The Ca2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum.

Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) signaling adaptor that is essential for the type I interferon response to DNA pathogens. Aberrant activation of STING is linked to the pathology of autoimmune and autoinflammatory diseases. The rate-limiting step for the activation of STING is its translocation from the ER to the ER-Golgi intermediate compartment. Here, we found that deficiency in the Ca2+ sensor stromal interaction molecule 1 (STIM1) caused spontaneous activation of STING and enhanced expression of type I interferons under resting conditions in mice and a patient with combined immunodeficiency. Mechanistically, STIM1 associated with STING to retain it in the ER membrane, and coexpression of full-length STIM1 or a STING-interacting fragment of STIM1 suppressed the function of dominant STING mutants that cause autoinflammatory diseases. Furthermore, deficiency in STIM1 strongly enhanced the expression of type I interferons after viral infection and prevented the lethality of infection with a DNA virus in vivo. This work delineates a STIM1-STING circuit that maintains the resting state of the STING pathway.

Multiomics analyses reveal a critical role of selenium in controlling T cell differentiation in Crohn's disease.

Inflammatory bowel disease (IBD) mainly includes Crohn's disease (CD) and ulcerative colitis (UC). Immune disorders play an essential role in the pathogenesis of these two IBDs, but the differences in the immune microenvironment of the colon and their underlying mechanisms remain poorly investigated. Here we examined the immunological features and metabolic microenvironment of untreated individuals with IBD by multiomics analyses. Modulation of CD-specific metabolites, particularly reduced selenium, can obviously shape type 1 T helper (Th1) cell differentiation, which is specifically enriched in CD. Selenium supplementation suppressed the symptoms and onset of CD and Th1 cell differentiation via selenoprotein W (SELW)-mediated cellular reactive oxygen species scavenging. SELW promoted purine salvage pathways and inhibited one-carbon metabolism by recruiting an E3 ubiquitin ligase, tripartite motif-containing protein 21, which controlled the stability of serine hydroxymethyltransferase 2. Our work highlights selenium as an essential regulator of T cell responses and potential therapeutic targets in CD.

Limiting Cholesterol Biosynthetic Flux Spontaneously Engages Type I IFN Signaling.

Cellular lipid requirements are achieved through a combination of biosynthesis and import programs. Using isotope tracer analysis, we show that type I interferon (IFN) signaling shifts the balance of these programs by decreasing synthesis and increasing import of cholesterol and long chain fatty acids. Genetically enforcing this metabolic shift in macrophages is sufficient to render mice resistant to viral challenge, demonstrating the importance of reprogramming the balance of these two metabolic pathways in vivo. Unexpectedly, mechanistic studies reveal that limiting flux through the cholesterol biosynthetic pathway spontaneously engages a type I IFN response in a STING-dependent manner. The upregulation of type I IFNs was traced to a decrease in the pool size of synthesized cholesterol and could be inhibited by replenishing cells with free cholesterol. Taken together, these studies delineate a metabolic-inflammatory circuit that links perturbations in cholesterol biosynthesis with activation of innate immunity.

Envelope protein-specific B cell receptors direct lentiviral vector tropism in vivo.

While studying transgene expression after systemic administration of lentiviral vectors, we found that splenic B cells are robustly transduced, regardless of the types of pseudotyped envelope proteins. However, the administration of two different pseudotypes resulted in transduction of two distinct B cell populations, suggesting that each pseudotype uses unique and specific receptors for its attachment and entry into splenic B cells. Single-cell RNA sequencing analysis of the transduced cells demonstrated that different pseudotypes transduce distinct B cell subpopulations characterized by specific B cell receptor (BCR) genotypes. Functional analysis of the BCRs of the transduced cells demonstrated that BCRs specific to the pseudotyping envelope proteins mediate viral entry, enabling the vectors to selectively transduce the B cell populations that are capable of producing antibodies specific to their envelope proteins. Lentiviral vector entry via the BCR activated the transduced B cells and induced proliferation and differentiation into mature effectors, such as memory B and plasma cells. BCR-mediated viral entry into clonally specific B cell subpopulations raises new concepts for understanding the biodistribution of transgene expression after systemic administration of lentiviral vectors and offers new opportunities for BCR-targeted gene delivery by pseudotyped lentiviral vectors.

Immunization of Mice with Virus-Like Vesicles of Kaposi Sarcoma-Associated Herpesvirus Reveals a Role for Antibodies Targeting ORF4 in Activating Complement-Mediated Neutralization.

Infection by Kaposi sarcoma-associated herpesvirus (KSHV) can cause severe consequences, such as cancers and lymphoproliferative diseases. Whole inactivated viruses (WIV) with chemically destroyed genetic materials have been used as antigens in several licensed vaccines. During KSHV productive replication, virus-like vesicles (VLVs) that lack capsids and viral genomes are generated along with virions. Here, we investigated the immunogenicity of KSHV VLVs produced from a viral mutant that was defective in capsid formation and DNA packaging. Mice immunized with adjuvanted VLVs generated KSHV-specific T cell and antibody responses. Neutralization of KSHV infection by the VLV immune serum was low but was markedly enhanced in the presence of the complement system. Complement-enhanced neutralization and complement deposition on KSHV-infected cells was dependent on antibodies targeting viral open reading frame 4 (ORF4). However, limited complement-mediated enhancement was detected in the sera of a small cohort of KSHV-infected humans which contained few neutralizing antibodies. Therefore, vaccination that induces antibody effector functions can potentially improve infection-induced humoral immunity. Overall, our study highlights a potential benefit of engaging complement-mediated antibody functions in future KSHV vaccine development. IMPORTANCE KSHV is a virus that can lead to cancer after infection. A vaccine that prevents KSHV infection or transmission would be helpful in preventing the development of these cancers. We investigated KSHV VLV as an immunogen for vaccination. We determined that antibodies targeting the viral protein ORF4 induced by VLV immunization could engage the complement system and neutralize viral infection. However, ORF4-specific antibodies were seldom detected in the sera of KSHV-infected humans. Moreover, these human sera did not potently trigger complement-mediated neutralization, indicating an improvement that immunization can confer. Our study suggests a new antibody-mediated mechanism to control KSHV infection and underscores the benefit of activating the complement system in a future KSHV vaccine.

Faecalibacterium prausnitzii as a potential Antiatherosclerotic microbe.

BACKGROUND: The gut microbiota plays a crucial role in coronary artery disease (CAD) development, but limited attention has been given to the role of the microbiota in preventing this disease. This study aimed to identify key biomarkers using metagenomics and untargeted metabolomics and verify their associations with atherosclerosis. METHODS: A total of 371 participants, including individuals with various CAD types and CAD-free controls, were enrolled. Subsequently, significant markers were identified in the stool samples through gut metagenomic sequencing and untargeted metabolomics. In vivo and in vitro experiments were performed to investigate the mechanisms underlying the association between these markers and atherosclerosis. RESULTS: Faecal omics sequencing revealed that individuals with a substantial presence of Faecalibacterium prausnitzii had the lowest incidence of CAD across diverse CAD groups and control subjects. A random forest model confirmed the significant relationship between F. prausnitzii and CAD incidence. Notably, F. prausnitzii emerged as a robust, independent CAD predictor. Furthermore, our findings indicated the potential of the gut microbiota and gut metabolites to predict CAD occurrence and progression, potentially impacting amino acid and vitamin metabolism. F. prausnitzii mitigated inflammation and exhibited an antiatherosclerotic effect on ApoE-/- mice after gavage. This effect was attributed to reduced intestinal LPS synthesis and reinforced mechanical and mucosal barriers, leading to decreased plasma LPS levels and an antiatherosclerotic outcome. CONCLUSIONS: Sequencing of the samples revealed a previously unknown link between specific gut microbiota and atherosclerosis. Treatment with F. prausnitzii may help prevent CAD by inhibiting atherosclerosis.

Structure and mutagenesis reveal essential capsid protein interactions for KSHV replication.

Kaposi's sarcoma-associated herpesvirus (KSHV) causes Kaposi's sarcoma, a cancer that commonly affects patients with AIDS and which is endemic in sub-Saharan Africa. The KSHV capsid is highly pressurized by its double-stranded DNA genome, as are the capsids of the eight other human herpesviruses. Capsid assembly and genome packaging of herpesviruses are prone to interruption and can therefore be targeted for the structure-guided development of antiviral agents. However, herpesvirus capsids-comprising nearly 3,000 proteins and over 1,300 Å in diameter-present a formidable challenge to atomic structure determination and functional mapping of molecular interactions. Here we report a 4.2 Å resolution structure of the KSHV capsid, determined by electron-counting cryo-electron microscopy, and its atomic model, which contains 46 unique conformers of the major capsid protein (MCP), the smallest capsid protein (SCP) and the triplex proteins Tri1 and Tri2. Our structure and mutagenesis results reveal a groove in the upper domain of the MCP that contains hydrophobic residues that interact with the SCP, which in turn crosslinks with neighbouring MCPs in the same hexon to stabilize the capsid. Multiple levels of MCP-MCP interaction-including six sets of stacked hairpins lining the hexon channel, disulfide bonds across channel and buttress domains in neighbouring MCPs, and an interaction network forged by the N-lasso domain and secured by the dimerization domain-define a robust capsid that is resistant to the pressure exerted by the enclosed genome. The triplexes, each composed of two Tri2 molecules and a Tri1 molecule, anchor to the capsid floor via a Tri1 N-anchor to plug holes in the MCP network and rivet the capsid floor. These essential roles of the MCP N-lasso and Tri1 N-anchor are verified by serial-truncation mutageneses. Our proof-of-concept demonstration of the use of polypeptides that mimic the smallest capsid protein to inhibit KSHV lytic replication highlights the potential for exploiting the interaction hotspots revealed in our atomic structure to develop antiviral agents.

Surface Lattice Modulation Enables Stable Cycling of High-Loading All-solid-state Batteries at High Voltages.

Halide solid electrolytes, known for their high ionic conductivity at room temperature and good oxidative stability, face notable challenges in all-solid-state Li-ion batteries (ASSBs), especially with unstable cathode/solid electrolyte (SE) interface and increasing interfacial resistance during cycling. In this work, we have developed an Al3+-doped, cation-disordered epitaxial nanolayer on the LiCoO2 surface by reacting it with an artificially constructed AlPO4 nanoshell; this lithium-deficient layer featuring a rock-salt-like phase effectively suppresses oxidative decomposition of Li3InCl6 electrolyte and stabilizes the cathode/SE interface at 4.5 V. The ASSBs with the halide electrolyte Li3InCl6 and a high-loading LiCoO2 cathode demonstrated high discharge capacity and long cycling life from 3 to 4.5 V. Our findings emphasize the importance of specialized cathode surface modification in preventing SE degradation and achieving stable cycling of halide-based ASSBs at high voltages.

Survival outcomes correlate with the level of cell-free circulating DNA in ST-elevation myocardial infarction.

Background: Myocardial infarction (MI) can lead to higher cellular damage, making cell-free DNA (cfDNA) a potential biomarker for assessing disease severity. The aim of this study is to evaluate survival predictions using cfDNA measurements and assess its correlation with MI. Materials and Methods: A direct fluorescence assay was employed to measure cfDNA content in the blood samples of participants. The inclusion criteria included patients who gave informed consent, suffering from ST-elevation myocardial infraction (STEMI) based on established diagnostic criteria (joint ESC/ACC guidelines), between the age of 18 and 80 years old, and had elevated troponin biomarker levels. The study included 150 patients diagnosed with STEMI and 50 healthy volunteers as controls. Serial monitoring of patients was conducted to track their postdisease status. The rate of change of cfDNA was calculated and daily measurements for 7 days were recorded. Results: Mean levels of cfDNA were found to be 5.93 times higher in patients with STEMI compared to healthy controls, providing clear evidence of a clinical correlation between cfDNA and STEMI. Patients were further categorized based on their survival status within a 90-day period. The study observed a strong predictive relationship between the rate of change of cfDNA during daily measurements and survival outcomes. To assess its predictive capability, a receiver operating characteristics (ROC) curve analysis was performed. The ROC analysis identified an optimal cutoff value of 2.50 for cfDNA, with a sensitivity of 81.5% and specificity of 74.0% in predicting disease outcomes. Conclusion: This study demonstrates a robust association between cfDNA and STEMI, indicating that cfDNA levels can be a valuable early prognostic factor for patients. Serial measurements of cfDNA during early disease onset hold promise as an effective approach for predicting survival outcomes in MI patients.

Direct Ink Writing of Pickering Emulsions Generates Ultralight Conducting Polymer Foams with Hierarchical Structure and Multifunctionality.

Porous materials with multiple hierarchy levels can be useful as lightweight engineering structures, biomedical implants, flexible functional devices, and thermal insulators. Numerous routes have integrated bottom-up and top-down approaches for the generation of engineering materials with lightweight nature, complex structures, and excellent mechanical properties. It nonetheless remains challenging to generate ultralight porous materials with hierarchical architectures and multi-functionality. Here, the combined strategy based on Pickering emulsions and additive manufacturing leads to the development of ultralight conducting polymer foams with hierarchical pores and multifunctional performance. Direct writing of the emulsified inks consisting of the nano-oxidant-hydrated vanadium pentoxide nanowires-generated free-standing scaffolds, which are stabilized by the interfacial organization of the nanowires into network structures. The following in situ oxidative polymerization transforms the nano-oxidant scaffolds into foams consisting of a typical conducting polymer-polyaniline. The lightweight polyaniline foams featured by hierarchical pores and high surface areas show excellent performances in the applications of supercapacitor electrodes, planar micro-supercapacitors, and gas sensors. This emerging technology demonstrates the great potential of a combination of additive manufacturing with complex fluids for the generation of functional solids with lightweight nature and adjustable structure-function relationships.

Mutated CYP17A1 promotes atherosclerosis and early-onset coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is a multi-factor complex trait and is heritable, especially in early-onset families. However, the genetic factors affecting the susceptibility of early-onset CAD are not fully characterized. METHODS: In the present study, we identified a rare nonsense variant in the CYP17A1 gene from a Chinese Han family with CAD. To validate the effect of this variation on atherosclerosis and early-onset coronary artery disease, we conducted studies on population, cells, and mice. RESULTS: The mutation precisely congregated with the clinical syndrome in all the affected family members and was absent in unaffected family members and unrelated controls. Similar to the human phenotype, the CYP17A1-deficient mice present the phenotype of metabolic syndrome with hypertension, increased serum glucose concentration, and presentation of central obesity and fatty liver. Furthermore, CYP17A1 knockout mice or CYP17A1 + ApoE double knockout mice developed more atherosclerotic lesions than wild type (WT) with high fat diary. In cell models, CYP17A1 was found to be involved in glucose metabolism by increasing glucose intake and utilization, through activating IGF1/mTOR/HIF1-α signaling way, which was consistent in CYP17A1 knockout mice with impaired glucose tolerance and insulin resistance. CONCLUSIONS: Through our study of cells, mice and humans, we identified CYP17A1 as a key protein participating in the pathophysiology of the atherosclerotic process and the possible mechanism of CYP17A1 C987X mutation induced atherosclerosis and early-onset CAD involving glucose homeostasis regulation was revealed. Video Abstract.

Critical Care Pharmacist Attitudes and Perceptions of Neuromuscular Blocker Infusions in ARDS.

BACKGROUND: Current critical care pharmacist (CCP) practices and perceptions related to neuromuscular infusion (NMBI) use for acute respiratory distress syndrome (ARDS) maybe different with the COVID-19 pandemic and the publication of 2020 NMBI practice guidelines. OBJECTIVE: To evaluate CCP practices and perceptions regarding NMBI use for patients with moderate-severe ARDS. METHODS: We developed, tested, and electronically administered a questionnaire (7 parent-, 42 sub-questions) to 409 American College of Clinical Pharmacy (ACCP) Critical Care Practice and Research Network members in 12 geographically diverse states. The questionnaire focused on adults with moderate-severe ARDS (PaO2:FiO2<150) whose causes of dyssynchrony were addressed. Two reminders were sent at 10-day intervals. RESULTS: Respondents [131/409 (32%)] primarily worked in a medical intensive care unit (ICU) 102 (78%). Compared to COVID-negative(-) ARDS patients, COVID positive(+) ARDS patients were twice as likely to receive a NMBI (34 ± 18 vs.16 ± 17%; P < 0.01). Respondents somewhat/strongly agreed a NMBI should be reserved until after trials of deep sedation (112, 86%) or proning (92, 81%) and that NMBI reduced barotrauma (88, 67%), dyssynchrony (87, 66%), and plateau pressure (79, 60%). Few respondents somewhat/strongly agreed that a NMBI should be initiated at ARDS onset (23, 18%) or that NMBI reduced 90-day mortality (12, 10%). Only 2/14 potential NMBI risks [paralysis awareness (101, 82%) and prolonged muscle weakness (84, 68%)] were frequently reported to be of high/very high concern. Multiple NMBI titration targets were assessed as very/extremely important including arterial pH (109, 88%), dyssynchrony (107, 86%), and PaO2: FiO2 ratio (82, 66%). Train-of-four (55, 44%) and BIS monitoring (36, 29%) were deemed less important. Preferred NMBI discontinuation criteria included absence of dysschrony (84, 69%) and use ≥48 hour (72, 59%). CONCLUSIONS AND RELEVANCE: Current critical care pharmacists believe NMBI for ARDS patients are best reserved until after trials of deep sedation or proning; unique considerations exist in COVID+ patients. Our results should be considered when ICU NMBI protocols are being developed and bedside decisions regarding NMBI use in ARDS are being formulated.

Effects of a multilevel intervention of resistance training with or without beta-hydroxy-beta-methylbutyrate in medical ICU patients during entire hospitalisation: a four-arm multicentre randomised controlled trial.

BACKGROUND: Intensive care unit-acquired weakness (ICU-AW) is a prevalent and severe issue among ICU patients. Resistance training and beta-hydroxy-beta-methylbutyrate (HMB) intervention have demonstrated the potential to enhance muscle function in patients with sarcopenia and in older adults. The purpose of this study was to determine whether resistance training and/or HMB administration would improve physical function, muscle strength, and quality of life in medical ICU patients. METHODS: In this multicentre, four-arm, single-blind randomised control trial, a total of 112 adult patients with internal medical diagnoses admitted to the ICU were enrolled. These participants were then randomly assigned to one of four treatment groups: the resistance training group received protocol-based multilevel resistance exercise, the HMB group received 3 g/day of HMBCa, combination group and control groups received standard care, from the ICU to the general ward until discharge. The primary outcomes assessed at discharge included six-minute walking distance (6MWD) and short physical performance battery (SPPB). Secondary outcomes measured included muscle mass, MRC score, grip strength, and health reports quality of life at different time points. Data analysis was performed using a generalised linear mixed model, adhering to the principles of intention-to-treat analysis. RESULTS: Resistance training and combination treatment groups exhibited significant increases in SPPB scores (3.848 and 2.832 points, respectively) compared to the control group and substantial improvements in 6WMD (99.768 and 88.577 m, respectively) (all with P < 0.01). However, no significant changes were observed in the HMB group. Muscle strength, as indicated by MRC and grip strength tests conducted at both ICU and hospital discharge, showed statistically significant improvements in the resistance training and combination groups (P < 0.05). Nevertheless, no significant differences were found between the treatment groups and usual care in terms of 60-day mortality, prevalence of ICU-AW, muscle mass, quality of life, or other functional aspects. CONCLUSIONS: Resistance training with or without beta-hydroxy-beta-methylbutyrate during the entire hospitalisation intervention improves physical function and muscle strength in medical ICU patients, but muscle mass, quality of life, and 60-day mortality were unaffected. TRIAL REGISTRATION: ChiCTR2200057685 was registered on March 15th, 2022.

Sensitivity to thyroid hormone indices are associated with papillary thyroid carcinoma in Chinese patients with thyroid nodules.

BACKGROUND: The association between thyroid hormone sensitivity and thyroid cancer is unknown, and we aimed to investigate the association between sensitivity to thyroid hormone indices and papillary thyroid carcinoma (PTC) in Chinese patients with thyroid nodules (TNs). METHODS: A total of 1,998 patients undergoing thyroid surgery due to TNs from Nanjing Drum Tower Hospital were included in this study. We evaluated central sensitivity to thyroid hormones, such as thyroid stimulating hormone index (TSHI), TSH T4 resistance index (TT4RI), thyroid feedback quantile-based index (TFQI), and parametric thyroid feedback quantile-based Index (PTFQI). Peripheral sensitivity to thyroid hormone was evaluated by FT3 to FT4 ratio. Multivariate logistic regression analysis was performed to evaluate the association between sensitivity to thyroid hormone indices and PTC risk. RESULTS: The results showed that central indices of thyroid hormone sensitivity, including TSHI, TT4RI, TFQI, and PTFQI, were positively associated with PTC risk. For each SD increase in TSHI, TT4RI, TFQI, and PTFQI, the odds ratios (OR, 95% CI) of PTC were 1.31 (1.18-1.46), 1.01 (1.01-1.02), 1.94 (1.45-2.60), and 1.82 (1.41-2.34), respectively. On the other hand, the association between peripheral sensitivity to thyroid hormone and PTC was significantly negative. For each SD increase in FT3/FT4 ratio, the OR (95% CI) of PTC was 0.18 (0.03-0.96), and a negative correlation was found between FT3/FT4 ratio and TNM staging of PTC. CONCLUSIONS: Sensitivity to thyroid hormone indices could be used as new indicators for predicting PTC in Chinese patients with TNs. Future researches are still needed to confirm our findings.

Age and outcomes following personalized antiplatelet therapy in chronic coronary syndrome patients: a post hoc analysis of the randomized PATH-PCI trial.

It is particularly important to establish more effective and safer antiplatelet treatment strategies according to age. The present subanalysis of the PATH-PCI trial was to determine the safety and efficacy of any dual-antiplatelet therapy (DAPT) strategy in different age groups. We randomized 2285 chronic coronary syndrome (CCS) patients undergoing percutaneous coronary intervention (PCI) into a standard group or a personalized group from December 2016 to February 2018. The personalized group received personalized antiplatelet therapy (PAT) based on a novel platelet function test (PFT). The standard group received standard antiplatelet therapy (SAT). Then, all patients were divided according to age (under the age of 65 years and aged 65 years or over) to investigate the association and interaction of age on clinical outcomes at 180 days. In the patients under the age of 65 years, the incidence of NACEs was decreased in the personalized group compared to the standard group (5.1% vs. 8.8%, HR: 0.603, 95% CI: 0.409-0.888, P = .010). The rates of MACCEs (3.3% vs. 7.7%, HR: 0.450, 95% CI: 0.285-0.712, P = .001), MACEs (2.2% vs. 5.4%, HR: 0.423, 95% CI: 0.243-0.738, P = .002) also decreased. We did not find a significant difference in bleeding between the groups. In the patients aged 65 years or over, no difference in the primary endpoint was found (4.9% vs. 4.2%, P = .702), and comparable rates of survival were observed with the two strategies (all Ps > 0.05). The present study shows that PAT according to PFT was comparable to SAT at the 180-day follow-up for both ischemic and bleeding endpoints in CCS patients aged 65 years or over who underwent PCI. In patients under the age of 65 years, PAT can reduce ischemic events but does not increase bleeding, and it is an effective and safe treatment strategy. It may be necessary for young CCS patients after PCI to undergo PAT early after PCI.

What is the context? The PATH-PCI trial reported that personalized antiplatelet therapy (PAT) based on a novel platelet function test (PFT) can greatly reduce the incidence of ischemic events.Antiplatelet strategies may have very different effects on clinical outcomes in patients in China who are undergoing PCI at different ages.What is new? PL-12 is a new point-of-care platelet function analyzer that is used to test the platelet maximum aggregation rate (MAR).We explored the efficacy and safety of different antiplatelet strategies in chronic coronary syndrome (CCS) patients in different age groups.What is the impact? PAT according to PFT was comparable to standard antiplatelet therapy (SAT) at the 180-day follow-up for both ischemic and bleeding endpoints in CCS patients aged 65 years or over who underwent PCI.In patients under the age of 65 years, PAT can reduce ischemic events but not increase bleeding.PAT may be an effective and safe treatment strategy in CCS patients under the age of 65 years who underwent PCI.Abbreviation: PCI: percutaneous coronary intervention; CCS: chronic coronary syndrome; DAPT: dual antiplatelet therapy; PAT: personalized antiplatelet therapy; SAT: standard antiplatelet therapy; PFT: platelet function test; NACEs: net adverse clinical events; MACCEs: major adverse cardiac and cerebrovascular events; MACEs: major adverse cardiovascular events.

Epidemic trends of dyslipidemia in young adults: a real-world study including more than 20,000 samples.

BACKGROUND: There is an urgent need to learn more about the epidemiological features of dyslipidemia in youth to address the high burden of cardiovascular disease. METHODS: This experiment was an observational, cross-sectional study. The samples were collected from 22,379 college students at Xinjiang Medical University. RESULT: The overall prevalence of dyslipidemia was 13.17%, which was significantly higher in men (23%) than in women (7.2%), p < 0.01. Similarly, the prevalence rate of obesity in men (11.4%) was significantly higher than that in women (3.4%). The composition of blood lipids, such as triglyceride (TG), total cholesterol (TC), and low density lipoprotein cholesterol (LDL-C), began to increase gradually from the age of 22 and showed a sharp increase after the age of 30; however, a reverse trend was present in high density lipoprotein cholesterol (HDL-C). In terms of the proportion of dyslipidemia in both men and women, low HDL-C accounted for the largest proportion (74%), followed by elevated TGs (14.5%). The overall distribution of rates of dyslipidemia and excess weight showed a U-shaped trend with increasing age, with the lowest rates seen in the 20-24 age group. CONCLUSION: Our study sheds light on the epidemiological features of dyslipidemia in young adults and enriches the limited data available on dyslipidemia, providing a reference for the close monitoring and control of risk factors to reduce the occurrence and progression of atherosclerotic cardiovascular disease events.

TET2-mediated Cdkn2A DNA hydroxymethylation in midbrain dopaminergic neuron injury of Parkinson's disease.

It has been reported that abnormal epigenetic modification is associated with the occurrence of Parkinson's disease (PD). Here, we found that a ten-eleven translocation 2 (TET2), a staff of the DNA hydroxylases family, was increased in dopaminergic neurons in vitro and in vivo. Genome-wide mapping of DNA 5-hydroxymethylcytosine (5-hmC)-sequencing has revealed an aberrant epigenome 5-hmC landscape in 1-methyl-4-phenylpyridinium iodide (MPP+)-induced SH-SY5Y cells. The TET family of DNA hydroxylases could reverse DNA methylation by oxidization of 5-methylcytosine (5-mC) to 5-hmC. However, the relationship between modification of DNA hydroxymethylation and the pathogenesis of PD is not clear. According to the results of 5-hmC-sequencing studies, 5-hmC was associated with gene-rich regions in the genomes related to cell cycle, especially gene-cyclin-dependent kinase inhibitor 2A (Cdkn2A). Downregulation of TET2 expression could significantly rescue MPP+-stimulated SH-SY5Y cell damage and cell cycle arrest. Meanwhile, knockdown of Tet2 expression in the substantia nigra pars compacta of MPTP-induced PD mice resulted in attenuated MPTP-induced motor deficits and dopaminergic neuronal injury via p16 suppression. In this study, we demonstrated a critical function of TET2 in PD development via the CDKN2A activity-dependent epigenetic pathway, suggesting a potential new strategy for epigenetic therapy.

Regulation of Chirality in Metal-Organic Frameworks (MOFs) Based on Achiral Precursors through Substituent Modification.

The generation and regulation of chirality are closely related to the origin of life. Using achiral precursors to spontaneously build chiral MOFs remains a major challenge. Here, a method to synthesize chiral MOFs from achiral precursors by utilizing chiral fragments was achieved. The transformation from chiral fragments of 1 to chiral frameworks of 2 and 3 was realized by modifying the substituents, and the enantiomer resolution of 3-P41212 and 3-P43212 was achieved by d/l camphoric acid. 3 was then further studied in applications.

Sleep-Promotion Bundle Development, Implementation, and Evaluation in Critically Ill Adults: Roles for Pharmacists.

OBJECTIVE: To review evidence for intensive care unit (ICU) sleep improvement bundle use, identify preferred sleep bundle components and implementation strategies, and highlight the role for pharmacists in developing and evaluating bundle efforts. DATA SOURCES: Multiple databases were searched from January 1, 1990, to September 1, 2021, using the MeSH terms sleep, intensive care or critical care, protocol or bundle to identify comparative studies evaluating ICU sleep bundle implementation. STUDY SELECTION AND DATA EXTRACTION: Study screening, data extraction, and risk-of-bias evaluation were conducted in tandem. The ICU quality improvement literature and Institute for Healthcare Improvement bundle improvement guidance were also reviewed to identify recommended strategies for successful sleep bundle use. DATA SYNTHESIS: Nine studies (3 randomized, 1 quasi-experimental, 5 before-and-after) were identified. Bundle elements varied and were primarily focused on nonpharmacological interventions designed to be performed during either the day or night; only 2 studies included a medication-based strategy. Five studies were associated with reduced delirium; 2 studies were associated with improved total sleep time and 2 with improved patient-perceived sleep. Pharmacists were involved directly in 4 studies. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Sleep improvement bundles are recommended for use in all critically ill adults; specific bundle elements and ICU team member roles should be individualized at the institution/ICU level. Pharmacists can help lead bundle development efforts and routinely deliver key elements. CONCLUSIONS: Pharmacists can play an important role in the development and implementation of ICU sleep bundles. Further research regarding the relative benefit of individual bundle elements on relevant patient outcomes is needed.

Comparison of predictive value of risk scores for gastrointestinal bleeding in antiplatelet therapy.

Gastrointestinal bleeding (GIB) is the most common serious bleeding complication of antiplatelet therapy. The bleeding risk score (BRS) of GIB may help to determine the risk of bleeding, and provides a reference for the formulation of antiplatelet therapy regimen in clinical practice, but we found that no specific risk scores are available in East Asian patients. This study analyzed patients who were administered antiplatelet therapy from May 2015 to December 2018 in two medical centers. Patient's baseline data were obtained. We assessed four BRSs (New Score, RIETE Score, Cuschieri Score, de Groot Score) and compared them using the area under the receiver operating characteristic curve (AUC). The 4,052 patients enrolled in this study had an average age of 69.6 ± 10.8 years, and 65.9% of them were male. Among the 4,052 patients included, 171 patients experienced GIB within 6 months of follow-up. In the study population, the AUCs for the New, RIETE, Cuschieri, and de Groot scores were 0.673 (95% confidence interval (CI) 0.616-0.729, P < .001), 0.742 (95% CI 0.690-0.794, P < .001), 0.598 (95% CI 0.537-0.659, P = .002), and 0.875 (95% CI 0.839-0.912, P < .001), respectively. After validation, the de Groot Score has better performance. Among the four scores, the de Groot Score might be more suitable for helping Chinese clinicians to predict the risk of GIB in patients taking antiplatelet drugs, and reduce GIB events.