Self S-RNase inhibits ABF-LRX signaling to arrest pollen tube growth to achieve self-incompatibility in pear.

Gametophytic self-incompatibility (GSI) has been widely studied in flowering plants, but studies of the mechanisms underlying pollen tube growth arrest by self S-RNase in GSI species are limited. In the present study, two leucine-rich repeat extensin genes in pear (Pyrus bretschneideri), PbLRXA2.1 and PbLRXA2.2, were identified based on transcriptome and quantitative real-time PCR analyses. The expression levels of these two LRX genes were significantly higher in the pollen grains and pollen tubes of the self-compatible cultivar 'Jinzhui' (harboring a spontaneous bud mutation) than in those of the self-incompatible cultivar 'Yali'. Both PbLRXA2.1 and PbLRXA2.2 stimulated pollen tube growth and attenuated the inhibitory effects of self S-RNase on pollen tube growth by stabilizing the actin cytoskeleton and enhancing cell wall integrity. These results indicate that abnormal expression of PbLRXA2.1 and PbLRXA2.2 is involved in the loss of self-incompatibility in 'Jinzhui'. The PbLRXA2.1 and PbLRXA2.2 promoters were directly bound by the ABRE-binding factor PbABF.D.2. Knockdown of PbABF.D.2 decreased PbLRXA2.1 and PbLRXA2.2 expression and inhibited pollen tube growth. Notably, the expression of PbLRXA2.1, PbLRXA2.2, and PbABF.D.2 was repressed by self S-RNase, suggesting that self S-RNase can arrest pollen tube growth by restricting the PbABF.D.2-PbLRXA2.1/PbLRXA2.2 signal cascade. These results provide novel insight into pollen tube growth arrest by self S-RNase.

Persistence of antibodies 5 years after hepatitis B vaccination in preterm birth children: A retrospective cohort study using real-world data.

Previous studies did not provide substantial evidence for long-term immune persistence after the hepatitis B vaccine (HepB) in preterm birth (PTB) children. Consequently, there is ongoing controversy surrounding the booster immunization strategy for these children. Therefore, we conducted a retrospective cohort study to evaluate the disparities in immune persistence between PTB children and full-term children. A total of 1027 participants were enrolled in this study, including 505 PTB children in the exposure group and 522 full-term children in the control group. The negative rate of hepatitis B surface antibody (HBsAb) in the PTB group was significantly lower than that in the control group (47.9% vs. 41.4%, p = .035). The risk of HBsAb-negative in the exposure group was 1.5 times higher than that in the control group (adjusted odds ratio [aOR] = 1.5, 95% confidence interval [CI]: 1.1-2.0). The geometric mean concentration (GMC) of HBsAb was much lower for participants in the exposure group compared to participants in the control group (9.3 vs. 12.4 mIU/mL, p = .029). Subgroup analysis showed that the very preterm infants (gestational age <32 weeks) and the preterm low birth weight infants (birth weight <2000 g) had relatively low GMC levels of 3.2 mIU/mL (95% CI: 0.9-11.1) and 7.9 mIU/mL (95% CI: 4.2-14.8), respectively. Our findings demonstrated that PTB had a significant impact on the long-term persistence of HBsAb after HepB vaccination. The very preterm infants (gestational age <32 weeks) and the preterm low birth weight infants (birth weight <2000 g) may be special populations that should be given priority for HepB booster vaccination.

Cardiovascular health metrics defined by Life's Essential 8 scores and subsequent macrovascular and microvascular complications in individuals with type 2 diabetes: A prospective cohort study.

AIM: To investigate the association between cardiovascular health metrics defined by Life's Essential 8 (LE8) scores and vascular complications among individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: This prospective study included 11 033 participants with T2D, all devoid of macrovascular diseases (including cardiovascular and peripheral artery disease) and microvascular complications (e.g. diabetic retinopathy, neuropathy and nephropathy) at baseline from the UK Biobank. The LE8 score comprised eight metrics: smoking, body mass index, physical activity, non-high-density lipoprotein cholesterol, blood pressure, glycated haemoglobin, diet and sleep duration. Cox proportional hazards models were established to assess the associations of LE8 scores with incident macrovascular and microvascular complications. RESULTS: During a median follow-up of 12.1 years, we identified 1975 cases of incident macrovascular diseases and 1797 cases of incident microvascular complications. After adjusting for potential confounders, each 10-point increase in the LE8 score was associated with an 18% lower risk of macrovascular diseases and a 15% lower risk of microvascular complications. Comparing individuals in the highest and lowest quartiles of LE8 scores revealed hazard ratios of 0.55 (95% confidence interval 0.47-0.62) for incident macrovascular diseases, and 0.61 (95% confidence interval 0.53-0.70) for incident microvascular complications. This association remained robust across a series of sensitivity analyses and nearly all subgroups. CONCLUSION: Higher LE8 scores were associated with a lower risk of incident macrovascular and microvascular complications among individuals with T2D. These findings underscore the significance of adopting fundamental strategies to maintain optimal cardiovascular health and curtail the risk of developing diabetic vascular complications.

Upregulated LncRNA H19 Sponges MiR-106a-5p and Contributes to Aldosterone-Induced Vascular Calcification via Activating the Runx2-Dependent Pathway.

BACKGROUND: Excess aldosterone is implicated in vascular calcification (VC), but the mechanism by which aldosterone-MR (mineralocorticoid receptor) complex promotes VC is unclear. Emerging evidence indicates that long-noncoding RNA H19 (H19) plays a critical role in VC. We examined whether aldosterone-induced osteogenic differentiation of vascular smooth muscle cells (VSMCs) through H19 epigenetic modification of Runx2 (runt-related transcription factor-2) in a MR-dependent manner. METHODS: We induced in vivo rat model of chronic kidney disease using a high adenine and phosphate diet to explore the relationship among aldosterone, MR, H19, and VC. We also cultured human aortic VSMCs to explore the roles of H19 in aldosterone-MR complex-induced osteogenic differentiation and calcification of VSMCs. RESULTS: H19 and Runx2 were significantly increased in aldosterone-induced VSMC osteogenic differentiation and VC, both in vitro and in vivo, which were significantly blocked by the MR antagonist spironolactone. Mechanistically, our findings reveal that the aldosterone-activated MR bound to H19 promoter and increased its transcriptional activity, as determined by chromatin immunoprecipitation, electrophoretic mobility shift assay, and luciferase reporter assay. Silencing H19 increased microRNA-106a-5p (miR-106a-5p) expression, which subsequently inhibited aldosterone-induced Runx2 expression at the posttranscriptional level. Importantly, we observed a direct interaction between H19 and miR-106a-5p, and downregulation of miR-106a-5p efficiently reversed the suppression of Runx2 induced by H19 silencing. CONCLUSIONS: Our study clarifies a novel mechanism by which upregulation of H19 contributes to aldosterone-MR complex-promoted Runx2-dependent VSMC osteogenic differentiation and VC through sponging miR-106a-5p. These findings highlight a potential therapeutic target for aldosterone-induced VC.

Economic Evaluation of an Enhanced Post-Discharge Home-Based Care Program for Stroke Survivors.

OBJECTIVES: To examine the cost-effectiveness of an enhanced postdischarge home-based care program for stroke survivors compared with usual care. METHODS: This was a trial-based economic evaluation study. One hundred and sixteen patients with ischemic stroke were recruited from neurology units in a Chinese hospital and randomized into intervention (n = 58) or usual care groups (n = 58). The intervention commenced with predischarge planning and transitioned to home follow-up postdischarge. Trained nurse case managers supported by an interdisciplinary team provided comprehensive assessment, individualized goal setting, and skill training to support home-based rehabilitation for intervention group participants. Standard care was provided to usual care group participants. Total cost and quality-adjusted life-years gained at 3-month (T1), 6-month (T2), and 12-month (T3) follow-ups were calculated. The incremental cost-effectiveness ratios between the groups were obtained. RESULTS: The intervention group showed a significant increase in utility compared with the usual care group at T1 (P = .003), T2 (P = .007), and T3 (P < .001). The average total QALY gain from baseline for the intervention group was higher than for the usual care group at all time points. The likelihood of being cost-effective ranged from 61.9% to 67.2% from the provider perspective, and from 59.7% to 66.8% from the societal perspective. CONCLUSIONS: The results showed that the intervention program was cost-effective with significantly higher quality-adjusted life-years for stroke survivors when compared with usual care. It provides economic evidence to support the development of home-based stroke rehabilitation program, especially in the low- and middle-income countries.

Low mental health literacy is associated with depression and anxiety among adults: a population-based survey of 16,715 adults in China.

BACKGROUND: Mental health literacy is a predictor of health outcomes in psychological distress. However, limited research has explored whether low mental health literacy is associated with recent depression and anxiety. METHODS: We used data from the Guangdong Mental Health Survey, a provincial representative and a population-based survey with a multistage stratified cluster random sampling method. We included adults aged 18 and above living in communities from September to December 2021 in Guangdong, China. Eligible participants were those who completed the mental health literacy questionnaire and assessments for depression and anxiety symptoms. We assessed the proportion of individuals with low mental health literacy by categories of psychological symptoms and whether low mental health literacy was associated with depressive and anxiety symptoms in the general population and subgroups. RESULTS: A total of 16,715 adults were included. We found that individuals with more severe symptoms had a greater proportion of low mental health literacy- it went from 89.4% in participants without depression or anxiety to 96.2% in people who co-occurred with depression and anxiety (x2 = 21.457, P < 0.001). After controlling confounders, low mental health literacy was associated with depression (adjusted Odds Ratio, aOR [95%CI]:2.74 [1.92-4.04]) and anxiety (2.27 [1.49-3.64]) in the total sample, when compared with adequate mental health literacy. CONCLUSIONS: This study found a positive association between low mental health literacy and the presence of depression and anxiety. Tackling inadequate mental health literacy may be a key strategy to promote psychological well-being across the lifespan, especially for young adults.

Effect of comprehensive nursing intervention on the quality of life and clinical outcomes of patients with thyroid nodules treated by ultrasound-guided microwave ablation.

Objective: To evaluate the effects of comprehensive nursing intervention on the quality of life and clinical outcomes of patients with thyroid nodules treated by ultrasound-guided microwave ablation. Methods: This was a prospective study conducted from December 2020 to December 2022 at The Fifth Medical Center of Chinese PLA General Hospital. One hundred and twenty patients with benign thyroid nodules undergoing microwave ablation were included. Patients were randomly divided into control group and experimental group. Patients in the control group were given conventional intervention mode during the perioperative period, while those in the experimental group were given comprehensive nursing intervention mode on the basis of the control group. The differences in quality of life, cognitive level before and after intervention and satisfaction between the two groups were compared and analyzed. Results: The SF-36 scores in the experimental group were significantly higher than that in the control group after intervention. After the intervention, the SAS and SDS scores in the experimental group were significantly lower than those in the control group, with a statistically significant difference. The VAS scores in the experimental group were better than those in the control group at six, twelve and twenty four hour after operation, with statistically significant differences. After the intervention, the cognitive score of the experimental group was significantly higher than that of the control group. Conclusion: Comprehensive nursing intervention is worthy of clinical promotion in the treatment of patients with thyroid nodules treated by ultrasound-guided microwave ablation, leading to various benefits such as effectively improving patients' quality of life and relieving pain.

Hedgehog interacting protein activates sodium-glucose cotransporter 2 expression and promotes renal tubular epithelial cell senescence in a mouse model of type 1 diabetes.

AIMS/HYPOTHESIS: Senescent renal tubular cells may be linked to diabetic kidney disease (DKD)-related tubulopathy. We studied mice with or without diabetes in which hedgehog interacting protein (HHIP) was present or specifically knocked out in renal tubules (HhipRT-KO), hypothesising that local deficiency of HHIP in the renal tubules would attenuate tubular cell senescence, thereby preventing DKD tubulopathy. METHODS: Low-dose streptozotocin was employed to induce diabetes in both HhipRT-KO and control (Hhipfl/fl) mice. Transgenic mice overexpressing Hhip in renal proximal tubular cells (RPTC) (HhipRPTC-Tg) were used for validation, and primary RPTCs and human RPTCs (HK2) were used for in vitro studies. Kidney morphology/function, tubular senescence and the relevant molecular measurements were assessed. RESULTS: Compared with Hhipfl/fl mice with diabetes, HhipRT-KO mice with diabetes displayed lower blood glucose levels, normalised GFR, ameliorated urinary albumin/creatinine ratio and less severe DKD, including tubulopathy. Sodium-glucose cotransporter 2 (SGLT2) expression was attenuated in RPTCs of HhipRT-KO mice with diabetes compared with Hhipfl/fl mice with diabetes. In parallel, an increased tubular senescence-associated secretory phenotype involving release of inflammatory cytokines (IL-1ß, IL-6 and monocyte chemoattractant protein-1) and activation of senescence markers (p16, p21, p53) in Hhipfl/fl mice with diabetes was attenuated in HhipRT-KO mice with diabetes. In contrast, HhipRPTC-Tg mice had increased tubular senescence, which was inhibited by canagliflozin in primary RPTCs. In HK2 cells, HHIP overexpression or recombinant HHIP increased SGLT2 protein expression and promoted cellular senescence by targeting both ataxia-telangiectasia mutated and ataxia-telangiectasia and Rad3-related-mediated cell arrest. CONCLUSIONS/INTERPRETATION: Tubular HHIP deficiency prevented DKD-related tubulopathy, possibly via the inhibition of SGLT2 expression and cellular senescence.

Different Metabolic Phenotypes of Obesity and Risk of Coronary Artery Calcium Progression and Incident Cardiovascular Disease Events: The CARDIA Study.

BACKGROUND: To investigate whether obesity with or without metabolic syndrome is prospectively associated with coronary artery calcium (CAC) progression and incident cardiovascular disease events. METHODS: A total of 1730 participants from the CARDIA study (Coronary Artery Risk Development in Young Adults) were included (age, 40.1±3.6 years; 38.3% men), who completed computed tomography of CAC at baseline (year 15: 2000-2001) and follow-up (year 20 or 25). Metabolically healthy obesity (MHO) was defined as body mass index≥30 kg/m2 without any metabolic syndrome components in our main analysis. Sensitivity analyses were conducted for several conditions characterizing 4 metabolic phenotypes. RESULTS: During a mean follow-up of 9.1 years, 439 participants had CAC progression. MHO subjects had a significantly higher risk of CAC progression than their metabolically healthy normal weight counterparts (adjusted hazard ratios [95% CIs] from 1.761 [1.369-2.264] to 2.047 [1.380-3.036]) depending on the definition of MHO adopted. Obesity with unhealthy metabolic profile remained the highest significant risk of CAC progression and cardiovascular disease events whatever the definitions adopted for metabolically unhealthy status. Up to 60% of participants with MHO converted to metabolically unhealthy obesity from year 15 to year 20 or year 25. Further sensitivity analysis showed that MHO throughout carried a similar risk of incident cardiovascular disease events compared with metabolically healthy normal weight throughout. CONCLUSIONS: Different metabolic phenotypes of obesity beginning at a young age exhibit distinct risks of CAC progression and subsequent cardiovascular disease events in later midlife. MHO represents an intermediate phenotype between metabolically low- to high-risk obese individuals. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00005130.

Fish Rhbdd3 positively regulates IFN response through RIG-I signaling pathway.

Rhomboid domain-containing protein 3 (Rhbdd3) is a member of the rhomboid family, which can modulate the innate immune response in mammals. Nonetheless, the function and regulatory mechanism of fish Rhbdd3 during viral infection have not been characterized. In this study, Rhbdd3 was firstly cloned from common carp (Cyprinus carpio) and nominated as CcRhbdd3. Phylogenetically characterization showed that CcRhbdd3 shared a relatively long evolutionary distance with its mammalian homologs. In vivo experiment demonstrated that spring viraemia of carp virus (SVCV) infection promoted the expression of CcRhbdd3 in the liver, spleen, kidney and muscle tissues. Furthermore, overexpression of CcRhbdd3 significantly inhibited SVCV propagation, whereas knockdown of CcRhbdd3 markedly promoted SVCV replication in susceptible cells. RNA-seq and following validation showed that CcRhbdd3 overexpression upregulated the expression of several RIG-I signaling related genes, including TRIM25, TRAF2, MDA5, LGP2, IFN1, IFN3, RIG-I, IRF3 and ISG15. Moreover, CcRhbdd3 promoted the expression of NF-κB, a central immune regulator. Subcellular localization experiments showed that CcRhbdd3 was primarily distributed in the cytoplasm and co-localized with Rab5 in the early endosomes. Truncation experiments further demonstrated that the C-terminus containing the ubiquitin-binding associated domain, was crucial for both the subcellular localization and antiviral activity of CcRhbdd3. The findings in this study provide new insight into the host antiviral mechanism against aquatic RNA virus infection, and will facilitate the development of therapeutic strategies for the infection of SVCV.

Whey protein powder with milk fat globule membrane attenuates Alzheimer's disease pathology in 3×Tg-AD mice by modulating neuroinflammation through the peroxisome proliferator-activated receptor γ signaling pathway.

Whey protein powder (PP), which is mainly derived from bovine milk, is rich in milk fat globule membrane (MFGM). The MGFM has been shown to play a role in promoting neuronal development and cognition in the infant brain. However, its role in Alzheimer's disease (AD) has not been elucidated. Here, we showed that the cognitive ability of 3×Tg-AD mice (a triple-transgenic mouse model of AD) could be improved by feeding PP to mice for 3 mo. In addition, PP ameliorated amyloid peptide deposition and tau hyperphosphorylation in the brains of AD mice. We found that PP could alleviate AD pathology by inhibiting neuroinflammation through the peroxisome proliferator-activated receptor γ (PPARγ)-nuclear factor-κB signaling pathway in the brains of AD mice. Our study revealed an unexpected role of PP in regulating the neuroinflammatory pathology of AD in a mouse model.

Learning from multiple annotators for medical image segmentation.

Supervised machine learning methods have been widely developed for segmentation tasks in recent years. However, the quality of labels has high impact on the predictive performance of these algorithms. This issue is particularly acute in the medical image domain, where both the cost of annotation and the inter-observer variability are high. Different human experts contribute estimates of the "actual" segmentation labels in a typical label acquisition process, influenced by their personal biases and competency levels. The performance of automatic segmentation algorithms is limited when these noisy labels are used as the expert consensus label. In this work, we use two coupled CNNs to jointly learn, from purely noisy observations alone, the reliability of individual annotators and the expert consensus label distributions. The separation of the two is achieved by maximally describing the annotator's "unreliable behavior" (we call it "maximally unreliable") while achieving high fidelity with the noisy training data. We first create a toy segmentation dataset using MNIST and investigate the properties of the proposed algorithm. We then use three public medical imaging segmentation datasets to demonstrate our method's efficacy, including both simulated (where necessary) and real-world annotations: 1) ISBI2015 (multiple-sclerosis lesions); 2) BraTS (brain tumors); 3) LIDC-IDRI (lung abnormalities). Finally, we create a real-world multiple sclerosis lesion dataset (QSMSC at UCL: Queen Square Multiple Sclerosis Center at UCL, UK) with manual segmentations from 4 different annotators (3 radiologists with different level skills and 1 expert to generate the expert consensus label). In all datasets, our method consistently outperforms competing methods and relevant baselines, especially when the number of annotations is small and the amount of disagreement is large. The studies also reveal that the system is capable of capturing the complicated spatial characteristics of annotators' mistakes.

Liposome-Based Carriers for CRISPR Genome Editing.

The CRISPR-based genome editing technology, known as clustered regularly interspaced short palindromic repeats (CRISPR), has sparked renewed interest in gene therapy. This interest is accompanied by the development of single-guide RNAs (sgRNAs), which enable the introduction of desired genetic modifications at the targeted site when used alongside the CRISPR components. However, the efficient delivery of CRISPR/Cas remains a challenge. Successful gene editing relies on the development of a delivery strategy that can effectively deliver the CRISPR cargo to the target site. To overcome this obstacle, researchers have extensively explored non-viral, viral, and physical methods for targeted delivery of CRISPR/Cas9 and a guide RNA (gRNA) into cells and tissues. Among those methods, liposomes offer a promising approach to enhance the delivery of CRISPR/Cas and gRNA. Liposomes facilitate endosomal escape and leverage various stimuli such as light, pH, ultrasound, and environmental cues to provide both spatial and temporal control of cargo release. Thus, the combination of the CRISPR-based system with liposome delivery technology enables precise and efficient genetic modifications in cells and tissues. This approach has numerous applications in basic research, biotechnology, and therapeutic interventions. For instance, it can be employed to correct genetic mutations associated with inherited diseases and other disorders or to modify immune cells to enhance their disease-fighting capabilities. In summary, liposome-based CRISPR genome editing provides a valuable tool for achieving precise and efficient genetic modifications. This review discusses future directions and opportunities to further advance this rapidly evolving field.

Interaction of RIPK1 and A20 modulates MAPK signaling in murine acetaminophen toxicity.

Acetaminophen (APAP)-induced liver necrosis is a form of regulated cell death (RCD) in which APAP activates the mitogen-activated protein kinases (MAPKs) and specifically the c-Jun-N-terminal kinase (JNK) pathway, leading to necrotic cell death. Previously, we have shown that receptor interacting protein kinase-1 (RIPK1) knockdown is also protective against APAP RCD upstream of JNK. However, whether the kinase or platform function of RIPK1 is involved in APAP RCD is not known. To answer this question, we used genetic mouse models of targeted hepatocyte RIPK1 knockout (RIPK1HepCKO) or kinase dead knock-in (RIPK1D138N) and adult hepatocyte specific knockout of the cytoprotective protein A20 (A20HepCKO), known to interact with RIPK1, to study its potential involvement in MAPK signaling. We observed no difference in injury between WT and RIPK1D138N mice post APAP. However, RIPK1HepCKO was protective. We found that RIPK1HepCKO mice had attenuated pJNK activation, while A20 was simultaneously upregulated. Conversely, A20HepCKO markedly worsened liver injury from APAP. Mechanistically, we observed a significant upregulation of apoptosis signal-regulating kinase 1 (ASK1) and increased JNK activation in A20HepCKO mice compared with littermate controls. We also demonstrated that A20 coimmunoprecipitated (co-IP) with both RIPK1 and ASK1, and that in the presence of RIPK1, there was less A20-ASK1 association than in its absence. We conclude that the kinase-independent platform function of RIPK1 is involved in APAP toxicity. Adult RIPK1HepCKO mice are protected against APAP by upregulating A20 and attenuating JNK signaling through ASK1, conversely, A20HepCKO worsens injury from APAP.

Angiotensin II type-2-receptor stimulation ameliorates focal and segmental glomerulosclerosis in mice.

Podocyte damage and loss are the early event in the development of focal segmental glomerulosclerosis (FSGS). Podocytes express angiotensin II type-2-receptor (AT2R), which may play a key role in maintaining kidney integrity and function. Here, we examined the effects of AT2R deletion and AT2R agonist compound 21 (C21) on the evolution of FSGS. FSGS was induced by adriamycin (ADR) injection in both male wild-type (WT) and AT2R knockout (KO) mice. C21 was administered to WT-FSGS mice either one day before or 7 days after ADR (Pre-C21 or Post-C21), using two doses of C21 at either 0.3 (low dose, LD) or 1.0 (high dose, HD) mg/kg/day. ADR-induced FSGS was more severe in AT2RKO mice compared with WT-FSGS mice, and included profound podocyte loss, glomerular fibrosis, and albuminuria. Glomerular cathepsin L expression increased more in AT2RKO-FSGS than in WT-FSGS mice. C21 treatment ameliorated podocyte injury, most significantly in the Pre C21-HD group, and inhibited glomerular cathepsin L expression. In vitro, Agtr2 knock-down in mouse podocyte cell line given ADR confirmed the in vivo data. Mechanistically, C21 inhibited cathepsin L expression, which protected synaptopodin from destruction and stabilized actin cytoskeleton. C21 also prevented podocyte apoptosis. In conclusion, AT2R activation by C21 ameliorated ADR-induced podocyte injury in mice by the inhibition of glomerular cathepsin L leading to the maintenance of podocyte integrity and prevention of podocyte apoptosis.

Inhibitory regulation of calcium transients in prefrontal dendritic spines is compromised by a nonsense Shank3 mutation.

The SHANK3 gene encodes a postsynaptic scaffold protein in excitatory synapses, and its disruption is implicated in neurodevelopmental disorders such as Phelan-McDermid syndrome, autism spectrum disorder, and schizophrenia. Most studies of SHANK3 in the neocortex and hippocampus have focused on disturbances in pyramidal neurons. However, GABAergic interneurons likewise receive excitatory inputs and presumably would also be a target of constitutive SHANK3 perturbations. In this study, we characterize the prefrontal cortical microcircuit in awake mice using subcellular-resolution two-photon microscopy. We focused on a nonsense R1117X mutation, which leads to truncated SHANK3 and has been linked previously to cortical dysfunction. We find that R1117X mutants have abnormally elevated calcium transients in apical dendritic spines. The synaptic calcium dysregulation is due to a loss of dendritic inhibition via decreased NMDAR currents and reduced firing of dendrite-targeting somatostatin-expressing (SST) GABAergic interneurons. Notably, upregulation of the NMDAR subunit GluN2B in SST interneurons corrects the excessive synaptic calcium signals and ameliorates learning deficits in R1117X mutants. These findings reveal dendrite-targeting interneurons, and more broadly the inhibitory control of dendritic spines, as a key microcircuit mechanism compromised by the SHANK3 dysfunction.

Low-Carbohydrate Diet Score and Coronary Artery Calcium Progression: Results From the CARDIA Study.

OBJECTIVE: To investigate whether low-carbohydrate diets (LCDs) were associated with coronary artery calcium (CAC) progression. Approach and Results: We included the participants who completed computed tomography assessment of baseline CAC in 2000 to 2001 (year 15) and follow-up (year 20 or 25) and food frequency questionnaire (years 0, 7, and 20) in the CARDIA study (Coronary Artery Risk Development in Young Adults). CAC progression was defined as CAC >0 at follow-up among participants with baseline CAC of 0 and an annualized change of 10 or percent change of ≥10% for those with 0

Effects of a transitional home-based care program for stroke survivors in Harbin, China: a randomized controlled trial.

BACKGROUND: China has the biggest stroke burden in the world. Continued measures have been taken to enhance post-stroke rehabilitation management in the last two decades. The weak link is with home-based rehabilitation, with more attention and resources devoted to inpatient rehabilitation. OBJECTIVE: to address the service gap, this study tested a home-based transitional care model for stroke survivors. METHODS: a randomized controlled trial was conducted from February 2019 to May 2020 in Harbin, China, involving 116 patients with ischemic stroke. The intervention group participants (n = 58, 50%) received a 12-week home-based care program with components of transitional care measures and the national guidelines for facilitating patients to perform home-based exercises with continued monitoring and gradual progression. Control group participants received standard care including medication advice, rehabilitation exercise and one nurse-initiated follow-up call. Data were collected at baseline and after a 90-day (post-intervention) and a 180-day (post-intervention) follow-up. The primary outcome was quality of life (QOL), measured using the EuroQol-Five Dimension 5-Level scale (EQ-5D-5L). RESULTS: both intervention and control groups showed improvement in EQ-5D-5L from baseline to post-intervention (0.66 versus 0.83, P < 0.001) and (0.66 versus 0.77, P < 0.001), respectively, and there was significant group-by-time interaction in EuroQol-Visual Analogue Scale from baseline to post-intervention at 90 days and follow-up at 180 days with the intervention group experiencing better improvement. Similarly, significant interaction effects were also found in the Stroke Impact Symptom scale, self-efficacy and modified Barthel Index. CONCLUSIONS: home-based transitional care was effective in improving QOL, symptoms, self-efficacy and activities of daily living.

Associations of long-term physical activity trajectories with coronary artery calcium progression and cardiovascular disease events: results from the CARDIA study.

OBJECTIVE: The study aimed to assess the associations of physical activity (PA) trajectories across a 25-year span with coronary artery calcium (CAC) progression, and subsequent risk of cardiovascular disease (CVD) events. METHODS: We included 2497 participants from the Coronary Artery Disease Risk Development in Young Adults study who had computed tomography-assessment of CAC at baseline (year 15: 2000-2001) and follow-up (year 20 or 25) and at least three measures of PA from year 0 to year 25. Long-term PA trajectories were determined by latent class modelling using a validated questionnaire. RESULTS: Among the included participants, 1120 (44.9%) were men, 1418 (56.8%) were white, and the mean (SD) age was 40.4 (3.6) years. We identified three distinct PA trajectories based on PA average levels and change patterns: low (below PA guidelines, n=1332; 53.3%); moderate (meeting and slightly over PA guidelines, n=919; 36.8%) and high (about three times PA guidelines or more, n=246; 9.9%). During a mean (SD) follow-up of 8.9 (2.1) years, 640 (25.6%) participants had CAC progression. Participants in the high PA trajectory group had a higher risk of CAC progression than those in the low PA trajectory group after adjustment for traditional cardiovascular risk factors (HR 1.51; 95% CI 1.18 to 1.94). However, high PA trajectory was not associated with an increased risk of incident CVD events (HR 1.01; 95% CI 0.44 to 2.31) and the incidence of CVD events in participants with CAC progression was similar across all three PA trajectory groups (p=0.736). CONCLUSION: Long-term PA about three times the guidelines or more is independently associated with CAC progression; however, no additional risk of incident CVD events could be detected.

Multiple accounting and driving factors of water resources use: A case study of Shanghai.

Previous research papers on urban water resources accounting were confined to the perspectives of production and consumption, ignoring the perspective of income. This paper proposes a systems framework to analyze the income, production, and consumption-based water uses and underlying driving forces of a city based on the methods of multi-scale input-output analysis and structural decomposition analysis. A case study is performed for Shanghai as a megacity. The results show that the income, production and consumption-based water uses of Shanghai had decreased from 5.70 billion m3, 10.85 billion m3 and 28.45 billion m3 in 2007 to 2.80 billion m3, 6.20 billion m3 and 24.10 billion m3 in 2017, respectively. Domestic imported primary inputs had emerged as an important virtual water supplier of Shanghai and its share of total supply-side water use had increased from 23.92% in 2007 to 42.95% in 2017. Meanwhile, about 46% and 40% of Shanghai's total consumption-based water use had been imported from other Chinese regions and foreign countries in 2017, respectively. It is revealed that trade played an important role in relieving water use pressure in Shanghai. The factors that had increased the uses of water resources in Shanghai include population, per capita value-added, per capita output, final consumption structure, and per capita final consumption. The factors that had reduced the water uses in Shanghai include technology, value added mix, output structure, value added structure, domestic import, commodity mix, and foreign import. It is suggested that in addition to curbing urban water use from the production side, more targeted water-saving measures should be devised from the supply (e.g., restricting loan to heavy water-consuming enterprises) and consumption sides (e.g., encouraging residents to buy low-water products).