Progressive alterations of resting-state hypothalamic dysconnectivity in schizophrenia.

BACKGROUND: The hypothalamus may be involved in the pathogenesis of schizophrenia. Investigating hypothalamus dysfunction in schizophrenia and probing how it is related to symptoms and responds to antipsychotic medication is crucial for understanding the potential mechanism of hypothalamus dysfunction under the long-term illness. METHODS: We recruited 216 patients with schizophrenia, including 140 antipsychotic-naïve first-episode patients (FES, including 44 patients with 1-year follow-up data), 76 chronically treated schizophrenia (CTS), and 210 healthy controls (HC). Hypothalamic seed-based functional connectivity (FC) was calculated and compared among the FES, CTS, and HC groups using analysis of covariance. Exploratory analysis was conducted between the FES patients at baseline and after 1-year follow-up. Significantly altered hypothalamic FCs were then related to clinical symptomology, while age- and illness-related regression analyses were also conducted and compared between diagnostic groups. RESULTS: The FES patients showed decreased hypothalamic FCs with the midbrain and right thalamus, whereas the CTS patients showed more severe decreased hypothalamic FCs with the midbrain, right thalamus, left putamen, right caudate, and bilateral anterior cingulate cortex compared to HCs. These abnormalities were not correlated to the symptomology or illness duration, or not reversed by the antipsychotic treatment. Age-related hypothalamic FC decrease was also identified in the abovementioned regions, and a faster age-related decline of the hypothalamic FC was observed with the left putamen and bilateral anterior cingulate cortex. CONCLUSION: Age-related hypothalamic FC decrease extends the functional alterations that characterize the neurodegenerative nature of schizophrenia. Future studies are required to further probe the hormonal or endocrinal underpinnings of such alterations and trace the precise progressive trajectories.

Jiawei Bai-Hu-decoction ameliorated heat stroke-induced brain injury by inhibiting TLR4/NF-κB signal and mitophagy of glial cell.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiawei Bai-Hu-Decoction (JWBHD), a prescription formulated with seven traditional Chinese medicinal material has demonstrated clinical efficacy in mitigating brain injury among heat stroke (HS) patients. AIM OF THE STUDY: This study aimed to evaluate the therapeutic efficacy of JWBHD on rat model of HS and to explore its therapeutic mechanisms by integrating network pharmacology and pharmacodynamic methodologies, which major components were analyzed by using UPLC-MS/MS. MATERIALS AND METHODS: The network pharmacology analysis was firstly conducted to predict the potential active ingredients and therapeutic targets of JWBHD. The anti-HS effectiveness of JWBHD was then evaluated on rats experienced HS. Rat brain tissues were harvested for a comprehensive array of experiments, including Western blot, PCR, H&E staining, Nissl staining, ELISA, transmission electron microscope, flow cytometry and immunofluorescence to validate the protective effects of JWBHD against HS-induced brain damage. Furthermore, the inhibitory effects of JWBHD on TLR4/NF-κB signal and mitophagy of glial were further verified on HS-challenged F98 cell line. Finally, the chemical compositions of the water extract of JWBHD were analyzed by using UPLC-MS/MS. RESULTS: Network pharmacology has identified fifty core targets and numerous HS-related signaling pathways as potential therapeutic targets of JWBHD. Analysis of protein-protein interaction (PPI) and GO suggests that JWBHD may suppress HS-induced inflammatory signals. In experiments conducted on HS-rats, JWBHD significantly reduced the core temperature, restored blood pressure and alleviated neurological defect. Furthermore, JWBHD downregulated the counts of white blood cells and monocytes, decreased the levels of inflammatory cytokines such as IL-1ß, IL-6 and TNF-α in peripheral blood, and suppressed the expression of TLR4 and NF-κB in the cerebral cortex of HS-rats. Besides, JWBHD inhibited the apoptosis of cortical cells and mitigated the damage to the cerebral cortex in HS group. Conversely, overactive mitophagy was observed in the cerebral cortex of HS-rats. However, JWBHD restored the mitochondrial membrane potential and downregulated expressions of mitophagic proteins including Pink1, Parkin, LC3B and Tom20. JWBHD reduced the co-localization of Pink1 and GFAP, a specific marker of astrocytes in the cerebral cortex of HS-rats. In addition, the inhibitory effect of JWBHD on TLR4/NF-κB signaling and overactive mitophagy were further confirmed in F98 cells. Finally, UPLC-MS/MS analysis showed that the main components of JWBHD include isoliquiritigenin, liquiritin, dipotassium glycyrrhizinate, ginsenoside Rb1, ginsenoside Re, etc. CONCLUSIONS: JWBHD protected rats from HS and prevented HS-induced damage in the cerebral cortex by suppressing TLR4/NF-κB signaling and mitophagy of glial.

Comparisons of long-term clinical outcomes with left bundle branch pacing, left ventricular septal pacing, and biventricular pacing for cardiac resynchronization therapy.

BACKGROUND: Left bundle branch pacing (LBBP) and left ventricular septal pacing (LVSP) are referred to as left bundle branch area pacing. OBJECTIVE: This study investigated whether long-term clinical outcomes differ in patients undergoing LBBP, LVSP, and biventricular pacing (BiVP) for cardiac resynchronization therapy (CRT). METHODS: Consecutive patients with reduced left ventricular ejection fraction (LVEF <50%) undergoing CRT were prospectively enrolled if they underwent successful LBBP, LVSP, or BiVP. The primary composite end point was all-cause mortality or heart failure hospitalization. Secondary end points included all-cause mortality, heart failure hospitalization, and echocardiographic measures of reverse remodeling. RESULTS: A total of 259 patients (68 LBBP, 38 LVSP, and 153 BiVP) were observed for a mean duration of 28.8 ± 15.8 months. LBBP was associated with a significantly reduced risk of the primary end point by 78% compared with both BiVP (7.4% vs 41.2%; adjusted hazard ratio [aHR], 0.22 [0.08-0.57]; P = .002) and LVSP (7.4% vs 47.4%; aHR, 0.22 [0.08-0.63]; P = .004]. The adjusted risk of all-cause mortality was significantly higher in LVSP than in BiVP (31.6% vs 7.2%; aHR, 3.19 [1.38-7.39]; P = .007) but comparable between LBBP and BiVP (2.9% vs 7.2%; aHR, 0.33 [0.07-1.52], P = .155). Propensity score adjustment also obtained similar results. LBBP showed a higher rate of echocardiographic response (ΔLVEF ≥10%: 60.0% vs 36.2% vs 16.1%; P < .001) than BiVP or LVSP. CONCLUSION: LBBP yielded long-term clinical outcomes superior to those of BiVP and LVSP. The role of LVSP for CRT needs to be reevaluated because of its high mortality risk.

Anisotropic Magnetic Polymeric Particles with a Controllable Structure via Seeded Emulsion Polymerization.

Magnetic polymer composites have been widely utilized in potential applications in material science, such as reduction of dyes, immunodiagnostics, biomedicals, and magnetically controllable photonic crystals owing to large surface areas, fast separation, and recyclable performance. In this work, anisotropic magnetic particles were prepared by seeded emulsion polymerization, with morphologies of "Fe3O4-shell", "hemisphere-like", "raspberry-like", "multiple lobes-like", and "sandwich-like". Poly(styrene/divinylbenzene/mono-2-(methacryloxy)ethyl succinate)@ Fe3O4 (P(St/DVB/MMES)@Fe3O4) were the seed microspheres, and P(St/DVB/MMES)@Fe3O4@polymer particles are achieved by seeded emulsion polymerizations. The morphology of the particles depends on polymerization conditions (monomer ratios and surfactant), particle properties, and so on. Then, the minimum surface free energy change principles were used to predict the equilibrium morphologies of the magnetic polymer composites. Through theory, the model gives the correct tendency and good agreement with the equilibrium morphology which was in tandem with TEM results. Lastly, after in situ surface deposition of Ag nanoparticles, magnetic composite particles with sandwich-like morphology were applied for the catalytic degradation of 4-nitrophenol (4-NP) reacting with NaBH4. The apparent rate coefficient is 0.0069 s-1, and it can keep mainly about 80% efficiency in catalysis after five cycles.

Validation of the Rome Severity Classification of Chronic Obstructive Pulmonary Disease Exacerbation: A Multicenter Cohort Study.

Background: The Rome severity classification is an objective assessment tool for the severity of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) based on readily measurable variables but has not been widely validated. The aim of this study is to evaluate the validity of the Rome classification in distinguishing the severity of AECOPD based on short-term mortality and other adverse outcomes. Methods: The Rome severity classification was applied to a large multicenter cohort of inpatients with AECOPD. Differences in clinical features, in-hospital and 60-day mortality, intensive care unit (ICU) admission, mechanical ventilation (MV) and invasive mechanical ventilation (IMV) usage were compared among the mild, moderate and severe AECOPD according to the Rome proposal. Moreover, univariate logistic analysis and Kaplan Meier survival analysis were also performed to find the association between the Rome severity classification and those adverse outcomes. Results: A total of 7712 patients hospitalized for AECOPD were included and classified into mild (41.88%), moderate (40.33%), or severe (17.79%) group according to the Rome proposal. The rate of ICU admission (6.4% vs 12.0% vs 14.9%, P <0.001), MV (11.7% vs 33.7% vs 45.3%, P <0.001) and IMV (1.4% vs 6.8% vs 8.9%, P <0.001) increased significantly with the increase of severity classification from mild to moderate to severe AECOPD. The 60-day mortality was higher in the moderate or severe group than in the mild group (3.5% vs 1.9%, 4.3% vs 1.9%, respectively, P <0.05) but showed no difference between the moderate and severe groups (2.6% vs 2.5%, P >0.05), results for in-hospital mortality showed the same trends. Similar findings were observed by univariate logistic analysis and survival analysis. Conclusion: Rome severity classification demonstrated excellent performance in predicting ICU admission and the need for MV or IMV, but how it performs in differentiating short-term mortality still needs to be confirmed.

The mediating role of sleep problems and depressed mood between psychological abuse/neglect and suicidal ideation in adolescent childhood: a multicentred, large sample survey in Western China.

BACKGROUND: Adolescent suicidal ideation are associated with factors including psychological abuse/neglect, sleep problems, and depressed mood, but the systematic effects of these factors on suicidal ideation remain unclear, which is a research gap this work aims to fill. METHODS: A multi-center, the cluster sampling method was employed to collect general demographic data, such as age, gender, the experience of being left behind, and parents' marital status, from 12,192 students across 17 secondary schools in China. The Child Psychological Abuse and Neglect Scale (CPANS), Pittsburgh Sleep Quality Index (PSQI), the Chinese version of the Depressed mood, Anxiety and Stress Scale - 21 Items (DASS-21) and Chinese version of Positive and Negative Suicide Ideation Inventory (PANSI) were utilized. Data were analyzed using t-tests, chi-square tests, correlation analyses, and structural equation modeling mediation analyses. RESULTS: The prevalence of psychological abuse/neglect and adolescent suicidal ideation was 34.8% and 13%, respectively. This mediation analysis suggests that, in the relationship between psychological abuse/neglect and suicidal ideation, sleep problems and depressed mood play both parallel and sequential mediating roles. CONCLUSION: Sleep problems and depressed mood play a mediating role in the development of suicidal ideation in adolescents. Good sleep habits and depressed mood interventions help reduce the risk of suicidal ideation in adolescents who experience psychological neglect/abuse.

Choroid plexus volume enlargement in first-episode antipsychotic-naïve schizophrenia.

Investigation of the choroid plexus in schizophrenia has seen growing interest due to its role in the interaction between neuroinflammation and brain dysfunction. Most previous studies included treated and long-term ill patients, while antipsychotics and illness course might both affect the choroid plexus. Here, we recruited first-episode antipsychotic-naïve schizophrenia patients, performed high-resolution structural brain scan and manually extracted choroid plexus volume. Choroid plexus volume was compared between patients and healthy controls after controlling for age, sex and intracranial volume. Age and sex effects were examined on choroid plexus volume in patient and healthy control groups respectively. In patients, we also examined the correlation of choroid plexus volume with volume measures of cortical and subcortical gray matter, white matter, lateral ventricular as well as symptom severity and cognitive function. Schizophrenia patients showed significantly enlarged choroid plexus volume compared with healthy controls. Choroid plexus volume was positively correlated with age in only patient group and we found significantly larger choroid plexus volumes in males than females in both patient and healthy control groups, while the sex effects did not differ between groups. Choroid plexus volume was only found correlated with lateral ventricular volume among the brain volume measures. No significant correlation between choroid plexus volume and clinical ratings or cognitive performance was observed. Without potential confounding effects of pharmacotherapy or illness course, our findings indicated the enlargement of choroid plexus in schizophrenia might be an enduring trait for schizophrenia.

Free water alterations in different inflammatory subgroups in schizophrenia.

BACKGROUND: Accumulating evidence suggests that inflammatory dysregulation both in blood and the brain is implicated in the pathogenesis of schizophrenia. Alterations in peripheral cytokines are not evident in all patients and there may be discrete altered inflammatory subgroups in schizophrenia. Recent studies using a novel and in vivo free-water imaging to detect inflammatory processes, have shown increased free water in white matter in schizophrenia. However, no studies to date have investigated the free water alterations in different inflammatory subgroups in schizophrenia. METHODS: Forty-four patients with schizophrenia and 49 controls were recruited. The serum levels of interleukin-1 beta (IL-1ß), IL-6, IL-10, and IL-12p70 were measured and used for cluster analysis with K-means and hierarchical algorithms. Diffusion tensor imaging (DTI) images were collected for all participants and voxel-wise free water and fractional anisotropy of tissue (FA-t) were compared between groups with Randomise running in FSL. Partial correlation analysis was employed to explore the association of the peripheral cytokine levels with free water. RESULTS: We identified two statistically quantifiable discrete subgroups of patients based on the cluster analysis of cytokine measures. The peripheral levels of IL-1ß (P < 0.001), IL-10 (P = 0.041), and IL-12p70 (P < 0.001) showed significant differences between the two different inflammatory subgroups. In the inflammatory subgroup with a predominantly higher IL-1ß level, increased free water values in white matter were found mainly in the left posterior limb of the internal capsule, posterior corona radiata, and partly in the left sagittal stratum. These affected areas did not overlap with the regions that showed significant free water differences between patients and healthy controls. In the inflammatory subgroup with lower IL-1ß levels, peripheral IL-1ß was significantly associated with free water values in white matter while no such association was detected in the patient group. CONCLUSIONS: Localized free water differences were demonstrated between the two identified inflammatory subgroups in our data, and free water appears to be a feasible in vivo neuroimaging biomarker guiding the target of inflammatory intervention and development of new therapeutic strategies in an individualized manner in schizophrenia.

Erratum: Author correction to "Neutralization of SARS-CoV-2 pseudovirus using ACE2-engineered extracellular vesicles" [Acta Pharmaceutica Sinica B 12 (2022) 1523-1533].

[This corrects the article DOI: 10.1016/j.apsb.2021.09.004.].

Comparison of the bioactive components and antioxidant activities of wild-type Zanthoxylum nitidum roots from various regions of Southern China.

Zanthoxylum nitidum is a traditional Chinese herb, but limited information is available concerning its antioxidant activity of Z. nitidum. In this study, the bioactive components, content, and antioxidant activity of Z. nitidum roots from various regions in southern China were detected and evaluated. The results revealed that the highest nitidine chloride content found in S13. The S1 contained significantly higher concentrations of hesperidin, total flavonoids, and total phenols than other samples. The samples from S13, S1, and S12 had the strongest comprehensive antioxidant activity. Stoichiometric analysis revealed that samples from various regions were effectively identified and classified. This is the first study to investigate the antioxidant activity of wild-type Z. nitidum in southern China. It lays the groundwork for Z. nitidum harvesting, origin identification, sensible use, as well as the quality evaluation of Z. nitidum resources, particularly in vitro antioxidant activity assessment.

Early left bundle branch pacing in heart failure with mildly reduced ejection fraction and left bundle branch block.

BACKGROUND: Left bundle branch pacing (LBBP) achieves resynchrony and improves cardiac function in heart failure (HF) patients with reduced ejection fraction (EF) by correcting left bundle branch block (LBBB). Few data on the efficacy of early LBBP in HF with mildly reduced EF (HFmrEF) and LBBB have been reported. OBJECTIVE: The purpose of this study was to explore the efficacy of early LBBP in patients with HFmrEF and LBBB. METHODS: Consecutive patients with HFmrEF (left ventricular EF [LVEF] 35%-50%) and LBBB were prospectively enrolled to receive LBBP (Early-LBBP group) plus guideline-directed medical therapy (GDMT) or GDMT alone (GDMT group). Study outcomes included changes in LVEF, LV end-diastolic diameter (LVEDD), New York Heart Association (NYHA) functional classification, and N-terminal pro-brain natriuretic peptide (NT-proBNP), and clinical events (HF rehospitalization or syncope). Subgroup analysis compared efficacy of LBBP between patients with LBBB only without comorbidities or late gadolinium enhancement (LGE) (LBBB-Only group) and patients with either comorbidities or LGE (LBBB-Combined group). RESULTS: Fifty-four patients were enrolled and analyzed (37 Early-LBBP group; 15 GDMT group). LBBP achieved greater improvement in LVEF (+14.75% ± 7.37% vs -2.42% ± 2.84%; P <.001), reduction of LVEDD (-7.51 ± 5.40 mm vs -0.87 ± 4.36 mm; P <.001) and NYHA classification (-0.84 ± 0.76 vs -0.13 ± 0.74; P = .004), and similar reduction of NT-proBNP (-408.83 ± 920.29 pg/mL vs -229.05 ± 1579.17 pg/mL; P = .610) at 6 months. Early LBBP showed significantly reduced clinical events (0.0% vs 40.0%; P <.001) after 20.68 ± 13.55 months of follow-up. Subgroup analysis showed patients in the LBBB-Only group benefited more from LBBP with regard to LVEF improvement and LVEDD reduction than the LBBB-Combined group. CONCLUSION: Early LBBP with GDMT demonstrated greater improvement of cardiac function and reduced clinical events than GDMT alone in patients with HFmrEF and LBBB.

Altered controllability of white matter networks and related brain function changes in first-episode drug-naive schizophrenia.

Understanding how structural connectivity alterations affect aberrant dynamic function using network control theory will provide new mechanistic insights into the pathophysiology of schizophrenia. The study included 140 drug-naive schizophrenia patients and 119 healthy controls (HCs). The average controllability (AC) quantifying capacity of brain regions/networks to shift the system into easy-to-reach states was calculated based on white matter connectivity and was compared between patients and HCs as well as functional network topological and dynamic properties. The correlation analysis between AC and duration of untreated psychosis (DUP) were conducted to characterize the controllability progression pattern without treatment effects. Relative to HCs, patients exhibited reduced AC in multiple nodes, mainly distributed in default mode network (DMN), visual network (VN), and subcortical regions, and increased AC in somatomotor network. These networks also had impaired functional topology and increased temporal variability in dynamic functional connectivity analysis. Longer DUP was related to greater reductions of AC in VN and DMN. The current study highlighted potential structural substrates underlying altered functional dynamics in schizophrenia, providing a novel understanding of the relationship of anatomic and functional network alterations.

Cerebellar Functional Dysconnectivity in Drug-Naïve Patients With First-Episode Schizophrenia.

BACKGROUND: Cerebellar functional dysconnectivity has long been implicated in schizophrenia. However, the detailed dysconnectivity pattern and its underlying biological mechanisms have not been well-charted. This study aimed to conduct an in-depth characterization of cerebellar dysconnectivity maps in early schizophrenia. STUDY DESIGN: Resting-state fMRI data were processed from 196 drug-naïve patients with first-episode schizophrenia and 167 demographically matched healthy controls. The cerebellum was parcellated into nine functional systems based on a state-of-the-art atlas, and seed-based connectivity for each cerebellar system was examined. The observed connectivity alterations were further associated with schizophrenia risk gene expressions using data from the Allen Human Brain Atlas. STUDY RESULTS: Overall, we observed significantly increased cerebellar connectivity with the sensorimotor cortex, default-mode regions, ventral part of visual cortex, insula, and striatum. In contrast, decreased connectivity was shown chiefly within the cerebellum, and between the cerebellum and the lateral prefrontal cortex, temporal lobe, and dorsal visual areas. Such dysconnectivity pattern was statistically similar across seeds, with no significant group by seed interactions identified. Moreover, connectivity strengths of hypoconnected but not hyperconnected regions were significantly correlated with schizophrenia risk gene expressions, suggesting potential genetic underpinnings for the observed hypoconnectivity. CONCLUSIONS: These findings suggest a common bidirectional dysconnectivity pattern across different cerebellar subsystems, and imply that such bidirectional alterations may relate to different biological mechanisms.

Randomized Trial of Left Bundle Branch vs Biventricular Pacing for Cardiac Resynchronization Therapy.

BACKGROUND: Left bundle branch pacing (LBBP) is the most rapidly growing conduction system pacing technique that is capable of correcting intrinsic left bundle branch block (LBBB). As such, it is potentially an optimal alternative to cardiac resynchronization therapy (CRT) with biventricular pacing (BiVP). OBJECTIVES: The authors sought to compare the efficacy of LBBP-CRT with BiVP-CRT in patients with heart failure and reduced left ventricular ejection fraction (LVEF). METHODS: This is a prospective, randomized trial of patients with nonischemic cardiomyopathy and LBBB with 6-month preplanned follow-up. Crossovers were allowed if LBBP or BiVP were unsuccessful. The primary endpoint was the difference in LVEF improvement between 2 groups. The secondary endpoints included changes in echocardiographic measurements, N-terminal pro-B-type natriuretic peptide (NT-proBNP), New York Heart Association functional class, 6-minute walk distance, QRS duration, and CRT response. RESULTS: The study included 40 consecutive patients (20 males, mean age 63.7 years, LVEF 29.7% ± 5.6%). Crossovers occurred in 10% of LBBP-CRT and 20% of BiVP-CRT. All patients completed follow-up. Intention-to-treat analysis showed significantly higher LVEF improvement at 6 months after LBBP-CRT than BiVP-CRT (mean difference: 5.6%; 95% CI: 0.3-10.9; P = 0.039). LBBP-CRT also appeared to have greater reductions in left ventricular end-systolic volume (-24.97 mL; 95% CI: -49.58 to -0.36 mL) and NT-proBNP (-1,071.80 pg/mL; 95% CI: -2,099.40 to -44.20 pg/mL), and comparable changes in New York Heart Association functional class, 6-minute walk distance, QRS duration, and rates of CRT response compared with BiVP-CRT. CONCLUSIONS: LBBP-CRT demonstrated greater LVEF improvement than BiVP-CRT in heart failure patients with nonischemic cardiomyopathy and LBBB. (Left Bundle Branch Pacing Versus Biventricular Pacing for Cardiac Resynchronization Therapy [LBBP-RESYNC]; NCT04110431).

Boron-Assisted Selective Citrulline Modification under Mild Conditions.

Protein citrullination is one type of protein post-translational modification. Previous methods entail the use of a strongly acidic condition (pH <1), which impedes its exploration under physiological and pathological conditions. Here, we developed a biocompatible method based on o-boron-assisted citrulline modification. We demonstrated that this method enables selective and mainly irreversible modification of citrulline residues under neutral conditions. We expect that it will provide a valuable tool for the study of protein citrullination.

Effects of Antipsychotic Medications and Illness Duration on Brain Features That Distinguish Schizophrenia Patients.

BACKGROUND AND HYPOTHESIS: Previous studies have reported effects of antipsychotic treatment and illness duration on brain features. This study used a machine learning approach to examine whether these factors in aggregate impacted the utility of MRI features for differentiating individual schizophrenia patients from healthy controls. STUDY DESIGN: This case-control study used patients with never-treated first-episode schizophrenia (FES, n = 179) and long-term ill schizophrenia (LTSZ, n = 30), with follow-up of the FES group after treatment (n = 71), a group of patients who had received long-term antipsychotic treatment (n = 93) and age and sex-matched healthy controls (n = 373) for each patient group. A multiple kernel learning classifier combining both structural and functional brain features was used to discriminate individual patients from controls. STUDY RESULTS: MRI features differentiated untreated FES (0.73) and LTSZ (0.83) patients from healthy controls with moderate accuracy, but accuracy was significantly higher in antipsychotic-treated FES (0.94) and LTSZ (0.98) patients. Treatment was associated with significantly increased accuracy of case identification in both early course and long-term ill patients (both p < .001). Effects of illness duration, examined separately in treated and untreated patients, were less robust. CONCLUSIONS: Our results demonstrate that initiation of antipsychotic treatment alters brain features in ways that further distinguish individual schizophrenia patients from healthy individuals, and have a modest effect of illness duration. Intrinsic illness-related brain alterations in untreated patients, regardless of illness duration, are not sufficiently robust for accurate identification of schizophrenia patients.

Causal effect of central obesity on left ventricular structure and function in preserved EF population: A Mendelian randomization study.

Background: Observational studies have shown that central obesity is associated with adverse cardiac structure and function. However, causal association between central obesity and left ventricular (LV) structure and function in preserved ejection fraction (EF) population is still uncertain. Methods: Genome-wide association studies summary data of waist circumference adjusted for body mass index (WCadjBMI) and waist-to-hip ratio adjusted for body mass index (WHRadjBMI) were selected as instrumental variables from the Genetic Investigation of Anthropometric Traits (GIANT) Consortium (n = 224,459). Outcome datasets for LV parameters including LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV ejection fraction (LVEF), LV mass (LVM), and LV mass-to-end-diastolic volume ratio (LVMVR) were obtained from the participants without prevalent myocardial infarction or heart failure (LVEF ≥ 50%) in UK Biobank Cardiovascular Magnetic Resonance sub-study (n = 16,923). Two-sample Mendelian randomization (MR) was performed with the inverse-variance weighted (IVW) method as the primary estimate and with the weighted median and MR-Egger as the supplemental estimates. Sensitivity analysis was used to assess the heterogeneity and pleiotropic bias in the MR results. Results: In the IVW analysis, every 1-standard deviation (SD) higher WHRadjBMI was significantly associated with higher LVMVR (ß = 0.4583; 95% confidence interval [CI]: 0.2921 to 0.6244; P = 6.418 × 10-8) and lower LVEDV (ß = -0.2395; 95% CI: -0.3984 to -0.0807; P = 0.0031) after Bonferroni adjustment. No heterogeneity and horizontal pleiotropy were detected in the analysis. No association of WCadjBMI was found with LVEF, LVEDV, LVESV, LVM, or LVMVR. Conclusion: Our findings provide evidence of significant causal association between WHRadjBMI and adverse changes in LV structure and function in preserved EF population.

Structural characteristics of Heparan sulfate required for the binding with the virus processing Enzyme Furin.

Furin is one of the nine-member proprotein convertase family. Furin cleaves proteins with polybasic residues, which includes many viral glycoproteins such as SARS-Cov-2 spike protein. The cleavage is required for the activation of the proteins. Currently, the mechanisms that regulate Furin activity remain largely unknown. Here we demonstrated that Furin is a novel heparin/heparan sulfate binding protein by the use of biochemical and genetic assays. The KD is 9.78 nM based on the biolayer interferometry assay. Moreover, we found that sulfation degree, site-specific sulfation (N-sulfation and 3-O-sulfation), and iduronic acid are the major structural determinants for the binding. Furthermore, we found that heparin inhibits the enzymatic activity of Furin when pre-mixes heparin with either Furin or Furin substrate. We also found that the Furin binds with cells of different origin and the binding with the cells of lung origin is the strongest one. These data could advance our understanding of the working mechanism of Furin and will benefit the Furin based drug discovery such as inhibitors targeting the interaction between heparan sulfate and Furin for inhibition of viral infection.

Neutralization of SARS-CoV-2 pseudovirus using ACE2-engineered extracellular vesicles.

The spread of coronavirus disease 2019 (COVID-19) throughout the world has resulted in stressful healthcare burdens and global health crises. Developing an effective measure to protect people from infection is an urgent need. The blockage of interaction between angiotensin-converting enzyme 2 (ACE2) and S protein is considered an essential target for anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs. A full-length ACE2 protein could be a potential drug to block early entry of SARS-CoV-2 into host cells. In this study, a therapeutic strategy was developed by using extracellular vesicles (EVs) with decoy receptor ACE2 for neutralization of SARS-CoV-2. The EVs embedded with engineered ACE2 (EVs-ACE2) were prepared; the EVs-ACE2 were derived from an engineered cell line with stable ACE2 expression. The potential effect of the EVs-ACE2 on anti-SARS-CoV-2 was demonstrated by both in vitro and in vivo neutralization experiments using the pseudovirus with the S protein (S-pseudovirus). EVs-ACE2 can inhibit the infection of S-pseudovirus in various cells, and importantly, the mice treated with intranasal administration of EVs-ACE2 can suppress the entry of S-pseudovirus into the mucosal epithelium. Therefore, the intranasal EVs-ACE2 could be a preventive medicine to protect from SARS-CoV-2 infection. This EVs-based strategy offers a potential route to COVID-19 drug development.