Cardiovascular comorbidities among patients with psoriasis: a national register-based study in China.

This study aims to illustrate epidemiology of comorbid CVD in the real-world clinical setting of patients with psoriasis in China. We used data of adult patients with psoriasis who were registered in the register of China National Clinical Center for Skin and Immune Diseases between August 2020 and September 2021. Psoriasis was clinically diagnosed following the national guidelines. Univariate and multivariate logistic regression models were used to examine the factors associated with comorbid CVD in patients with psoriasis. Of the 11,560 psoriasis patients (age ≥ 18 years, mean age 41.87 years, 64.88% males), 236 were ascertained with CVD, with the overall prevalence being 2.62%. Multivariate logistic regression analysis suggested that the odds ratio (95% confidence interval) of CVD in psoriasis patients was 2.27 (2.03-2.54) for older age (per 10-year increment), 0.65 (0.48-0.90) for female, 2.07 (1.39-3.06) for obesity (BMI ≥ 28 vs. < 24 kg/m2), 2.55 (1.85-2.52) for smoking, 7.63 (5.86-9.94) for hypertension, 4.27 (3.76-4.85) for diabetes, 1.14 (1.00-1.30) for having a history of drug allergy, 2.27 (1.61-3.20) for having family history of psoriasis, and 1.76 (1.16-2.67) for severe disease (severe vs. mild) with a dose-response relationship (Ptrend < 0.001). In patients with psoriasis, comorbid CVD was associated with smoking, obesity, hypertension, diabetes, history of drug allergy, family history of psoriasis, and the psoriasis severity.

Enhancer-driven gene regulatory networks inference from single-cell RNA-seq and ATAC-seq data.

Deciphering the intricate relationships between transcription factors (TFs), enhancers, and genes through the inference of enhancer-driven gene regulatory networks (eGRNs) is crucial in understanding gene regulatory programs in a complex biological system. This study introduces STREAM, a novel method that leverages a Steiner forest problem model, a hybrid biclustering pipeline, and submodular optimization to infer eGRNs from jointly profiled single-cell transcriptome and chromatin accessibility data. Compared to existing methods, STREAM demonstrates enhanced performance in terms of TF recovery, TF-enhancer linkage prediction, and enhancer-gene relation discovery. Application of STREAM to an Alzheimer's disease dataset and a diffuse small lymphocytic lymphoma dataset reveals its ability to identify TF-enhancer-gene relations associated with pseudotime, as well as key TF-enhancer-gene relations and TF cooperation underlying tumor cells.

Short-term high fat diet impairs memory, exacerbates the neuroimmune response, and evokes synaptic degradation via a complement-dependent mechanism in a mouse model of Alzheimer's disease.

Alzheimer's Disease (AD) is a neurodegenerative disease characterized by profound memory impairments, synaptic loss, neuroinflammation, and hallmark pathological markers. High-fat diet (HFD) consumption increases the risk of developing AD even after controlling for metabolic syndrome, pointing to a role of the diet itself in increasing risk. In AD, the complement system, an arm of the immune system which normally tags redundant or damaged synapses for pruning, becomes pathologically overactivated leading to tagging of healthy synapses. While the unhealthy diet to AD link is strong, the underlying mechanisms are not well understood in part due to confounding variables associated with long-term HFD which can independently influence the brain. Therefore, we experimented with a short-term diet regimen to isolate the diet's impact on brain function without causing obesity. This project investigated the effect of short-term HFD on 1) memory, 2) neuroinflammation including complement, 3) AD pathology markers, 4) synaptic markers, and 5) in vitro microglial synaptic phagocytosis in the 3xTg-AD mouse model. Following the consumption of either standard chow or HFD, 3xTg-AD and non-Tg mice were tested for memory impairments. In a separate cohort of mice, levels of hippocampal inflammatory markers, complement proteins, AD pathology markers, and synaptic markers were measured. For the last set of experiments, BV2 microglial phagocytosis of synapses was evaluated. Synaptoneurosomes isolated from the hippocampus of 3xTg-AD mice fed chow or HFD were incubated with equal numbers of BV2 microglia. The number of BV2 microglia that phagocytosed synaptoneurosomes was tracked over time with a live-cell imaging assay. Finally, we incubated BV2 microglia with a complement receptor inhibitor (NIF) and repeated the assay. Behavioral analysis showed 3xTg-AD mice had significantly impaired long-term contextual and cued fear memory compared to non-Tg mice that was further impaired by HFD. HFD significantly increased inflammatory markers and complement expression while decreasing synaptic marker expression only in 3xTg-AD mice, without altering AD pathology markers. Synaptoneurosomes from HFD-fed 3xTg-AD mice were phagocytosed at a significantly higher rate than those from chow-fed mice, suggesting the synapses were altered by HFD. The complement receptor inhibitor blocked this effect in a dose-dependent manner, demonstrating the HFD-mediated increase in phagocytosis was complement dependent. This study indicates HFD consumption increases neuroinflammation and over-activates the complement cascade in 3xTg-AD mice, resulting in poorer memory. The in vitro data point to complement as a potential mechanistic culprit and therapeutic target underlying HFD's influence in increasing cognitive vulnerability to AD.

A single-cell and spatial RNA-seq database for Alzheimer's disease (ssREAD).

Alzheimer's Disease (AD) pathology has been increasingly explored through single-cell and single-nucleus RNA-sequencing (scRNA-seq & snRNA-seq) and spatial transcriptomics (ST). However, the surge in data demands a comprehensive, user-friendly repository. Addressing this, we introduce a single-cell and spatial RNA-seq database for Alzheimer's disease (ssREAD). It offers a broader spectrum of AD-related datasets, an optimized analytical pipeline, and improved usability. The database encompasses 1,053 samples (277 integrated datasets) from 67 AD-related scRNA-seq & snRNA-seq studies, totaling 7,332,202 cells. Additionally, it archives 381 ST datasets from 18 human and mouse brain studies. Each dataset is annotated with details such as species, gender, brain region, disease/control status, age, and AD Braak stages. ssREAD also provides an analysis suite for cell clustering, identification of differentially expressed and spatially variable genes, cell-type-specific marker genes and regulons, and spot deconvolution for integrative analysis. ssREAD is freely available at https://bmblx.bmi.osumc.edu/ssread/ .

Global disease burden linked to diet high in red meat and colorectal cancer from 1990 to 2019 and its prediction up to 2030.

Background: Numerous studies have already identified an association between excessive consumption of red meat and colorectal cancer (CRC). However, there has been a lack of detailed understanding regarding the disease burden linked to diet high in red meat and CRC. Objective: We aim to offer evidence-based guidance for developing effective strategies that can mitigate the elevated CRC burden in certain countries. Methods: We used the data from the Global Burden of Disease (GBD) Study 2019 to evaluate global, regional, and national mortality rates and disability-adjusted Life years (DALYs) related to diet high in red meat. We also considered factors such as sex, age, the socio-demographic index (SDI), and evaluated the cross-national inequalities. Furthermore, we utilized DALYs data from 204 countries and regions to measure cross-country inequalities of CRC by calculating the slope index of inequality and concentration index as standard indicators of absolute and relative inequalities. Discussion: The results show that globally, the age-standardized mortality rate (ASMR) and age-standardized disability adjusted life year rate (ASDR) related to CRC due to diet high in red meat have decreased, with estimated annual percent change (EAPCs) of -0.32% (95% CI -0.37 to -0.28) and-0.18% (95% CI -0.25 to -0.11). Notably, the burden was higher among males and the elderly. The slope index of inequality rose from 22.0 (95% CI 18.1 to 25.9) in 1990 to 32.9 (95% CI 28.3 to 37.5) in 2019 and the concentration index fell from 59.5 (95% CI 46.4 to 72.6) in 1990 to 48.9 (95% CI 34.6 to 63.1) in 2019. Also, according to our projections, global ASDR and ASMR might tend to increase up to 2030. Conclusion: ASMR and ASDR for CRC associated with high red meat diets declined globally from 1990 to 2019, but the absolute number of cases is still rising, with men and the elderly being more affected. CRC associated with diets high in red meat exhibits significant income inequality, placing a disproportionate burden on wealthier countries. Moreover, according to our projections, ASMR and ASDR are likely to increase globally by 2030. In order to address this intractable disease problem, understanding changes in global and regional epidemiologic trends is critical for policy makers and others.

Effects of Litsea cubeba Essential Oil-Chitosan/Corn Starch Composite Films on the Quality and Shelf-Life of Strawberry (Fragaria × ananassa).

In this work, we have developed a composite chitosan film incorporating the Litsea cubeba essential oil (LCEO) and starch with good physical properties, and investigated the effect of coating strawberries with this composite film. The best formula of the LCEO/chitosan/corn starch/glycerol (LCEO/CH/CS/gly) composite films is 0.25% LCEO, 2.75% CH, 0.40% corn starch, and 0.75% glycerol. Coating strawberries with CH/CS/gly film or LCEO/CH/CS/gly films resulted in significantly lower respiration intensity and a slower decay rate, much slower decreases in the firmness, and reductions in the sugar and ascorbic acid content of the fruit during storage (p < 0.05). The coatings also led to a much slower accumulation of malondialdehyde and anthocyanins (p < 0.05). The LCEO/CH/CS/gly film was generally more effective than the CH/CS/gly film; however, the effect was more obvious in the later stages of storage. Thus, coating strawberries with CH/CS/gly film or LCEO/CH/CS/gly film can be a viable method for extending the shelf-life of the fruit.

Bidentate selenium-based chalcogen bond catalyzed cationic polymerization of p-methoxystyrene.

The application of selenium-based non-covalent bond catalysis in living cationic polymerization has rarely been reported. In this work, the cationic polymerization of p-methoxystyrene (pMOS) was performed using a bidentate selenium bond catalyst - a new water-tolerant Lewis acid catalyst. A polymer with controllable molecular weight and narrow molecular weight distribution can be obtained at room temperature, with a maximum molecular weight of 23.3 kDa. This selenium bond compound can also catalyze the controllable cationic polymerization of p-methoxy styrene under environmental conditions. By changing the monomer feeding ratio, a secondary feeding experiment and DFT analysis, it is shown that the selenium bond catalyst can induce polymer chain growth by reversibly activating dormant covalent bonds (C-OH).

DAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity.

Pathogenic tau accumulation fuels neurodegeneration in Alzheimer's disease (AD). Enhancing aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12) is critically involved in microglial immune responses. Previous studies have showed that mice lacking DAP12 in tauopathy mice exhibit higher tau pathology but are protected from tau-induced cognitive deficits. However, the exact mechanism remains elusive. Our current study uncovers a novel resilience mechanism via microglial interaction with oligodendrocytes. Despite higher tau inclusions, Dap12 deletion curbs tau-induced brain inflammation and ameliorates myelin and synapse loss. Specifically, removal of Dap12 abolished tau-induced disease-associated clusters in microglia (MG) and intermediate oligodendrocytes (iOli), which are spatially correlated with tau pathology in AD brains. Our study highlights the critical role of interactions between microglia and oligodendrocytes in tau toxicity and DAP12 signaling as a promising target for enhancing resilience in AD.

DAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity.

Pathogenic tau accumulation fuels neurodegeneration in Alzheimer's disease (AD). Enhancing aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12) is critically involved in microglial immune responses. Previous studies have showed that mice lacking DAP12 in tauopathy mice exhibit higher tau pathology but are protected from tau-induced cognitive deficits. However, the exact mechanism remains elusive. Our current study uncovers a novel resilience mechanism via microglial interaction with oligodendrocytes. Despite higher tau inclusions, Dap12 deletion curbs tau-induced brain inflammation and ameliorates myelin and synapse loss. Specifically, removal of Dap12 abolished tau-induced disease-associated clusters in microglia (MG) and intermediate oligodendrocytes (iOli), which are spatially correlated with tau pathology in AD brains. Our study highlights the critical role of interactions between microglia and oligodendrocytes in tau toxicity and DAP12 signaling as a promising target for enhancing resilience in AD.

Prevalence and Risk Factors of Pulmonary Embolism Combined with Tuberculosis and the Efficacy of Anticoagulation Combined with Anti-tuberculosis.

Objective: This retrospective study aimed to determine the prevalence and risk factors of combined pulmonary embolism (PE) among patients with pulmonary tuberculosis (TB), as well as evaluate the clinical efficacy of anticoagulation in combination with anti-tuberculosis therapy. Methods: A total of 96 TB patients were included in the study. Among them, 31 patients had combined PE (PE group) and 65 patients did not have PE (no-PE group). Various indicators including lung images, clinical symptoms, blood tests, coagulation function, and others were analyzed to identify risk factors for combined PE in TB patients. Within the PE group, patients were divided into a combined treatment group (received anticoagulation therapy alongside anti-tuberculosis treatment) and a control group (received only anti-tuberculosis treatment). The effectiveness of anticoagulation, serological indexes, and incidence of adverse reactions were compared between the two groups. Results: The prevalence of combined PE in TB patients was 32.29%. Encapsulated effusion or upper lobe predominance, dyspnea, and high creatinine levels were identified as risk factors for combined PE in TB patients. The combined treatment group showed a significantly higher anticoagulation efficiency rate (95.00%) compared to the control group (72.73%). After treatment, serum D-dimer levels were significantly lower in the rivaroxaban group compared to the warfarin group. The incidence of adverse reactions did not differ significantly between the two groups. Conclusion: Combined PE was found in 32.29% of TB patients. Encapsulated effusion or upper lobe predominance, dyspnea, and high creatinine levels were identified as risk factors for combined PE in TB patients. Anticoagulation combined with anti-tuberculosis therapy was effective and safe for managing TB patients with combined PE.

ssREAD: A Single-cell and Spatial RNA-seq Database for Alzheimer's Disease.

Alzheimer's Disease (AD) is a neurodegenerative malady predominantly affecting the elderly and exhibits its debilitating effects on a dementia-prone population. Recently, the advent of innovative technologies, such as single-cell and single-nucleus RNA-sequencing (scRNA-seq & snRNA-seq) and spatial transcriptomics (ST), has reformed our investigative approaches toward comprehending AD's neuropathological intricacies and underpinning regulatory mechanisms, encompassing sub-cellular, cellular, and spatial dimensions. In light of the overwhelming proliferation of single-cell and ST data associated with AD, the imperative for a comprehensive, user-friendly database that addresses the scientific community's analytical demands has never been more paramount. Introduced initially in 2020, scREAD presented itself as a pioneering repository that systematized publicly available scRNA-seq and snRNA-seq datasets derived from post-mortem human brain tissues and mouse models mirroring AD pathology. Here, we introduce ssREAD, a substantial upgrade over scREAD, enriching the platform with a broader spectrum of datasets, an optimized analytical pipeline, and enhanced usability and visibility. Specifically, ssREAD amalgamates an impressive portfolio of over 189 datasets extracted from 35 distinct AD-related scRNA-seq and snRNA-seq studies, encompassing a staggering 2,572,355 cells. In addition, we have diligently curated and archived 300 ST datasets, originating from 12 human and mouse brain studies, which include two focused on AD and ten control studies. Every dataset within our repository is meticulously annotated, bearing critical identifiers including species, gender, brain region, disease/control status, age, and AD stages. Besides the collection of above datasets in ssREAD, it delivers an exhaustive analysis suite offering cell clustering and annotation, inference of differentially expressed and spatially variable genes, identification of cell-type-specific marker genes and regulons, and spot deconvolution for integrative analysis of ST and scRNA-seq & snRNA-seq data from public domains. All these resources are freely accessible through a user-friendly, consolidated web portal available at https://bmblx.bmi.osumc.edu/ssread/.

Tetrabutylammonium Halides as Selectively Bifunctional Catalysts Enabling the Syntheses of Recyclable High Molecular Weight Salicylic Acid-Based Copolyesters.

To synthesize high molecular weight poly(phenolic ester) via a living ring-opening polymerization (ROP) of cyclic phenolic ester monomers remains a critical challenge due to serious transesterification and back-biting reactions. Both phenolic ester bonds in monomer and polymer chains are highly active, and it is difficult so far to distinguish them. In this work, an unprecedented selectively bifunctional catalytic system of tetra-n-butylammonium chloride (TBACl) was discovered to mediate the syntheses of high molecular weight salicylic acid-based copolyesters via a living ROP of salicylate cyclic esters (for poly(salicylic methyl glycolide) (PSMG), Mn =361.8 kg/mol, Ð<1.30). Compared to previous catalysis systems, the side reactions were suppressed remarkably in this catalysis system because phenolic ester bond in monomer can be selectively cleaved over that in polymer chains during ROP progress. Mechanistic studies reveal that the halide anion and alkyl-quaternaryammonium cation work synergistically, where the alkyl-quaternaryammonium cation moiety interacts with the carbonyl group of substrates via non-classical hydrogen bonding. Moreover, these salicylic acid-based copolyesters can be recycled to dimeric monomer under solution condition, and can be recycled to original monomeric monomers without catalyst under sublimation condition.

Original surgical technique for the treatment of patellofemoral instability after failure of conservative treatment.

INTRODUCTION: Acute patellar dislocation is a common but serious injury that can significantly impact a patient's functional prognosis. The objective of this retrospective study is to evaluate the clinical outcomes of arthroscopic medial patellofemoral ligament (MPFL) reconstruction and plication of the medial patellar retinaculum using suture anchors in adolescent patients with first-time acute patellar dislocation (APD) and MPFL insertion injury. HYPOTHESIS: Tightening repair of the medial retinaculum complex can result in favorable clinical and functional outcomes in this patient population. MATERIALS AND METHODS: A total of 84 adolescent patients with first-time APD and with an average age of 15.5 years (10-22) were included in the study. Of these patients, 61 (7 male and 54 female) underwent arthroscopic suture anchor plication for medial patellar retinaculum, while the other 23 were successfully treated non-operatively. Radiographic outcomes, including the congruence angle (CA), lateral patellofemoral angle (LPA), and patellar tilt angle (PTA), were evaluated preoperatively and at the last follow-up visit in the surgical group. Functional outcomes were assessed using the Lille Patello-Femoral Score, Lysholm Score, and Kujala Score at the same time points. In addition, the surgical and non-operative treatment success groups were compared in terms of both radiographic and functional outcomes. RESULTS: Mean follow-up was 40.9 months (24-60). Fifty-nine knees showed excellent or good results postoperatively, 2 patients had a recurrent patellar subluxation. The Lille Patello-Femoral Score was 96.9±4.7 at the last follow-up. The subjective Lysholm Score and Kujala Score improved significantly, from 58.6 to 91.9 and from 60.4 to 88.9, respectively. The radiographic CA, LPA and PTA improved significantly, from 19.8±2.1° to -6.7±1.7°, from -7.4±2.2° to 5.7±1.8° and from 23.8±2.9° to 12.3±2.3°, respectively. There was no statistically significant difference in functional and radiographic assessments between the success with non-operative treatment group and the surgery group. CONCLUSION: The results of this study suggest that arthroscopic MPFL insertion reconstruction and plication using suture anchors, which is less invasive and improves patella stability, can lead to favorable clinical and functional outcomes in adolescent patients with first-time acute patellar dislocation and insertion injury. This treatment approach should be considered as a viable option for this patient population. LEVEL OF EVIDENCE: IV; monocentric retrospective descriptive study.

Efficient Access to Sequence-Controlled Poly(α-hydroxy acids) with Ax(BC)yDz-Type and Ax(BC)yAz-Type Triblock Structures via Self-Switchable Ring-Opening Polymerization of Monomer Mixtures.

Synthesizing block-sequence-controlled poly(α-hydroxy acids) of three or four α-hydroxy acids remains challenging in one step. In this study, a strategy was employed using three monomers of O-carboxyanhydrides (OCAs) consisting of one α-hydroxy acid (A), asymmetric cyclic diester (B and C, two different α-hydroxy acids of B and C), and symmetric cyclic diester (one α-hydroxy acid of D) with remarkably different activities toward a stereoselective, regioselective, and chemoselective initiator of a zirconium complex. Then, via a self-switchable approach, these monomers can be copolymerized in a well-controlled block sequence of Ax(BC)yDz and Ax(BC)yAz without an external stimulus. Moreover, upon addition of more monomer mixtures during the copolymerization process, more complicated sequence-controlled poly(α-hydroxy acids) can be achieved with up to 15 blocks.

Monomer-Promoting Asymmetric Kinetic Resolution-Alternating Copolymerization To Afford AAB-Type Copolyesters.

Living copolymerization of mixed monomers can enrich the diversity of copolymer materials with well-defined performance via controlling both monomers and stereosequences. However, periodic sequence-controlled living copolymerization of same-type monomers with more than two components in synthetic polymer science remains a challenge. In this work, a new method of monomer-promoting asymmetric kinetic resolution-alternating copolymerization can let a tricomponent mixture of l-lactide (S,S-LA or l-LA) and two enantiomeric isomers of racemic tropic acid cyclic esters (tropicolactone) be polymerized into sequence-controlled -(ASASBS)n- type biodegradable copolyesters (the subscript S presents the configuration and A and B present lactic acid units and tropic acid units, respectively), and diblock copolymers of -(ASASBS)n-b-(ARARBR)n- can further be obtained upon addition of R,R-LA (d-LA). Compared to previous asymmetric kinetic resolutions of racemic chemicals via polymerization or organic reactions, no enantiopure catalyst/initiator is required in this system. After the resolution and alternating copolymerization of S,S-LA and rac-tropicolactone, the ee value of unreacted tropicolactone can reach 99.4%. The alternating probability between tropicolactone and lactide monomers is more than 96% in periodic sequence polymers of -(ASASBS)n-. The tetracomponent mixture of rac-lactide and rac-tropicolactone can be copolymerized into an alternating copolymer with a -((ASASBS)x-ran-(ARARBR)y)n- structure, in which the stereoselective linkage probability of 95% after S,S-lactide (R,R-lactide) followed by S-tropicolactone (R-tropicolactone) keeps very high too.

DJ-1 Molecular Chaperone Activity Depresses Tau Aggregation Propensity through Interaction with Monomers.

Tau aggregate-bearing lesions are pathological markers and potential mediators of tauopathic neurodegenerative diseases, including Alzheimer's disease. The molecular chaperone DJ-1 colocalizes with tau pathology in these disorders, but it has been unclear what functional link exists between them. In this study, we examined the consequences of tau/DJ-1 interaction as isolated proteins in vitro. When added to full-length 2N4R tau under aggregation-promoting conditions, DJ-1 inhibited both the rate and extent of filament formation in a concentration-dependent manner. Inhibitory activity was low affinity, did not require ATP, and was not affected by substituting oxidation incompetent missense mutation C106A for wild-type DJ-1. In contrast, missense mutations previously linked to familial Parkinson's disease and loss of α-synuclein chaperone activity, M26I and E64D, displayed diminished tau chaperone activity relative to wild-type DJ-1. Although DJ-1 directly bound the isolated microtubule-binding repeat region of tau protein, exposure of preformed tau seeds to DJ-1 did not diminish seeding activity in a biosensor cell model. These data reveal DJ-1 to be a holdase chaperone capable of engaging tau as a client in addition to α-synuclein. Our findings support a role for DJ-1 as part of an endogenous defense against the aggregation of these intrinsically disordered proteins.

Spatially resolved transcriptomics reveals genes associated with the vulnerability of middle temporal gyrus in Alzheimer's disease.

Human middle temporal gyrus (MTG) is a vulnerable brain region in early Alzheimer's disease (AD), but little is known about the molecular mechanisms underlying this regional vulnerability. Here we utilize the 10 × Visium platform to define the spatial transcriptomic profile in both AD and control (CT) MTG. We identify unique marker genes for cortical layers and the white matter, and layer-specific differentially expressed genes (DEGs) in human AD compared to CT. Deconvolution of the Visium spots showcases the significant difference in particular cell types among cortical layers and the white matter. Gene co-expression analyses reveal eight gene modules, four of which have significantly altered co-expression patterns in the presence of AD pathology. The co-expression patterns of hub genes and enriched pathways in the presence of AD pathology indicate an important role of cell-cell-communications among microglia, oligodendrocytes, astrocytes, and neurons, which may contribute to the cellular and regional vulnerability in early AD. Using single-molecule fluorescent in situ hybridization, we validated the cell-type-specific expression of three novel DEGs (e.g., KIF5A, PAQR6, and SLC1A3) and eleven previously reported DEGs associated with AD pathology (i.e., amyloid beta plaques and intraneuronal neurofibrillary tangles or neuropil threads) at the single cell level. Our results may contribute to the understanding of the complex architecture and neuronal and glial response to AD pathology of this vulnerable brain region.