Idiopathic Rapid Eye Movement Sleep Behavior Disorder (iRBD) Shares Similar Fecal Short-Chain Fatty Acid Alterations with Multiple System Atrophy (MSA) and Parkinson's Disease (PD).

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is considered as a prodromal stage of synucleinopathies. Fecal short-chain fatty acid (SCFA) changes in iRBD and the relationships with synucleinopathies have never been investigated. OBJECTIVES: To investigate fecal SCFA changes among iRBD, multiple system atrophy (MSA), and Parkinson's disease (PD), and evaluate their relationships. METHODS: Fecal SCFAs and gut microbiota were measured in 29 iRBD, 42 MSA, 40 PD, and 35 normal controls (NC) using gas chromatography-mass spectrometry and 16S rRNA gene sequencing. RESULTS: Compared with NC, fecal SCFA levels (propionic, acetic, and butyric acid) were lower in iRBD, MSA, and PD. Combinations of these SCFAs could differentiate NC from iRBD (AUC 0.809), MSA (AUC 0.794), and PD (AUC 0.701). Decreased fecal SCFAs were associated with the common reducing SCFA-producing gut microbiota in iRBD, MSA, and PD. CONCLUSIONS: iRBD shares similar fecal SCFA alterations with MSA and PD, and the combination of these SCFAs might be a potential synucleinopathies-related biomarker. © 2024 International Parkinson and Movement Disorder Society.

The role of SUMO specific peptidase 3 in secondary inflammation of ischemic stroke in mice.

Ischemic stroke is the main cause of death and disability, and microglia play a crucial role in the pathophysiology of hypoxic ischemic brain injury. We found that SENP3 is highly expressed in the early stages of ischemic stroke in both in vivo and in vitro mouse models, and may be related to the deSUMOylation of the key kinase MKK7 in the TLR4/p-JNK signaling pathway. Knocking down SENP3 can inhibit the deSUMOylation of MKK7, thereby inhibiting the activation of the TLR4/p-JNK signaling pathway in an in vitro stroke model. Proteomic analysis showed that SENP3 undergoes phosphorylation at the T429 site after ischemic stroke. Computer simulation predictions show a significant enhancement of the interaction between pT429-SENP3 and MKK7, which has been confirmed through experiments on the interaction of biological macromolecules (SPR). The mitochondrial metabolic abnormalities caused by energy abnormalities in the early stages of stroke provide a good explanation for the phosphorylation of SENP3. Therefore, we used the mitochondrial complex inhibitor TTFA to reverse demonstrate that the phosphorylation of SENP3 comes from the large amount of adenosine triphosphate produced by mitochondrial abnormal metabolism caused by early oxygen glucose deficiency. Finally, proteomic analysis indicates that a significant amount of oxidative phosphorylation does occur in the early stages of stroke. In summary, targeted regulation of SENP3 phosphorylation to affect the deSUMOylation of MKK7 may inhibit secondary inflammation in ischemic stroke.

A Polymer-Based Antigen Carrier Activates Two Innate Immune Pathways for Adjuvant-Free Subunit Vaccines.

The activation of multiple Pattern Recognition Receptors (PRRs) has been demonstrated to trigger inflammatory responses and coordinate the host's adaptive immunity during pathogen infections. The use of PRR agonists as vaccine adjuvants has been reported to synergistically induce specific humoral and cellular immune responses. However, incorporating multiple PRR agonists as adjuvants increases the complexity of vaccine design and manufacturing. In this study, we discovered a polymer that can activate both the Toll-like receptor (TLR) pathway and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. The polymer was then conjugated to protein antigens, creating an antigen delivery system for subunit vaccines. Without additional adjuvants, the antigen-polymer conjugates elicited strong antigen-specific humoral and cellular immune responses. Furthermore, the antigen-polymer conjugates, containing the Receptor Binding Domain (RBD) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein or the Monkeypox Antigen M1R as the antigens, were found to induce potent antigen-specific antibodies, neutralizing antibodies, and cytotoxic T cells. Immunization with M1R-polymer also resulted in effective protection in a lethal challenge model. In conclusion, this vaccine delivery platform offers an effective, safe, and simple strategy for inducing antigen-specific immunity against infectious diseases.

Overview of T-2 Toxin Enterotoxicity: From Toxic Mechanisms and Detoxification to Future Perspectives.

Fusarium species produce a secondary metabolite known as T-2 toxin, which is the primary and most harmful toxin found in type A trichothecenes. T-2 toxin is widely found in food and grain-based animal feed and endangers the health of both humans and animals. T-2 toxin exposure in humans and animals occurs primarily through food administration; therefore, the first organ that T-2 toxin targets is the gut. In this overview, the research progress, toxicity mechanism, and detoxification of the toxin T-2 were reviewed, and future research directions were proposed. T-2 toxin damages the intestinal mucosa and destroys intestinal structure and intestinal barrier function; furthermore, T-2 toxin disrupts the intestinal microbiota, causes intestinal flora disorders, affects normal intestinal metabolic function, and kills intestinal epidermal cells by inducing oxidative stress, inflammatory responses, and apoptosis. The primary harmful mechanism of T-2 toxin in the intestine is oxidative stress. Currently, selenium and plant extracts are mainly used to exert antioxidant effects to alleviate the enterotoxicity of T-2 toxin. In future studies, the use of genomic techniques to find upstream signaling molecules associated with T-2 enterotoxin toxicity will provide new ideas for the prevention of this toxicity. The purpose of this paper is to review the progress of research on the intestinal toxicity of T-2 toxin and propose new research directions for the prevention and treatment of T-2 toxin toxicity.

lncRNA-056298 Regulates GAP43 and Promotes Cardiac Intrinsic Autonomic Nerve Remodelling in a Canine Model of Atrial Fibrillation Induction after Ganglionated Plexus Ablation.

BACKGROUND: Cardiac intrinsic autonomic nerve remodelling has been reported to play an important role in the recurrence of atrial fibrillation after radiofrequency ablation, which significantly affects the long-term efficacy of this procedure. lncRNAs have been shown to interact in the pathological processes underlying heart diseases. However, the roles and mechanisms of lncRNAs in cardiac intrinsic autonomic nerve remodelling during atrial fibrillation reduction after ganglionated plexus ablation remain unknown. OBJECTIVES: The aim of this study was to investigate the mechanism by which lncRNA- 056298 modulates GAP43 to affect cardiac intrinsic autonomic nerve remodelling and facilitate the induction of atrial fibrillation after ganglionated plexus ablation. METHODS: A canine model of right atrial ganglionated plexus ablation was established. The atrial electrophysiological characteristics and neural markers were detected before and after 6 months of ganglionated plexus ablation. High-throughput sequencing was used to screen differentially expressed lncRNAs in target atrial tissues, and lncRNA- 056298 was selected to further explore its effects and mechanisms on cardiac intrinsic autonomic nerve remodelling. RESULTS: The induction rate of atrial fibrillation increased in dogs after ganglionated plexus ablation. Overexpression of lncRNA-056298 by lentivirus can shorten the atrial effective refractory period and increase the induction of atrial fibrillation. lncRNA- 056298 promoted cardiac intrinsic autonomic nerve remodelling via endogenous competition with cfa-miR-185 to induce transcription of its target gene GAP43, thereby affecting the induction of atrial fibrillation. CONCLUSIONS: lncRNA-056298 regulates GAP43 by sponging miR-185, which affects cardiac intrinsic autonomic nerve remodelling and mediates atrial fibrillation induction after ganglionated plexus ablation.

Microtubule disruption synergizes with STING signaling to show potent and broad-spectrum antiviral activity.

The activation of stimulator of interferon genes (STING) signaling induces the production of type I interferons (IFNs), which play critical roles in protective innate immunity for the host to defend against viral infections. Therefore, achieving sustained or enhanced STING activation could become an antiviral immune strategy with potential broad-spectrum activities. Here, we discovered that various clinically used microtubule-destabilizing agents (MDAs) for the treatment of cancer showed a synergistic effect with the activation of STING signaling in innate immune response. The combination of a STING agonist cGAMP and a microtubule depolymerizer MMAE boosted the activation of STING innate immune response and showed broad-spectrum antiviral activity against multiple families of viruses. Mechanistically, MMAE not only disrupted the microtubule network, but also switched the cGAMP-mediated STING trafficking pattern and changed the distribution of Golgi apparatus and STING puncta. The combination of cGAMP and MMAE promoted the oligomerization of STING and downstream signaling cascades. Importantly, the cGAMP plus MMAE treatment increased STING-mediated production of IFNs and other antiviral cytokines to inhibit viral propagation in vitro and in vivo. This study revealed a novel role of the microtubule destabilizer in antiviral immune responses and provides a previously unexploited strategy based on STING-induced innate antiviral immunity.

Relationships Between Rapid Eye Movement Sleep Behavior Disorder and Parkinson's Disease: Indication from Gut Microbiota Alterations.

Rapid eye movement sleep behavior disorder (RBD) has a close relationship with Parkinson's disease (PD) and was even regarded as the most reliable hallmark of prodromal PD. RBD might have similar changes in gut dysbiosis to PD, but the relationship between RBD and PD in gut microbial alterations is rarely studied. In this study, we aim to investigate whether there were consistent changes between RBD and PD in gut microbiota, and found some specific biomarkers in RBD that might indicate phenoconversion to PD. Alpha-diversity showed no remarkable difference and beta-diversity showed significant differences based on the unweighted (R = 0.035, P = 0.037) and weighted (R = 0.0045, P = 0.008) UniFrac analysis among idiopathic RBD (iRBD), PD with RBD, PD without RBD and normal controls (NC). Enterotype distribution indicated iRBD, PD with RBD and PD without RBD were Ruminococcus-dominant while NC were Bacteroides-dominant. 7 genera (4 increased: Aerococcus, Eubacterium, Gordonibacter and Stenotrophomonas, 3 decreased: Butyricicoccus, Faecalibacterium and Haemophilus) were consistently changed in iRBD and PD with RBD. Among them, 4 genera (Aerococcus, Eubacterium, Butyricicoccus, Faecalibacterium) remained distinctive in the comparison between PD with RBD and PD without RBD. Through clinical correlation analysis, Butyricicoccus and Faecalibacterium were found negatively correlated with the severity of RBD (RBD-HK). Functional analysis showed iRBD had similarly increased staurosporine biosynthesis to PD with RBD. Our study indicates that RBD had similar gut microbial changes to PD. Decreased Butyricicoccus and Faecalibacterium might be potential hallmarks of phenoconversion of RBD to PD.

CT characteristics of recurrent acute pancreatitis and acute pancreatitis in different stages-a retrospective cross-sectional study.

Background: Acute pancreatitis (AP), recurrent acute pancreatitis (RAP), and chronic pancreatitis (CP) are a continuum of the same disease. The course of RAP and AP is a dynamic process. Previous studies are contradictory regarding the severity of RAP and AP. We conducted this study to investigate the computed tomography (CT) characteristics of RAP and AP in the early and late stages; respectively. Methods: Patients who underwent contrast-enhanced computed tomography for symptoms during RAP or AP episodes were retrospectively collected from three tertiary hospitals in Sichuan Province, China from January 2015 to December 2019. The patients were categorized into RAP and AP groups based on recurrence and initial events. Both the RAP and AP groups were divided into early (first week) and late stages (after the first week) based on the 2012 revised Atlanta classification (RAC). Patient demographic data, RAC, CT findings, CT severity index (CTSI) scores, and extrapancreatic inflammation on CT scores in the early and late phases were analyzed between the two groups. The Wilcoxon signed-rank test, χ2 test, and Fisher's exact test were used to compare continuous and categorical variables between the two groups respectively. Results: In 683 RAP and 1,829 AP patients, the most common etiologies were hypertriglyceridemia and cholelithiasis, respectively. The RAP group had lower extrapancreatic inflammation on CT scores and Acute Physiology and Chronic Health Evaluation II scores than the AP group in the early stage (both P<0.001). The RAP group had higher CTSI scores than the AP group in the late stage (P=0.022). Conclusions: Compared with AP patients, the most common cause of RAP patients was hypertriglyceridemia in China, and the severity of RAP was lower than that of initial AP in the early stage and higher than that of initial AP in the late stage.

Association of fecal short-chain fatty acids with clinical severity and gut microbiota in essential tremor and its difference from Parkinson's disease.

Diagnosis of essential tremor (ET) at an early stage can be difficult, especially when distinguishing it from healthy controls (HCs) and Parkinson's disease (PD). Recently, stool sample analysis of gut microbiota and its metabolites provides new ways to detect novel biomarkers for neurodegenerative diseases. Short-chain fatty acids (SCFAs), as the main metabolites of gut microbiota, were reduced in the feces of PD. However, fecal SCFAs in ET have never been investigated. We aimed to investigate the fecal SCFA levels in ET, assess their relationships with clinical symptoms and gut microbiota, and identify their potential diagnostic abilities. Fecal SCFAs and gut microbiota in 37 ET, 37 de novo PD and 35 HC were measured. Constipation, autonomic dysfunction and tremor severity were evaluated by scales. ET had lower fecal propionic, butyric and isobutyric acid levels than HC. Combined propionic, butyric and isobutyric acid distinguished ET from HC with an AUC of 0.751 (95% CI: 0.634-0.867). ET had lower fecal isovaleric and isobutyric acid levels than PD. Isovaleric and isobutyric acid differentiated ET from PD with an AUC of 0.743 (95% CI: 0.629-0.857). Fecal propionic acid was negatively correlated with constipation and autonomic dysfunction. Isobutyric and isovaleric acid were negatively associated with tremor severity. Lowered fecal SCFAs were related to a decreased abundance of Faecalibacterium and Catenibacterium in ET. In conclusion, fecal SCFAs were decreased in ET and correlated with clinical severity and gut microbiota changes. Fecal propionic, butyric, isobutyric and isovaleric acid might be potential diagnostic and differential diagnostic biomarkers for ET.

Predicting the Prognosis of Multiple System Atrophy Using Cluster and Principal Component Analysis.

BACKGROUND: Multiple system atrophy (MSA) is an intractable neurodegenerative disorder with poorly understanding of prognostic factors. OBJECTIVE: The purpose of this retrospective longitudinal study was to explore the main predictors of survival of MSA patients with new clinical subtypes based on cluster analysis. METHODS: A total of 153 Chinese MSA patients were recruited in our study. The basic demographic data and motor and nonmotor symptoms were assessed. Cluster and principal component analysis (PCA) were used to eliminate collinearity and search for new clinical subtypes. The multivariable Cox regression was used to find factors associated with survival in MSA patients. RESULTS: The median survival time from symptom onset to death (estimated using data from all patients by Kaplan-Meier analysis) was 6.3 (95% CI = 6.1-6.7) years. The survival model showed that a shorter survival time was associated with motor principal component (PC)1 (HR = 1.71, 95% CI: 1.26-2.30, p < 0.001) and nonmotor PC3 (HR = 1.68, 95% CI: 1.31-2.10, p < 0.001) through PCA. Four clusters were identified: Cluster 1 (mild), Cluster 2 (mood disorder-dominant), Cluster 3 (axial symptoms and cognitive impairment-dominant), and Cluster 4 (autonomic failure-dominant). Multivariate Cox regression indicated that Cluster 3 (HR = 4.15, 95% CI: 1.73-9.90, p = 0.001) and Cluster 4 (HR = 4.18, 95% CI: 1.73-10.1, p = 0.002) were independently associated with shorter survival time. CONCLUSION: More serious motor symptoms, axial symptoms such as falls and dysphagia, orthostatic hypotension, and cognitive impairment were associated with poor survival in MSA via PCA and cluster analysis.

Engineered Histidine-Rich Peptides Enhance Endosomal Escape for Antibody-Targeted Intracellular Delivery of Functional Proteins.

Currently, the clinical application of protein/peptide therapeutics is mainly limited to the modulation of diseases in extracellular spaces. Intracellular targets are hardly accessed, owing largely to the endosomal entrapment of internalized proteins/peptides. Here, we report a strategy to design and construct peptides that enable endosome-to-cytosol delivery based on an extension of the "histidine switch" principle. By substituting the Arg/Lys residues in cationic cell-penetrating peptides (CPPs) with histidine, we obtained peptides with pH-dependent membrane-perturbation activity. These peptides do not randomly penetrate cells like CPPs, but imitate the endosomal escape of CPPs following cellular uptake. Working with one such 16-residue peptide (hsLMWP) with high endosomal escape capacity, we engineered modular fusion proteins and achieved antibody-targeted delivery of diverse protein cargoes-including the pro-apoptotic protein BID (BH3-interacting domain death agonist) and Cre recombinase-into the cytosol of multiple cancer cell types. After extensive in vitro testing, an in vivo analysis with xenograft mice ultimately demonstrated that a trastuzumab-hsLMWP-BID fusion conferred strong anti-tumor efficacy without apparent side effects. Notably, our fusion protein features a modular design, allowing flexible applications for any antibody/cargo combination of choice. Therefore, the potential applications extend throughout life science and biomedicine, including gene editing, cancer treatment, and immunotherapy.

Early changes of fecal short-chain fatty acid levels in patients with mild cognitive impairments.

AIMS: To compare the fecal levels of short-chain fatty acids (SCFAs) in patients with mild cognitive impairment (MCI) and normal controls (NCs) and to examine whether fecal SCFAs could be used as the biomarker for the identification of patients with MCI. To examine the relationship between fecal SCFAs and amyloid-ß (Aß) deposition in the brain. METHODS: A cohort of 32 MCI patients, 23 Parkinson's disease (PD) patients, and 27 NC were recruited in our study. Fecal levels of SCFAs were measured using chromatography and mass spectrometry. Disease duration, ApoE genotype, body mass index, constipation, and diabetes were evaluated. To assess cognitive impairment, we used the Mini-Mental Status Examination (MMSE). To assess brain atrophy, the degree of medial temporal atrophy (MTA score, Grade 0-4) was measured by structural MRI. Aß positron emission tomography with 18 F-florbetapir (FBP) was performed in seven MCI patients at the time of stool sampling and in 28 MCI patients at an average of 12.3 ± 0.4 months from the time of stool sampling to detect and quantify Aß deposition in the brain. RESULTS: Compared with NC, MCI patients had significantly lower fecal levels of acetic acid, butyric acid, and caproic acid. Among fecal SCFAs, acetic acid performed the best in discriminating MCI from NC, achieved an AUC of 0.752 (p = 0.001, 95% CI: 0.628-0.876), specificity of 66.7%, and sensitivity of 75%. By combining fecal levels of acetic acid, butyric acid, and caproic acid, the diagnostic specificity was significantly improved, reaching 88.9%. To better verify the diagnostic performance of SCFAs, we randomly assigned 60% of participants into training dataset and 40% into testing dataset. Only acetic acid showed significantly difference between these two groups in the training dataset. Based on the fecal levels of acetic acid, we achieved the ROC curve. Next, the ROC curve was evaluated in the independent test data and 61.5% (8 in 13) of patients with MCI, and 72.7% (8 in 11) of NC could be identified correctly. Subgroup analysis showed that reduced fecal SCFAs in MCI group were negatively associated with Aß deposition in cognition-related brain regions. CONCLUSION: Reductions in fecal SCFAs were observed in patients with MCI compared with NC. Reduced fecal SCFAs were negatively associated with Aß deposition in cognition-related brain regions in MCI group. Our findings suggest that gut metabolite SCFAs have the potential to serve as early diagnostic biomarkers for distinguishing patients with MCI from NC and could serve as potential targets for preventing AD.

Promotion of Lung Cancer Metastasis by SIRT2-Mediated Extracellular Protein Deacetylation.

Acetylation of extracellular proteins has been observed in many independent studies where particular attention has been given to the dynamic change of the microenvironmental protein post-translational modifications. While extracellular proteins can be acetylated within the cells prior to their micro-environmental distribution, their deacetylation in a tumor microenvironment remains elusive. Here it is described that multiple acetyl-vWA domain-carrying proteins including integrin ß3 (ITGB3) and collagen 6A (COL6A) are deacetylated by Sirtuin family member SIRT2 in extracellular space. SIRT2 is secreted by macrophages following toll-like receptor (TLR) family member TLR4 or TLR2 activation. TLR-activated SIRT2 undergoes autophagosome translocation. TNF receptor associated factor 6 (TRAF6)-mediated autophagy flux in response to TLR2/4 activation can then pump SIRT2 into the microenvironment to function as extracellular SIRT2 (eSIRT2). In the extracellular space, eSIRT2 deacetylates ITGB3 on aK416 involved in cell attachment and migration, leading to a promotion of cancer cell metastasis. In lung cancer patients, significantly increased serum eSIRT2 level correlates with dramatically decreased ITGB3-K416 acetylation in cancer cells. Thus, the extracellular space is a subcellular organelle-like arena where eSIRT2 promotes cancer cell metastasis via catalyzing extracellular protein deacetylation.

Programming cell-surface signaling by phase-separation-controlled compartmentalization.

The landscape of cell-surface signaling is formidably complex. Robust tools capable of manipulating the spatiotemporal distribution of cell-surface proteins (CSPs) for dissecting signaling are in high demand. Some CSPs are regulated via multivalency-driven liquid-liquid phase separation (LLPS). Employing the robustness and versatility of LLPS, we decided to engineer LLPS-based tools for precisely manipulating CSPs. We generated membrane-tethering LLPS systems by fusing multivalent modular phase-separation scaffold pairs with CSP binders. Phase separation of the scaffold pairs, concomitant compartmentalization of CSPs on membranes, and cluster-dependent signaling outputs of CSPs require membrane recruitment of one or both scaffolds. We also engineered orthogonal phase-separation systems to segregate CSPs into mutually exclusive compartments. The engineered phase-separation systems can robustly cluster individual CSPs, co-cluster two or more CSPs, or segregate different CSPs into distinct compartments on cell surfaces. These tools will enable the dissection of complicated cell-signaling landscapes with high precision.

Loss of LOXL2 Promotes Uterine Hypertrophy and Tumor Progression by Enhancing H3K36ac-Dependent Gene Expression.

Lysyl oxidase-like 2 (LOXL2) is a member of the scavenger receptor cysteine-rich (SRCR) repeat carrying LOX family. Although LOXL2 is suspected to be involved in histone association and chromatin modification, the role of LOXL2 in epigenetic regulation during tumorigenesis and cancer progression remains unclear. Here, we report that nuclear LOXL2 associates with histone H3 and catalyzes H3K36ac deacetylation and deacetylimination. Both the N-terminal SRCR repeats and the C-terminal catalytic domain of LOXL2 carry redundant deacetylase catalytic activity. Overexpression of LOXL2 markedly reduced H3K36 acetylation and blocked H3K36ac-dependent transcription of genes, including c-MYC, CCND1, HIF1A, and CD44. Consequently, LOXL2 overexpression reduced cancer cell proliferation in vitro and inhibited xenograft tumor growth in vivo. In contrast, LOXL2 deficiency resulted in increased H3K36 acetylation and aberrant expression of H3K36ac-dependent genes involved in multiple oncogenic signaling pathways. Female LOXL2-deficient mice spontaneously developed uterine hypertrophy and uterine carcinoma. Moreover, silencing LOXL2 in cancer cells enhanced tumor progression and reduced the efficacy of cisplatin and anti-programmed cell death 1 (PD-1) combination therapy. Clinically, low nuclear LOXL2 expression and high H3K36ac levels corresponded to poor prognosis in uterine endometrial carcinoma patients. These results suggest that nuclear LOXL2 restricts cancer development in the female reproductive system via the regulation of H3K36ac deacetylation. SIGNIFICANCE: LOXL2 loss reprograms the epigenetic landscape to promote uterine cancer initiation and progression and repress the efficacy of anti-PD-1 immunotherapy, indicating that LOXL2 is a tumor suppressor.

MAO-B Polymorphism Associated with Progression in a Chinese Parkinson's Disease Cohort but Not in the PPMI Cohort.

Introduction: Genetic factors play an important role in Parkinson's disease (PD) risk. However, the genetic contribution to progression in Chinese PD patients has rarely been studied. This study investigated genetic associations with progression based on 30 PD risk loci common in a longitudinal cohort of Chinese PD patients and the Parkinson's Progression Markers Initiative (PPMI) cohort. Methods: PD patients from the true world (TW) Chinese PD longitudinal cohort and the PPMI cohort with demographic information and assessment scales were assessed. A panel containing 30 PD risk single nucleotide polymorphisms was tested. Progression rates of each scale were derived from random-effect slope values of mixed-effects regression models. Progression rates of multiple assessments were combined by using principal component analysis (PCA) to derive scores for composite, motor, and nonmotor progression. The association of genetic polymorphism and separate scales or PCA progression was analysed via linear regression. Results: In the Chinese PD cohort, MAOB rs1799836 was associated with progression based on the Montreal Cognitive Assessment, the top 3 principal components (PCs) of nonmotor PCA and PC1 of the composite PCA. In the PPMI cohort, both MDS-Unified Parkinson's Disease Rating Scale II and motor PC1 progression were associated with RIT2 rs12456492. The PARK16 haplotype was associated with Geriatric Depression Scale and the State-Trait Anxiety Inventory for Adults progression, and the SNCA haplotype was associated with the Hoehn-Yahr staging progression and motor PC1 progression. Ethnicity-stratified analysis showed that the association between MAOB rs1799836 and PD progression may be specific to Asian or Chinese patients. Conclusion: MAOB rs1799836 was associated with the progression of nonmotor symptoms, especially cognitive impairment, and the composite progression of motor and nonmotor symptoms within our Chinese PD cohort. The RIT2 rs12456492 and SNCA haplotypes were associated with motor function decline, and the PARK16 haplotype was associated with progression in mood in the PPMI cohort.

Computed tomography characteristics of acute pancreatitis based on different etiologies at different onset times: a retrospective cross-sectional study.

Background: The clinical characteristics and imaging findings of acute pancreatitis (AP) are different across the various etiologies, the results are conflicting, and their time from symptom onset to imaging varies. The imaging findings of different etiologies at different onset times are unclear. This study aimed to investigate the computed tomography (CT) characteristics of AP based on different etiologies at different onset times. Methods: Patients who underwent plain and contrast-enhanced computed tomography (CECT) for the first attack of AP in 3 hospitals (Affiliated Hospital of North Sichuan Medical College, Chinese People's Liberation Army Western Theater General Hospital, and Suining Central Hospital) from 2015 to 2019 were recruited. According to the different etiologies of AP, the patients were divided into 5 subgroups: biliary AP (n=591), alcoholic AP (n=267), hypertriglyceridemic AP (n=258), mixed causes subgroups (n=199), and "other/idiopathic" AP (n=545). According to the time from onset to CT examination (e.g., 1-3, 4-7, 8-14, 15-28, and >28 days), the onset time was divided into 5 respective phases (I-V). The CT characteristics and clinical and laboratory features were retrospectively reviewed and compared among the different etiology subgroups and onset time. Results: The positive rate of CT findings in AP diagnosis based on CECT was 96.7% (1,860/1,924). Necrotizing pancreatitis (NP) occurred in 33.2% (617/1,860) of AP patients with positive CECT findings. Among patients with NP, local complications and severe AP of the modified CT severity index (MCTSI) increased over time in those with biliary AP from 17.1%, 25.2%, and 20.0% in Phase I to 42.9%, 44.0%, and 39.7% in Phase IV [all P<0.05, 95% confidence interval (CI): 0.15 to 0.52, 0.28 to 0.63, and 0.18 to 0.82, respectively]. In contrast, NP, local complications and severe AP of MCTSI in those with hypertriglyceridemic AP decreased over time from 24.3%, 22.5%, and 22.7% in Phase I to 1.3%, 1.2%, and 1.9% in Phase V (all P<0.05, 95% CI: 3.20 to 181.74, 3.31 to 175.74, and 2.00 to 120.78, respectively). Conclusions: The proportion of NP was 33.2% of positive CECT findings. There may be differences in the CT and clinical manifestations of the different etiologies, and those differences may be related to the onset time.

CT Characteristics of Acute Pancreatitis with Preexisting Fatty Liver and Its Impact on Pancreatitis Severity and Persistent Systemic Inflammatory Response Syndrome.

Purpose: To study the CT characteristics of acute pancreatitis (AP) associated with preexisting fatty liver (FL) and the impact of preexisting FL on the severity of AP and persistent systemic inflammatory response syndrome (SIRS). Patients and Methods: A total of 189 patients with AP were divided into AP with and without preexisting FL. The CT features, clinical characteristics, severity of AP, and presence of persistent SIRS between the two groups were compared. Univariate and multivariate analyses were performed to determine the risk factors for predicting SIRS. The diagnostic performances of the risk factors were evaluated by receiver operating characteristic (ROC) curve analysis. Results: Among the 189 patients, 49.7% (94/189) had preexisting FL. On CT, AP patients with preexisting FL were more likely to develop necrosis (23.4% vs 10.5%, p=0.021), local complications (45.7% vs 29.5%, p=0.025) and persistent SIRS (59.6% vs 27.4%, p<0.001). Multivariate analysis showed that preexisting FL (OR=2.863, 95% CI: 1.264-6.486, p=0.012), APACHE II≥6 (OR=1.334, 95% CI: 1.117-1.594, p=0.002), and MCTSI ≥4 (OR=1.489, 95% CI: 1.046-2.119, p=0.027) could be independent risk factors for persistent SIRS. The areas under the ROC curve of preexisting FL, APACHE II, and MCISI in diagnosing AP patients with persistent SIRS were 0.664, 0.703, and 0.783, respectively. Conclusion: Patients with preexisting FL were more likely to develop necrosis and local complications on CT and present more severe AP and persistent SIRS. Preexisting FL can be an independent risk factor in predicting the presence of persistent SIRS in patients with AP.

Specific gut microbiota alterations in essential tremor and its difference from Parkinson's disease.

Essential tremor (ET) is the most common movement disorder and share overlapping symptoms with Parkinson's disease (PD), making differential diagnosis challenging. Gut dysbiosis is regarded crucial in the pathogenesis of PD. Since ET patients also has comorbidity in gastrointestinal disorders, the relationship between gut microbiota and ET really worth investigating and may help distinguishing ET from PD. Fecal samples from 54 ET, 67 de novo PD and 54 normal controls (NC) were collected for 16S ribosomal RNA gene sequencing and quantitative real-time PCR. ET showed lower species richness (Chao1 index) than NC and PD. ET was with Bacteroides-dominant enterotype, while PD was with Ruminococcus-dominant enterotype. Compared with NC, 7 genera were significantly reduced in ET, 4 of which (Ruminococcus, Romboutsia, Mucispirillum, and Aeromonas) were identified to be distinctive with an area under the curve (AUC) of 0.705. Compared to PD, 26 genera were found significantly different from ET, 4 of which (Bacteroides, Fusobacterium, Phascolarctobacterium, and Lachnospira) were found distinguishable with an AUC of 0.756. Clinical association results indicated that Proteus was associated with disease severity (TETRAS) of ET, while Klebsiella was linked to depression and anxiety in ET. Functional predictions revealed that 4 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were altered in ET. This study reveals gut dysbiosis in ET and it provides new insight into the pathogenesis of ET and helps distinguishing ET from PD.

Urinary polycyclic aromatic hydrocarbon metabolites, plasma p-tau231 and mild cognitive impairment in coke oven workers.

BACKGROUND: As a group of environmental pollutants, polycyclic aromatic hydrocarbons (PAHs) may be neurotoxic，especially in high-exposure occupational populations. However, the effect of PAHs on mild cognitive impairment (MCI) is still unclear. OBJECTIVE: We aimed to investigate the relationship between PAH metabolites and MCI and to explore whether plasma p-tau231 can be used as a potential biomarker to reflect MCI in coke oven workers. METHOD: A total of 330 workers were recruited from a coke oven plant as the exposure group, and 234 workers were recruited from a water treatment plant as the control group. The concentrations of eleven PAH metabolites and plasma p-tau231 were determined by high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) and ELISA. Cognitive function was measured by the Montreal Cognitive Assessment (MoCA) questionnaire. A multivariate logistic regression model and multiple linear regression model were used to analyze the associations of urinary PAH metabolites with the detection rate of MCI, MoCA scores and plasma p-tau231. The dose-response relationships were evaluated using restricted cubic spline models. RESULTS: We found 146 MCI-positive workers in coke oven plant (44.24%), and 69 MCI-positive workers in water treatment plant (29.49%). In addition, the urinary sum of PAH metabolites (Æ©-OH PAHs) was significantly associated with MCI (OR, 1.371; 95% CI:1.102-1.705). Each one-unit increase in ln-transformed Æ©-OH PAHs was associated with a 0.429 decrease in the sum of MoCA, a 0.281 reduction in the visuospatial/executive function and a 9.416 increase in the level of plasma P-Tau231. We found a negative association between plasma P-Tau231 and visuospatial/executive function (ß = -0.007, 95% CI: -0.011, -0.003). CONCLUSION: Our data indicated that urinary Æ©-OH PAHs levels of workers were positively associated with MCI and the level of plasma P-Tau231.