INHBB in the TECs was able to activate interstitial fibroblasts and initiate interstitial fibrosis. In vitro, overexpression of INHBB in TECs led to the secretion of activin B, thereby promoting the proliferation and activation of interstitial fibroblasts through activin B/Smad signaling. Furthermore, inhibition of activin B/Smad signaling attenuated the fibrotic response caused by tubular INHBB. Mechanistically, the upregulation of INHBB depended on the transcription factor Sox9 in the injured TECs. Clinical analyses also identified a positive correlation between Sox9 and INHBB expression in human specimens, suggesting the Sox9/INHBB axis as a positive regulator of renal fibrosis. In conclusion, tubule-derived INHBB is implicated in the pathogenesis of renal fibrosis by activating the surrounding fibroblasts in a paracrine manner, thereby exhibiting as a potential therapeutic target. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

NF-κB, A Potential Therapeutic Target in Cardiovascular Diseases.

Cardiovascular diseases (CVDs) are the leading cause of death globally. Atherosclerosis is the basis of major CVDs - myocardial ischemia, heart failure, and stroke. Among numerous functional molecules, the transcription factor nuclear factor κB (NF-κB) has been linked to downstream target genes involved in atherosclerosis. The activation of the NF-κB family and its downstream target genes in response to environmental and cellular stress, hypoxia, and ischemia initiate different pathological events such as innate and adaptive immunity, and cell survival, differentiation, and proliferation. Thus, NF-κB is a potential therapeutic target in the treatment of atherosclerosis and related CVDs. Several biologics and small molecules as well as peptide/proteins have been shown to regulate NF-κB dependent signaling pathways. In this review, we will focus on the function of NF-κB in CVDs and the role of NF-κB inhibitors in the treatment of CVDs.

Insights into the metabolic pathways and biodegradation mechanisms of chloroacetamide herbicides.

Chloroacetamide herbicides are widely used around the world due to their high efficiency, resulting in increasing levels of their residues in the environment. Residual chloroacetamides and their metabolites have been frequently detected in soil, water and organisms and shown to have toxic effects on non-target organisms, posing a serious threat to the ecosystem. As such, rapid and efficient techniques that eliminate chloroacetamide residues from the ecosystem are urgently needed. Degradation of these herbicides in the environment mainly occurs through microbial metabolism. Microbial strains such as Acinetobacter baumannii DT, Bacillus altitudinis A16, Pseudomonas aeruginosa JD115, Sphingobium baderi DE-13, Catellibacterium caeni DCA-1, Stenotrophomonas acidaminiphila JS-1, Klebsiella variicola B2, and Paecilomyces marquandii can effectively degrade chloroacetamide herbicides. The degradation pathway of chloroacetamide herbicides in aerobic bacteria is mainly initiated by an N/C-dealkylation reaction, followed by aromatic ring hydroxylation and cleavage processes, whereas dechlorination is the initial reaction in anaerobic bacteria. The molecular mechanisms associated with bacterial degradation of chloroacetamide herbicides have been explored, with amidase, hydrolase, reductase, ferredoxin and cytochrome P450 oxygenase currently known to play a pivotal role in the catabolic pathways of chloroacetamides. The fungal pathway for the degradation of these herbicides is more complex with more diversified products, and the degradation enzymes and genes involved remain to be discovered. However, there are few reviews specifically summarizing the microbial degrading species and biochemical mechanisms of chloroacetamide herbicides. Here, we briefly summarize the latest progress resulting from research on microbial strain resources and enzymes involved in degradation of these herbicides and their corresponding genes. Furthermore, we explore the biochemical pathways and molecular mechanisms for biodegradation of chloroacetamide herbicides in depth, thereby providing a reference for further research on the bioremediation of such herbicides.

New roles for Bacillus thuringiensis in the removal of environmental pollutants.

For a long time, the well-known Gram-positive bacterium Bacillus thuringiensis (Bt) has been extensively studied and developed as a biological insecticide for Lepidoptera and Coleoptera pests due to its ability to secrete a large number of specific insecticidal proteins. In recent years, studies have found that Bt strains can also potentially biodegrade residual pollutants in the environment. Many researchers have isolated Bt strains from multiple sites polluted by exogenous compounds and characterized and identified their xenobiotic-degrading potential. Furthermore, its pathway for degradation was also investigated at molecular level, and a number of major genes/enzymes responsible for degradation have been explored. At present, a variety of xenobiotics involved in degradation in Bt have been reported, including inorganic pollutants (used in the field of heavy metal biosorption and recovery and precious metal recovery and regeneration), pesticides (chlorpyrifos, cypermethrin, 2,2-dichloropropionic acid, etc.), organic tin, petroleum and polycyclic aromatic hydrocarbons, reactive dyes (congo red, methyl orange, methyl blue, etc.), and ibuprofen, among others. In this paper, the biodegrading ability of Bt is reviewed according to the categories of related pollutants, so as to emphasize that Bt is a powerful agent for removing environmental pollutants.

Microbial degradation as a powerful weapon in the removal of sulfonylurea herbicides.

Sulfonylurea herbicides have been widely used worldwide and play a significant role in modern agricultural production. However, these herbicides have adverse biological effects that can damage the ecosystems and harm human health. As such, rapid and effective techniques that remove sulfonylurea residues from the environment are urgently required. Attempts have been made to remove sulfonylurea residues from environment using various techniques such as incineration, adsorption, photolysis, ozonation, and microbial degradation. Among them, biodegradation is regarded as a practical and environmentally responsible way to eliminate pesticide residues. Microbial strains such as Talaromyces flavus LZM1, Methylopila sp. SD-1, Ochrobactrum sp. ZWS16, Staphylococcus cohnii ZWS13, Enterobacter ludwigii sp. CE-1, Phlebia sp. 606, and Bacillus subtilis LXL-7 can almost completely degrade sulfonylureas. The degradation mechanism of the strains is such that sulfonylureas can be catalyzed by bridge hydrolysis to produce sulfonamides and heterocyclic compounds, which deactivate sulfonylureas. The molecular mechanisms associated with microbial degradation of sulfonylureas are relatively poorly studied, with hydrolase, oxidase, dehydrogenase and esterase currently known to play a pivotal role in the catabolic pathways of sulfonylureas. Till date, there are no reports specifically on the microbial degrading species and biochemical mechanisms of sulfonylureas. Hence, in this article, the degradation strains, metabolic pathways, and biochemical mechanisms of sulfonylurea biodegradation, along with its toxic effects on aquatic and terrestrial animals, are discussed in depth in order to provide new ideas for remediation of soil and sediments polluted by sulfonylurea herbicides.

Pseudomonas aeruginosa based concurrent degradation of beta-cypermethrin and metabolite 3-phenoxybenzaldehyde, and its bioremediation efficacy in contaminated soils.

Beta-cypermethrin is one of the widely used pyrethroid insecticides, and problems associated with the accumulation of its residues have aroused public attention. Thus, there is an urgent need to effectively remove the beta-cypermethrin that is present in the environment. Biodegradation is considered a cost-effective and environmentally friendly method for removing pesticide residues. However, the beta-cypermethrin-degrading microbes that are currently available are not optimal. In this study, Pseudomonas aeruginosa PAO1 was capable of efficiently degrading beta-cypermethrin and its major metabolite 3-phenoxybenzaldehyde in water/soil environments. Strain PAO1 could remove 91.4% of beta-cypermethrin (50 mg/L) in mineral salt medium within 120 h. At the same time, it also possesses a significant ability to metabolize 3-phenoxybenzaldehyde-a toxic intermediate of beta-cypermethrin. The Andrews equation showed that the maximum substrate utilization concentrations of beta-cypermethrin and 3-phenoxybenzaldehyde by PAO1 were 65.3558 and 49.6808 mg/L, respectively. Box-Behnken design-based response surface methodology revealed optimum conditions for the PAO1 strain-based degradation of beta-cypermethrin as temperature 30.6 °C, pH 7.7, and 0.2 g/L inoculum size. The results of soil remediation experiments showed that indigenous micro-organisms helped to promote the biodegradation of beta-cypermethrin in soil, and beta-cypermethrin half-life in non-sterilized soil was 6.84 days. The bacterium transformed beta-cypermethrin to produce five possible metabolites, including 3-phenoxybenzyl alcohol, methyl 2-(4-hydroxyphenoxy)benzoate, diisobutyl phthalate, 3,5-dimethoxyphenol, and 2,2-dimethyl-1-(4-phenoxyphenyl)propanone. Among them, methyl 2-(4-hydroxyphenoxy)benzoate and 3,5-dimethoxyphenol were first identified as the intermediate products during the beta-cypermethrin degradation. In addition, we propose a degradation pathway for beta-cypermethrin that is metabolized by strain PAO1. Beta-cypermethrin could be biotransformed firstly by hydrolysis of its carboxylester linkage, followed by cleavage of the diaryl bond and subsequent metabolism. Based on the above results, P. aeruginosa PAO1 could be a potent candidate for the beta-cypermethrin-contaminated environmental bioremediation.

Biomineralized tetramethylpyrazine-loaded PCL/gelatin nanofibrous membrane promotes vascularization and bone regeneration of rat cranium defects.

Conventional electrospinning produces nanofibers with smooth surfaces that limit biomineralization ability. To overcome this disadvantage, we fabricated a tetramethylpyrazine (TMP)-loaded matrix-mimicking biomineralization in PCL/Gelatin composite electrospun membranes with bubble-shaped nanofibrous structures. PCL/Gelatin membranes (PG), PCL/Gelatin membranes containing biomineralized hydroxyapatite (HA) (PGH), and PCL/Gelatin membranes containing biomineralized HA and loaded TMP (PGHT) were tested. In vitro results indicated that the bubble-shaped nanofibrous surface increased the surface roughness of the nanofibers and promoted mineralization. Furthermore, sustained-release TMP had an excellent drug release efficiency. Initially released vigorously, it reached stabilization at day 7, and the slow-release rate stabilized at 61.0 ± 1.8% at 28 days. All membranes revealed an intact cytoskeleton, cell viability, and superior adhesion and proliferation when stained with Ghost Pen Cyclic Peptide, CCK-8, cell adhesion, and EdU. In PGHT membranes, the osteogenic and vascularized gene expression of BMSCs and human vascular endothelial cells was significantly upregulated compared with that in other groups, indicating the PGHT membranes exhibited an effective vascularization role. Subsequently, the membranes were implanted in a rat cranium defect model for 4 and 8 weeks. Micro-CT and histological analysis results showed that the PGHT membranes had better bone regenerative patterns. Additionally, the levels of CD31 and VEGF significantly increased in the PGHT membrane compared with those in other membranes. Thus, PGHT membranes could accelerate the repair of cranium defects in vivo via HA and TMP synergistic effects.

SUMOylation of the ubiquitin ligase IDOL decreases LDL receptor levels and is reversed by SENP1.

Inducible degrader of the low-density lipoprotein receptor (IDOL) is an E3 ubiquitin ligase mediating degradation of low-density lipoprotein (LDL) receptor (LDLR). IDOL also controls its own stability through autoubiquitination, primarily at lysine 293. Whether IDOL may undergo other forms of posttranslational modification is unknown. In this study, we show that IDOL can be modified by small ubiquitin-like modifier 1 at the K293 residue at least. The SUMOylation of IDOL counteracts its ubiquitination and augments IDOL protein levels. SUMOylation and the associated increase of IDOL protein are effectively reversed by SUMO-specific peptidase 1 (SENP1) in an activity-dependent manner. We further demonstrate that SENP1 affects LDLR protein levels by modulating IDOL. Overexpression of SENP1 increases LDLR protein levels and enhances LDL uptake in cultured cells. On the contrary, loss of SENP1 lowers LDLR levels in an IDOL-dependent manner and reduces LDL endocytosis. Collectively, our results reveal SUMOylation as a new regulatory posttranslational modification of IDOL and suggest that SENP1 positively regulates the LDLR pathway via deSUMOylation of IDOL and may therefore be exploited for the treatment of cardiovascular disease.

Representations of Complex Contexts: A Role for Hippocampus.

The hippocampus plays a critical role in supporting episodic memory, in large part by binding together experiences and items with surrounding contextual information. At present, however, little is known about the roles of different hippocampal subfields in supporting this item-context binding. To address this question, we constructed a task in which items were affiliated with differing types of context-cognitive associations that vary at the local, item level and membership in temporally organized lists that linked items together at a global level. Participants made item recognition judgments while undergoing high-resolution fMRI. We performed voxel pattern similarity analyses to answer the question of how human hippocampal subfields represent retrieved information about cognitive states and the time at which a past event took place. As participants recollected previously presented items, activity patterns in the CA23DG subregion carried information about prior cognitive states associated with these items. We found no evidence to suggest reinstatement of information about temporal context at the level of list membership, but exploratory analyses revealed representations of temporal context at a coarse level in conjunction with representations of cognitive contexts. Results are consistent with characterizations of CA23DG as a critical site for binding together items and contexts in the service of memory retrieval.

Associations of genetic risk, BMI trajectories, and the risk of non-small cell lung cancer: a population-based cohort study.

BACKGROUND: Body mass index (BMI) has been found to be associated with a decreased risk of non-small cell lung cancer (NSCLC); however, the effect of BMI trajectories and potential interactions with genetic variants on NSCLC risk remain unknown. METHODS: Cox proportional hazards regression model was applied to assess the association between BMI trajectory and NSCLC risk in a cohort of 138,110 participants from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. One-sample Mendelian randomization (MR) analysis was further used to access the causality between BMI trajectories and NSCLC risk. Additionally, polygenic risk score (PRS) and genome-wide interaction analysis (GWIA) were used to evaluate the multiplicative interaction between BMI trajectories and genetic variants in NSCLC risk. RESULTS: Compared with individuals maintaining a stable normal BMI (n = 47,982, 34.74%), BMI trajectories from normal to overweight (n = 64,498, 46.70%), from normal to obese (n = 21,259, 15.39%), and from overweight to obese (n = 4,371, 3.16%) were associated with a decreased risk of NSCLC (hazard ratio [HR] for trend = 0.78, P < 2×10-16). An MR study using BMI trajectory associated with genetic variants revealed no significant association between BMI trajectories and NSCLC risk. Further analysis of PRS showed that a higher GWAS-identified PRS (PRSGWAS) was associated with an increased risk of NSCLC, while the interaction between BMI trajectories and PRSGWAS with the NSCLC risk was not significant (PsPRS= 0.863 and PwPRS= 0.704). In GWIA analysis, four independent susceptibility loci (P < 1×10-6) were found to be associated with BMI trajectories on NSCLC risk, including rs79297227 (12q14.1, located in SLC16A7, Pinteraction = 1.01×10-7), rs2336652 (3p22.3, near CLASP2, Pinteraction = 3.92×10-7), rs16018 (19p13.2, in CACNA1A, Pinteraction = 3.92×10-7), and rs4726760 (7q34, near BRAF, Pinteraction = 9.19×10-7). Functional annotation demonstrated that these loci may be involved in the development of NSCLC by regulating cell growth, differentiation, and inflammation. CONCLUSIONS: Our study has shown an association between BMI trajectories, genetic factors, and NSCLC risk. Interestingly, four novel genetic loci were identified to interact with BMI trajectories on NSCLC risk, providing more support for the aetiology research of NSCLC. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov , NCT01696968 .

Temporal Dynamics of Memory-guided Cognitive Control and Generalization of Control via Overlapping Associative Memories.

Goal-directed behavior can benefit from proactive adjustments of cognitive control that occur in anticipation of forthcoming cognitive control demands (CCD). Predictions of forthcoming CCD are thought to depend on learning and memory in two ways: First, through direct experience, associative encoding may link previously experienced CCD to its triggering item, such that subsequent encounters with the item serve to cue retrieval of (i.e., predict) the associated CCD. Second, in the absence of direct experience, pattern completion and mnemonic integration mechanisms may allow CCD to be generalized from its associated item to other items related in memory. While extant behavioral evidence documents both types of CCD prediction, the neurocognitive mechanisms giving rise to these predictions remain largely unexplored. Here, we tested two hypotheses: (1) memory-guided predictions about CCD precede control adjustments due to the actual CCD required; and (2) generalization of CCD can be accomplished through integration mechanisms that link partially overlapping CCD-item and item-item associations in memory. Supporting these hypotheses, the temporal dynamics of theta and alpha power in human electroencephalography data (n = 43, 26 females) revealed that an associative CCD effect emerges earlier than interaction effects involving actual CCD. Furthermore, generalization of CCD from one item (X) to another item (Y) was predicted by a decrease in alpha power following the presentation of the X-Y pair. These findings advance understanding of the mechanisms underlying memory-guided adjustments of cognitive control.SIGNIFICANCE STATEMENT Cognitive control adaptively regulates information processing to align with task goals. Experience-based expectations enable adjustments of control, leading to improved performance when expectations match the actual control demand required. Using EEG, we demonstrate that memory for past cognitive control demand proactively guides the allocation of cognitive control, preceding adjustments of control triggered by the demands of the present environment. Furthermore, we demonstrate that learned cognitive control demands can be generalized through mnemonic integration processes, enabling the spread of expectations about cognitive control demands to items associated in memory. We reveal that this generalization is linked to decreased alpha oscillation in medial frontal channels. Collectively, these findings provide new insights into how memory-control interactions facilitate goal-directed behavior.

Evaluation of fecal microbiota transplantation in Parkinson's disease patients with constipation.

Parkinson's disease (PD) is a neurodegenerative disorder and 70-80% of PD patients suffer from gastrointestinal dysfunction such as constipation. We aimed to assess the efficacy and safety of fecal microbiota transplantation (FMT) for treating PD related to gastrointestinal dysfunction. We conducted a prospective, single- study. Eleven patients with PD received FMT. Fecal samples were collected before and after FMT and subjected to 16S ribosomal DNA (rDNA) gene sequencing. Hoehn-Yahr (H-Y) grade, Unified Parkinson's Disease Rating Scale (UPDRS) score, and the Non-Motion Symptom Questionnaire (NMSS) were used to assess improvements in motor and non-motor symptoms. PAC-QOL score and Wexner constipation score were used to assess the patient's constipation symptoms. All patients were tested by the small intestine breath hydrogen test, performed before and after FMT. Community richness (chao) and microbial structure in before-FMT PD patients were significantly different from the after-FMT. We observed an increased abundance of Blautia and Prevotella in PD patients after FMT, while the abundance of Bacteroidetes decreased dramatically. After FMT, the H-Y grade, UPDRS, and NMSS of PD patients decreased significantly. Through the lactulose H2 breath test, the intestinal bacterial overgrowth (SIBO) in PD patients returned to normal. The PAC-QOL score and Wexner constipation score in after-FMT patients decreased significantly. Our study profiles specific characteristics and microbial dysbiosis in the gut of PD patients. FMT might be a therapeutic potential for reconstructing the gut microbiota of PD patients and improving their motor and non-motor symptoms.

Ganoderic acid alleviates chemotherapy-induced fatigue in mice bearing colon tumor.

Chemotherapy-related fatigue (CRF) is increasingly being recognized as one of the severe symptoms in patients undergoing chemotherapy, which not only largely reduces the quality of life in patients, but also diminishes their physical and social function. At present, there is no effective drug for preventing and treating CRF. Ganoderic acid (GA), isolated from traditional Chinese medicine Ganoderma lucidum, has shown a variety of pharmacological activities such as anti-tumor, anti-inflammation, immunoregulation, etc. In this study, we investigated whether GA possessed anti-fatigue activity against CRF. CT26 tumor-bearing mice were treated with 5-fluorouracil (5-FU, 30 mg/kg) and GA (50 mg/kg) alone or in combination for 18 days. Peripheral and central fatigue-related behaviors, energy metabolism and inflammatory factors were assessed. We demonstrated that co-administration of GA ameliorated 5-FU-induced peripheral muscle fatigue-like behavior via improving muscle quality and mitochondria function, increasing glycogen content and ATP production, reducing lactic acid content and LDH activity, and inhibiting p-AMPK, IL-6 and TNF-α expression in skeletal muscle. Co-administration of GA also retarded the 5-FU-induced central fatigue-like behavior accompanied by down-regulating the expression of IL-6, iNOS and COX2 in the hippocampus through inhibiting TLR4/Myd88/NF-κB pathway. These results suggest that GA could attenuate 5-FU-induced peripheral and central fatigue in tumor-bearing mice, which provides evidence for GA as a potential drug for treatment of CRF in clinic.