Ameliorating parkinsonian motor dysfunction by targeting histamine receptors in entopeduncular nucleus-thalamus circuitry.

In Parkinson's disease (PD), reduced dopamine levels in the basal ganglia have been associated with altered neuronal firing and motor dysfunction. It remains unclear whether the altered firing rate or pattern of basal ganglia neurons leads to parkinsonism-associated motor dysfunction. In the present study, we show that increased histaminergic innervation of the entopeduncular nucleus (EPN) in the mouse model of PD leads to activation of EPN parvalbumin (PV) neurons projecting to the thalamic motor nucleus via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels coupled to postsynaptic H2R. Simultaneously, this effect is negatively regulated by presynaptic H3R activation in subthalamic nucleus (STN) glutamatergic neurons projecting to the EPN. Notably, the activation of both types of receptors ameliorates parkinsonism-associated motor dysfunction. Pharmacological activation of H2R or genetic upregulation of HCN2 in EPNPV neurons, which reduce neuronal burst firing, ameliorates parkinsonism-associated motor dysfunction independent of changes in the neuronal firing rate. In addition, optogenetic inhibition of EPNPV neurons and pharmacological activation or genetic upregulation of H3R in EPN-projecting STNGlu neurons ameliorate parkinsonism-associated motor dysfunction by reducing the firing rate rather than altering the firing pattern of EPNPV neurons. Thus, although a reduced firing rate and more regular firing pattern of EPNPV neurons correlate with amelioration in parkinsonism-associated motor dysfunction, the firing pattern appears to be more critical in this context. These results also confirm that targeting H2R and its downstream HCN2 channel in EPNPV neurons and H3R in EPN-projecting STNGlu neurons may represent potential therapeutic strategies for the clinical treatment of parkinsonism-associated motor dysfunction.

Allele-dependent expression and functionality of lipid enzyme phospholipid:diacylglycerol acyltransferase affect diatom carbon storage and growth.

In the acyl-CoA-independent pathway of triacylglycerol (TAG) synthesis unique to plants, fungi, and algae, TAG formation is catalyzed by the enzyme phospholipid:diacylglycerol acyltransferase (PDAT). The unique PDAT gene of the model diatom Phaeodactylum tricornutum strain CCMP2561 boasts 47 single nucleotide variants within protein coding regions of the alleles. To deepen our understanding of TAG synthesis, we observed the allele-specific expression of PDAT by the analysis of 87 published RNA-sequencing (RNA-seq) data and experimental validation. The transcription of one of the two PDAT alleles, Allele 2, could be specifically induced by decreasing nitrogen concentrations. Overexpression of Allele 2 in P. tricornutum substantially enhanced the accumulation of TAG by 44% to 74% under nutrient stress; however, overexpression of Allele 1 resulted in little increase of TAG accumulation. Interestingly, a more serious growth inhibition was observed in the PDAT Allele 1 overexpression strains compared with Allele 2 counterparts. Heterologous expression in yeast (Saccharomyces cerevisiae) showed that enzymes encoded by PDAT Allele 2 but not Allele 1 had TAG biosynthetic activity, and 7 N-terminal and 3 C-terminal amino acid variants between the 2 allele-encoded proteins substantially affected enzymatic activity. P. tricornutum PDAT, localized in the innermost chloroplast membrane, used monogalactosyldiacylglycerol and phosphatidylcholine as acyl donors as demonstrated by the increase of the 2 lipids in PDAT knockout lines, which indicated a common origin in evolution with green algal PDATs. Our study reveals unequal roles among allele-encoded PDATs in mediating carbon storage and growth in response to nitrogen stress and suggests an unsuspected strategy toward lipid and biomass improvement for biotechnological purposes.

Association between alcohol consumption and sleep traits: observational and mendelian randomization studies in the UK biobank.

Previous studies have shown that excessive alcohol consumption is associated with poor sleep. However, the health risks of light-to-moderate alcohol consumption in relation to sleep traits (e.g., insomnia, snoring, sleep duration and chronotype) remain undefined, and their causality is still unclear in the general population. To identify the association between alcohol consumption and multiple sleep traits using an observational and Mendelian randomization (MR) design. Observational analyses and one-sample MR (linear and nonlinear) were performed using clinical and individual-level genetic data from the UK Biobank (UKB). Two-sample MR was assessed using summary data from genome-wide association studies from the UKB and other external consortia. Phenotype analyses were externally validated using data from the National Health and Nutrition Examination Survey (2017-2018). Data analysis was conducted from January 2022 to October 2022. The association between alcohol consumption and six self-reported sleep traits (short sleep duration, long sleep duration, chronotype, snoring, waking up in the morning, and insomnia) were analysed. This study included 383,357 UKB participants (mean [SD] age, 57.0 [8.0] years; 46% male) who consumed a mean (SD) of 9.0 (10.0) standard drinks (one standard drink equivalent to 14 g of alcohol) per week. In the observational analyses, alcohol consumption was significantly associated with all sleep traits. Light-moderate-heavy alcohol consumption was linearly linked to snoring and the evening chronotype but nonlinearly associated with insomnia, sleep duration, and napping. In linear MR analyses, a 1-SD (14 g) increase in genetically predicted alcohol consumption was associated with a 1.14-fold (95% CI, 1.07-1.22) higher risk of snoring (P < 0.001), a 1.28-fold (95% CI, 1.20-1.37) higher risk of evening chronotype (P < 0.001) and a 1.24-fold (95% CI, 1.13-1.36) higher risk of difficulty waking up in the morning (P < 0.001). Nonlinear MR analyses did not reveal significant results after Bonferroni adjustment. The results of the two-sample MR analyses were consistent with those of the one-sample MR analyses, but with a slightly attenuated overall estimate. Our findings suggest that even low levels of alcohol consumption may affect sleep health, particularly by increasing the risk of snoring and evening chronotypes. The negative effects of alcohol consumption on sleep should be made clear to the public in order to promote public health.

Optimising first-line subtyping-based therapy in triple-negative breast cancer (FUTURE-SUPER): a multi-cohort, randomised, phase 2 trial.

BACKGROUND: Triple-negative breast cancers display heterogeneity in molecular drivers and immune traits. We previously classified triple-negative breast cancers into four subtypes: luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Here, we aimed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer. METHODS: FUTURE-SUPER is an ongoing, open-label, randomised, controlled phase 2 trial being conducted at Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. Eligible participants were females aged 18-70 years, with an Eastern Cooperative Oncology Group performance status of 0-1, and histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. After categorising participants into five cohorts according to molecular subtype and genomic biomarkers, participants were randomly assigned (1:1) with a block size of 4, stratified by subtype, to receive, in 28-day cycles, nab-paclitaxel (100 mg/m2, intravenously on days 1, 8, and 15) alone (control group) or with a subtyping-based regimen (subtyping-based group): pyrotinib (400 mg orally daily) for the LAR-HER2mut subtype, everolimus (10 mg orally daily) for the LAR-PI3K/AKTmut and MES-PI3K/AKTmut subtypes, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (20 mg orally daily) for the immunomodulatory subtype, and bevacizumab (10 mg/kg intravenously on days 1 and 15) for the BLIS/MES-PI3K/AKTWT subtype. The primary endpoint was investigator-assessed progression-free survival for the pooled subtyping-based group versus the control group in the intention-to-treat population (all randomly assigned participants). Safety was analysed in all patients with safety records who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT04395989). FINDINGS: Between July 28, 2020, and Oct 16, 2022, 139 female participants were enrolled and randomly assigned to the subtyping-based group (n=69) or control group (n=70). At the data cutoff (May 31, 2023), the median follow-up was 22·5 months (IQR 15·2-29·0). Median progression-free survival was significantly longer in the pooled subtyping-based group (11·3 months [95% CI 8·6-15·2]) than in the control group (5·8 months [4·0-6·7]; hazard ratio 0·44 [95% CI 0·30-0·65]; p<0·0001). The most common grade 3-4 treatment-related adverse events were neutropenia (21 [30%] of 69 in the pooled subtyping-based group vs 16 [23%] of 70 in the control group), anaemia (five [7%] vs none), and increased alanine aminotransferase (four [6%] vs one [1%]). Treatment-related serious adverse events were reported for seven (10%) of 69 patients in the subtyping-based group and none in the control group. No treatment-related deaths were reported in either group. INTERPRETATION: These findings highlight the potential clinical benefits of using molecular subtype-based treatment optimisation in patients with triple-negative breast cancer, suggesting a path for further clinical investigation. Phase 3 randomised clinical trials assessing the efficacy of subtyping-based regimens are now underway. FUNDING: National Natural Science Foundation of China, Natural Science Foundation of Shanghai, Shanghai Hospital Development Center, and Jiangsu Hengrui Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

The oxidized phospholipid PGPC impairs endothelial function by promoting endothelial cell ferroptosis via FABP3.

Ferroptosis is a novel cell death mechanism that is mediated by iron-dependent lipid peroxidation. It may be involved in atherosclerosis development. Products of phospholipid oxidation play a key role in atherosclerosis. 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) is a phospholipid oxidation product present in atherosclerotic lesions. It remains unclear whether PGPC causes atherosclerosis by inducing endothelial cell ferroptosis. In this study, human umbilical vein endothelial cells (HUVECs) were treated with PGPC. Intracellular levels of ferrous iron, lipid peroxidation, superoxide anions (O2•-), and glutathione were detected, and expression of fatty acid binding protein-3 (FABP3), glutathione peroxidase 4 (GPX4), and CD36 were measured. Additionally, the mitochondrial membrane potential (MMP) was determined. Aortas from C57BL6 mice were isolated for vasodilation testing. Results showed that PGPC increased ferrous iron levels, the production of lipid peroxidation and O2•-, and FABP3 expression. However, PGPC inhibited the expression of GPX4 and glutathione production and destroyed normal MMP. These effects were also blocked by ferrostatin-1, an inhibitor of ferroptosis. FABP3 silencing significantly reversed the effect of PGPC. Furthermore, PGPC stimulated CD36 expression. Conversely, CD36 silencing reversed the effects of PGPC, including PGPC-induced FABP3 expression. Importantly, E06, a direct inhibitor of the oxidized 1-palmitoyl-2-arachidonoyl-phosphatidylcholine IgM natural antibody, inhibited the effects of PGPC. Finally, PGPC impaired endothelium-dependent vasodilation, ferrostatin-1 or FABP3 inhibitors inhibited this impairment. Our data demonstrate that PGPC impairs endothelial function by inducing endothelial cell ferroptosis through the CD36 receptor to increase FABP3 expression. Our findings provide new insights into the mechanisms of atherosclerosis and a therapeutic target for atherosclerosis.

Phase 1/2 study of CPX-351 for patients with Int-2 or high risk International Prognostic Scoring System myelodysplastic syndromes and chronic myelomonocytic leukaemia after failure to hypomethylating agents.

Failure after hypomethylating agents (HMAs) is associated with dismal outcomes in higher risk myelodysplastic syndromes (HR-MDS) or chronic myelomonocytic leukaemia (CMML). We aimed to evaluate the safety and preliminary activity of lower doses of CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, in a single-centre, phase 1/2 study for patients with HR-MDS or CMML after HMA failure. Four doses of CPX-351 (10, 25, 50 and 75 units/m2 ) administered on Days 1, 3 and 5 of induction and Days 1 and 3 of consolidation were evaluated. Between June 2019 and June 2023, 25 patients were enrolled (phase 1: n = 15; phase 2: n = 10) including 19 (76%) with HR-MDS and 6 (24%) with CMML. Most common grade 3-4 non-haematological treatment-emergent adverse events were febrile neutropenia (n = 12, 48%) and lung infection (n = 5, 20%). Three patients (age >75) experienced cardiac toxicity at the 75 units/m2 dose. Further enrolment continued at 50 units/m2 . Four- and 8-week mortality were 0% and 8% respectively. The overall response rate was 56% with median relapse-free and overall survivals of 9.2 (95% CI 3.2-15.1 months) and 8.7 months (95% CI 1.8-15.6 months) respectively. These data suggest that lower doses of CPX-351 are safe. Further studies are needed to evaluate its activity.

Visual Omics: a web-based platform for omics data analysis and visualization with rich graph-tuning capabilities.

SUMMARY: With the continuous development of high-throughput sequencing technology, bioinformatic analysis of omics data plays an increasingly important role in life science research. Many R packages are widely used for omics analysis, such as DESeq2, clusterProfiler and STRINGdb. And some online tools based on them have been developed to free bench scientists from programming with these R packages. However, the charts generated by these tools are usually in a fixed, non-editable format and often fail to clearly demonstrate the details the researchers intend to express. To address these issues, we have created Visual Omics, an online tool for omics data analysis and scientific chart editing. Visual Omics integrates multiple omics analyses which include differential expression analysis, enrichment analysis, protein domain prediction and protein-protein interaction analysis with extensive graph presentations. It can also independently plot and customize basic charts that are involved in omics analysis, such as various PCA/PCoA plots, bar plots, box plots, heat maps, set intersection diagrams, bubble charts and volcano plots. A distinguishing feature of Visual Omics is that it allows users to perform one-stop omics data analyses without programming, iteratively explore the form and layout of graphs online and fine-tune parameters to generate charts that meet publication requirements. AVAILABILITY AND IMPLEMENTATION: Visual Omics can be used at http://bioinfo.ihb.ac.cn/visomics. Source code can be downloaded at http://bioinfo.ihb.ac.cn/software/visomics/visomics-1.1.tar.gz. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A pioneer nematode effector suppresses plant reactive oxygen species burst by interacting with the class III peroxidase.

Bursaphelenchus xylophilus is the pathogen of pine wilt disease, which can devastate the pine forest ecosystem. Usually, plant cells generate reactive oxygen species (ROS) as a defensive substance or signalling molecules to resist the infection of nematodes. However, little is known about how B. xylophilus effectors mediate the plant ROS metabolism. Here, we identified a pioneer B. xylophilus Prx3-interacting effector 1 (BxPIE1) expressed in the dorsal gland cells and the intestine. Silencing of the BxPIE1 gene resulted in reduced nematode reproduction and a delay in disease progression during parasitic stages, with the upregulation of pathogenesis-related (PR) genes PtPR-3 (class Ⅳ chitinase) and PtPR-9 (peroxidase). The protein-protein interaction assays further demonstrated that BxPIE1 interacts with a Pinus thunbergii class III peroxidase (PtPrx3), which produces H2O2 under biotic stress. The expression of BxPIE1 and PtPrx3 was upregulated during the infection stage. Furthermore, BxPIE1 effectively inhibited H2O2 generating from class III peroxidase and ascorbate can recover the virulence of siBxPIE1-treated B. xylophilus by scavenging H2O2. Taken together, BxPIE1 is an important virulence factor, revealing a novel mechanism utilized by nematodes to suppress plant immunity.

How effort-based self-interest motivation shapes altruistic donation behavior and brain responses.

Prosocial behaviors are central to individual and societal well-being. Although the relationship between effort and prosocial behavior is increasingly studied, the impact of effort-based self-interested motivation on prosocial behavior has received less attention. In the current study, we carried out two experiments to examine the effect of motivation to obtain a reward for oneself on donation behavior and brain response. We observed that individuals who accumulated more money in the effort-expenditure rewards task (EEfRT) donated a lower proportion of their earnings. The sigmoid model fitted participants' choices in the EEfRT task, and the effort-reward bias and sigma parameters negatively correlated with the amount of money donated in the donation task. Additionally, the effort-reward bias and sigma parameters negatively predicted N2 amplitude during processing of charitable donation-related information. We propose that individuals who exhibit a lower level of effort-based self-interest motivation may allocate more cognitive control or attentional resources when processing information related to charitable donations. Our work adds weight to understanding the relationship between effort-based self-interest motivation and prosocial behavior and provides electrophysiological evidence.

Stable Mg Single-Atom Solid Base Catalysts Anchored on Metal-Organic Framework-Derived Nitrogen-Doped Carbon.

Solid base catalysts are widely used in the chemical industry owing to their advantages of environmental friendliness and easy separation. However, their application is limited by basic site aggregation and poor stability. In this study, we report the preparation of magnesium (Mg) single-atom catalysts with high activity and stability by a sublimation-trapping strategy. The Mg net was sublimated as Mg vapor at 620 °C, subsequently transported through argon, and finally trapped on the defects of nitrogen-doped carbon derived from metal-organic framework ZIF-8, producing Mg1/NC. Because of the atomically dispersed Mg sites, the obtained Mg1/NC exhibits high catalytic activity and stability for Knoevenagel condensation of benzaldehyde with malononitrile, which is a typical base-catalyzed reaction. The Mg1/NC catalyst achieves a high efficiency with a turnover frequency of 49.6 h-1, which is much better than that of the traditional counterpart MgO/NC (7.7 h-1). In particular, the activity of Mg1/NC shows no decrease after five catalytic cycles, while that of MgO/NC declines due to the instability of basic sites.

Construction of Nickel Single Atoms by Using the Inherent Confined Space in Template-Occupied Mesoporous Silica.

Due to their maximum atomic use of metal sites, single-atom catalysts (SACs) exhibit excellent catalytic activity in a variety of reactions. Although many techniques have been reported for the production of SACs, the construction of single atoms through a convenient strategy is still challenging. Here, we provide a facile method to prepare nickel SACs by utilizing the inherent confined space between the template and silica walls in template-occupied mesoporous silica KIT-6 (TOK). After the introduction of nickel-containing precursors into the inherent confined space of the TOK by solid-phase grinding, Ni SACs can be produced promptly during calcination. Single Ni atoms create a covalent Ni-O-Si structure in the TOK, as indicated by density functional theory (DFT) calculations and experimental data. This synthetic approach is easy to scale up, and 10 g of sample can be effortlessly synthesized using ball milling. The resultant Ni SACs were applied to the oxygen evolution reaction and exhibited higher catalytic activity and stability than the comparative sample synthesized in the absence of confined space.

Recent advance of ATP citrate lyase inhibitors for the treatment of cancer and related diseases.

ATP citrate lyase (ACLY), a strategic metabolic enzyme that catalyzes the glycolytic to lipidic metabolism, has gained increasing attention as an attractive therapeutic target for hyperlipidemia, cancers and other human diseases. Despite of continual research efforts, targeting ACLY has been very challenging. In this field, most reported ACLY inhibitors are "substrate-like" analogues, which occupied with the same active pockets. Besides, some ACLY inhibitors have been disclosed through biochemical screening or high throughput virtual screening. In this review, we briefly summarized the cancer-related functions and the recent advance of ACLY inhibitors with a particular focus on the SAR studies and their modes of action. We hope to provide a timely and updated overview of ACLY and the discovery of new ACLY inhibitors.

The Relationship between physical activity, nutritional status, and sarcopenia in community- dwelling older adults with type 2 diabetes: a cross-sectional study.

AIM: This study was conducted in Urumqi, Xinjiang, to assess the prevalence of sarcopenia and to determine the relationship between physical activity, nutritional status, and sarcopenia among community-dwelling patients with type 2 diabetes mellitus. METHODS: Four hundred eight cases of older people patients with type 2 diabetes mellitus in the community in Urumqi, Xinjiang, from May to August 2022 were selected for a cross-sectional on-site survey, and general information questionnaires, clinical information surveys, physical function measurements, and criteria developed by the Asian sarcopenia working group in 2019 were selected for diagnosis of sarcopenia, and unifactorial and multifactorial binary Logistic regression were applied to analyze the influencing factors of T2DM combined with sarcopenia in patients with sarcopenia. RESULTS: Among the 408 patients, 84 (20.6%) had sarcopenia, with a prevalence of 12.6%, 32.1%, and 51.9% in those aged 60-70, 71- 80, and 81 or older respectively. The prevalence increased significantly with age. Adjusting for variables, the study found that FFM of the Left Leg (OR: 0.710, 95% CI: 0.612-0.804, P = 0.024), FFM of the Right Arm (OR: 0.710, 95% CI: 0.612-0.804, P < 0.001), Age (OR: 1.246, 95% CI: 1.031-1.505, P = 0.023), Fasting Blood Glucose (OR: 1.649, 95% CI: 1.066-2.550, P = 0.025), and Post-Prandial Blood Glucose (OR: 1.455, 95% CI: 0.999-2.118, P = 0.025) were independent associated factors. An increase in MNA score (OR: 0.398, 95% CI: 0.244-0.6500, P < 0.001), ASMI (OR: 0.000, 95% CI: 0.00-0.01, P < 0.001) walking energy expenditure (MET-min) (OR: 0.998, 95% CI: 0.996-0.999, P = 0.001) reduced the prevalence of sarcopenia. CONCLUSION: This study shows that increased age, increased skeletal muscle mass index, decreased right arm FFM, increased postprandial glucose, increased MNA scores, and increased walking energy expenditure (MET-min) were associated with type 2 diabetes with sarcopenia.

Efficacy of Acupuncture for Chronic Spontaneous Urticaria : A Randomized Controlled Trial.

BACKGROUND: The effectiveness of acupuncture for patients with chronic spontaneous urticaria (CSU), reported in a few small-scale studies, is not convincing. OBJECTIVE: To investigate whether acupuncture leads to better effects on CSU than sham acupuncture or waitlist control. DESIGN: A multicenter, randomized, sham-controlled trial. (Chinese Clinical Trial Registry: ChiCTR1900022994). SETTING: Three teaching hospitals in China from 27 May 2019 to 30 July 2022. PARTICIPANTS: 330 participants diagnosed with CSU. INTERVENTION: Participants were randomly assigned in a 1:1:1 ratio to receive acupuncture, sham acupuncture, or waitlist control over an 8-week study period (4 weeks for treatment and another 4 weeks for follow-up). MEASUREMENTS: The primary outcome was the mean change from baseline in the Weekly Urticaria Activity Score (UAS7) at week 4. Secondary outcomes included itch severity scores, self-rated improvement, and Dermatology Life Quality Index scores. RESULTS: The mean change in UAS7 (range, 0 to 42) for acupuncture from baseline (mean score, 23.5 [95% CI, 21.8 to 25.2]) to week 4 (mean score, 15.3 [CI, 13.6 to 16.9]) was -8.2 (CI, -9.9 to -6.6). The mean changes in UAS7 for sham acupuncture and waitlist control from baseline (mean scores, 21.9 [CI, 20.2 to 23.6] and 22.1 [CI, 20.4 to 23.8], respectively) to week 4 (mean scores, 17.8 [CI, 16.1 to 19.5] and 20.0 [CI, 18.3 to 21.6], respectively) were -4.1 (CI, -5.8 to -2.4) and -2.2 (CI, -3.8 to -0.5), respectively. The mean differences between acupuncture and sham acupuncture and waitlist control were -4.1 (CI, -6.5 to -1.8) and -6.1 (CI, -8.4 to -3.7), respectively, which did not meet the threshold for minimal clinically important difference. Fifteen participants (13.6%) in the acupuncture group and none in the other groups reported adverse events. Adverse events were mild or transient. LIMITATION: Lack of complete blinding, self-reported outcomes, limited generalizability because antihistamine use was disallowed, and short follow-up period. CONCLUSION: Compared with sham acupuncture and waitlist control, acupuncture produced a greater improvement in UAS7, although the difference from control was not clinically significant. Increased adverse events were mild or transient. PRIMARY FUNDING SOURCE: The National Key R&D Program of China and the Science and Technology Department of Sichuan Province.

A Social Media-Based Mindfulness Psycho-Behavioral Intervention (MCARE) for Patients With Acute Coronary Syndrome: Randomized Controlled Trial.

BACKGROUND: Psychological distress is common among patients with acute coronary syndrome (ACS) and has considerable adverse impacts on disease progression and health outcomes. Mindfulness-based intervention is a promising complementary approach to address patients' psychological needs and promote holistic well-being. OBJECTIVE: This study aims to examine the effects of a social media-based mindfulness psycho-behavioral intervention (MCARE) on psychological distress, psychological stress, health-related quality of life (HRQoL), and cardiovascular risk factors among patients with ACS. METHODS: This study was a 2-arm, parallel-group randomized controlled trial. We recruited 178 patients (mean age 58.7, SD 8.9 years; 122/178, 68.5% male) with ACS at 2 tertiary hospitals in Jinan, China. Participants were randomly assigned to the MCARE group (n=89) or control group (n=89). The 6-week intervention consisted of 1 face-to-face session (phase I) and 5 weekly WeChat (Tencent Holdings Ltd)-delivered sessions (phase II) on mindfulness training and health education and lifestyle modification. The primary outcomes were depression and anxiety. Secondary outcomes included psychological stress, HRQoL, and cardiovascular risk factors (ie, smoking status, physical activity, dietary behavior, BMI, blood pressure, blood lipids, and blood glucose). Outcomes were measured at baseline (T0), immediately after the intervention (T1), and 12 weeks after the commencement of the intervention (T2). RESULTS: The MCARE group showed significantly greater reductions in depression (T1: ß=-2.016, 95% CI -2.584 to -1.449, Cohen d=-1.28, P<.001; T2: ß=-2.089, 95% CI -2.777 to -1.402, Cohen d=-1.12, P<.001) and anxiety (T1: ß=-1.024, 95% CI -1.551 to -0.497, Cohen d=-0.83, P<.001; T2: ß=-0.932, 95% CI -1.519 to -0.346, Cohen d=-0.70, P=.002). Significantly greater improvements were also observed in psychological stress (ß=-1.186, 95% CI -1.678 to -0.694, Cohen d=-1.41, P<.001), physical HRQoL (ß=0.088, 95% CI 0.008-0.167, Cohen d=0.72, P=.03), emotional HRQoL (ß=0.294, 95% CI 0.169-0.419, Cohen d=0.81, P<.001), and general HRQoL (ß=0.147, 95% CI 0.070-0.224, Cohen d=1.07) at T1, as well as dietary behavior (ß=0.069, 95% CI 0.003-0.136, Cohen d=0.75, P=.04), physical activity level (ß=177.542, 95% CI -39.073 to 316.011, Cohen d=0.51, P=.01), and systolic blood pressure (ß=-3.326, 95% CI -5.928 to -0.725, Cohen d=-1.32, P=.01) at T2. The overall completion rate of the intervention (completing ≥5 sessions) was 76% (68/89). Positive responses to the questions of the acceptability questionnaire ranged from 93% (76/82) to 100% (82/82). CONCLUSIONS: The MCARE program generated favorable effects on psychological distress, psychological stress, HRQoL, and several aspects of cardiovascular risk factors in patients with ACS. This study provides clues for guiding clinical practice in the recognition and management of psychological distress and integrating the intervention into routine rehabilitation practice. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000033526; https://www.chictr.org.cn/showprojEN.html?proj=54693.

Selection on the promoter regions plays an important role in complex traits during duck domestication.

BACKGROUND: Identifying the key factors that underlie complex traits during domestication is a great challenge for evolutionary and biological studies. In addition to the protein-coding region differences caused by variants, a large number of variants are located in the noncoding regions containing multiple types of regulatory elements. However, the roles of accumulated variants in gene regulatory elements during duck domestication and economic trait improvement are poorly understood. RESULTS: We constructed a genomics, transcriptomics, and epigenomics map of the duck genome and assessed the evolutionary forces that have been in play across the whole genome during domestication. In total, 304 (42.94%) gene promoters have been specifically selected in Pekin duck among all selected genes. Joint multi-omics analysis reveals that 218 genes (72.01%) with selected promoters are located in open and active chromatin, and 267 genes (87.83%) with selected promoters were highly and differentially expressed in domestic trait-related tissues. One important candidate gene ELOVL3, with a strong signature of differentiation on the core promoter region, is known to regulate fatty acid elongation. Functional experiments showed that the nearly fixed variants in the top selected ELOVL3 promoter in Pekin duck decreased binding ability with HLF and increased gene expression, with the overexpression of ELOVL3 able to increase lipid deposition and unsaturated fatty acid enrichment. CONCLUSIONS: This study presents genome resequencing, RNA-Seq, Hi-C, and ATAC-Seq data of mallard and Pekin duck, showing that selection of the gene promoter region plays an important role in gene expression and phenotypic changes during domestication and highlights that the variants of the ELOVL3 promoter may have multiple effects on fat and long-chain fatty acid content in ducks.

Transcriptome analysis revealed the existence of family-specific regulation of growth traits in grass carp.

The grass carp (Ctenopharyngodon idella) is the world's most prolific freshwater fish. Little is known, however, about the functional genes and genetic regulatory networks that govern its growth traits. We created three grass carp families in this study by using two grass carp parents with fast-growing offspring and two grass carp parents with slow-growing offspring, namely the fast-growing × fast-growing family (FF), the slow-growing × slow-growing family (SS), and the fast-growing × slow-growing family (FS). Under the satiation and starvation feeding modes, the average body weight of these families' offspring exhibited a consistent ordering (FF > FS > SS). The transcriptomes of grass carp whole brain and hepatopancreas were then acquired for each family, and it was discovered that the number of differentially expressed genes (DEGs) in the different organs demonstrated family specificity. DEGs were mostly identified in the hepatopancreas of FF and the whole brain of SS, but they were more evenly distributed in FS. There were 14 DEGs that were found in all three families, including three that were negatively correlated in hepatopancreas (ahsg2, lect2) or in brain (drd5), and 11 that were positively connected in hepatopancreas (sycn, pabpc4, zgc:112294, cel, endou, ela2, prss3, zbtb41, ela3) or in brain (fabp7, endod1). The deletion of ahsg2 boosted the growth rate only in certain zebrafish, suggesting that the growth-promoting effects of ahsg2 varies among individuals. Furthermore, we examined the SNP in each family and conducted preliminary research on the probable genetic pathways of family-specific control of growth traits. The family specificity of the growth regulation mechanism of grass carp at the transcriptional level was revealed for the first time in this study, and it was discovered that growth differences among individuals in the FF family were primarily due to differences in nutrient metabolism, whereas growth differences among individuals in the SS family may be primarily due to differences in foraging ability caused by differences in brain development. This research adds to our understanding of the genetic regulatory mechanism of grass carp growth.

Exploration of decision aids to support advance care planning: A scoping review.

BACKGROUND: Advance care planning is a process through which people communicate their goals and preferences for future medical care. Due to the complexity of the decision-making process, decision aids can assist individuals in balancing potential benefits and risks of treatment options. OBJECTIVE: While decision aids have the potential to better promote advance care planning, their characteristics, content and application effectiveness are unclear and lack systematic review. Therefore, we aimed to explore these three aspects and establish a foundation for future research. DESIGN: Scoping review. METHODS: This scoping review adheres to the framework proposed by Arksey and O'Malley and the PRISMA-ScR list. Six English-language databases were systematically searched from the time of construction until 1 December 2023. Two researchers conducted the article screening and data extraction, and the extracted data was presented in written tables and narrative summaries. RESULTS: Of the 1479 titles and abstracts, 20 studies fulfilled the inclusion criteria. Types of decision aids were employed, mainly websites and videos. Decision aid's primary components center around 11 areas, such as furnishing information, exploring treatment and care preferences. The main manifestations were a significant increase in knowledge and improved recognition of patients' target value preferences. Among the aids, websites and videos for advance care planning have relatively high content acceptability and decision-making process satisfaction, but their feasibility has yet to be tested. CONCLUSIONS: Decision aids were varied, with content focused on describing key information and exploring treatment and care preferences. Regarding application effects, the aids successfully facilitated the advance care planning process and improved the quality of participants' decisions. Overall, decision aids are efficient in improving the decision-making process for implementing advance care planning in cancer and geriatric populations. In the future, personalised decision aids should be developed based on continuous optimization of tools' quality and promoted for clinical application. REPORTING METHOD: The paper has adhered to the EQUATOR guidelines and referenced the PRISMAg-ScR checklist. NO PATIENT OR PUBLIC CONTRIBUTION: This is a review without patient and public contribution. REGISTRATION: https://doi.org/10.17605/OSF.IO/YPHKF, Open Science DOI: 10.17605/OSF.IO/YPHKF.

The current perspective and opportunities of small nucleic acid-based therapeutics.

Compared to traditional small molecule and antibody drugs, RNA-based drugs offer a simple design, short research and development cycles, high specificity, broad treatment fields, and long-term efficacy. As a result, RNA-based drugs are extensively used to treat genetic diseases, tumors, viral infections, and other illnesses, suggesting that they have the potential to become the third-largest drug class after small molecule and antibody drugs. Currently, more than 10 small nucleic acid drugs have gained regulatory approval. The commercialization successes of small nucleic acid drugs will stimulate the development of RNA-based drugs. Small nucleic acid drugs primarily target liver diseases, metabolic diseases, genetic diseases, and tumors, and there is also significant potential for expanding indications in the future. This review provides a brief overview of the advantages and development of small nucleic acid-based therapeutics and shows a focus on platform technologies such as chemical modifications and delivery systems that have enabled the clinical translation of small nucleic acid-based therapeutics. Additionally, we summarize the latest clinical progress in small nucleic acid-based therapeutics for the treatment of various diseases, including rare diseases, liver diseases, metabolic diseases, and tumors. Finally, we highlight the future prospects for this promising treatment approach.

Unraveling the Molecular Basis of Color Variation in Dioscorea alata Tubers: Integrated Transcriptome and Metabolomics Analysis.

Dioscorea alata L. (Dioscoreaceae) is a widely cultivated tuber crop with variations in tuber color, offering potential value as health-promoting foods. This study focused on the comparison of D. alata tubers possessing two distinct colors, white and purple, to explore the underlying mechanisms of color variation. Flavonoids, a group of polyphenols known to influence plant color and exhibit antioxidant properties, were of particular interest. The total phenol and total flavonoid analyses revealed that purple tubers (PTs) have a significantly higher content of these metabolites than white tubers (WTs) and a higher antioxidant activity than WTs, suggesting potential health benefits of PT D. alata. The transcriptome analysis identified 108 differentially expressed genes associated with the flavonoid synthesis pathway, with 57 genes up-regulated in PTs, including CHS, CHI, DFR, FLS, F3H, F3'5'H, LAR, ANS, and ANR. The metabolomics analysis demonstrated that 424 metabolites, including 104 flavonoids and 8 tannins, accumulated differentially in PTs and WTs. Notably, five of the top ten up-regulated metabolites were flavonoids, including 6-hydroxykaempferol-7-O-glucoside, pinocembrin-7-O-(6″-O-malonyl)glucoside, 6-hydroxykaempferol-3,7,6-O-triglycoside, 6-hydroxykaempferol-7-O-triglycoside, and cyanidin-3-O-(6″-O-feruloyl)sophoroside-5-O-glucoside, with the latter being a precursor to anthocyanin synthesis. Integrating transcriptome and metabolomics data revealed that the 57 genes regulated 20 metabolites within the flavonoid synthesis pathway, potentially influencing the tubers' color variation. The high polyphenol content and antioxidant activity of PTs indicate their suitability as nutritious and health-promoting food sources. Taken together, the findings of this study provide insights into the molecular basis of tuber color variation in D. alata and underscore the potential applications of purple tubers in the food industry and human health promotion. The findings contribute to the understanding of flavonoid biosynthesis and pigment accumulation in D. alata tubers, opening avenues for future research on enhancing the nutritional quality of D. alata cultivars.