Major depressive disorder (MDD) is common and disabling, but its neuropathophysiology remains unclear. Most studies of functional brain networks in MDD have had limited statistical power and data ...analysis approaches have varied widely. The REST-meta-MDD Project of resting-state fMRI (R-fMRI) addresses these issues. Twenty-five research groups in China established the REST-meta-MDD Consortium by contributing R-fMRI data from 1,300 patients with MDD and 1,128 normal controls (NCs). Data were preprocessed locally with a standardized protocol before aggregated group analyses. We focused on functional connectivity (FC) within the default mode network (DMN), frequently reported to be increased in MDD. Instead, we found decreased DMN FC when we compared 848 patients with MDD to 794 NCs from 17 sites after data exclusion. We found FC reduction only in recurrent MDD, not in first-episode drug-naïve MDD. Decreased DMN FC was associated with medication usage but not with MDD duration. DMN FC was also positively related to symptom severity but only in recurrent MDD. Exploratory analyses also revealed alterations in FC of visual, sensory-motor, and dorsal attention networks in MDD. We confirmed the key role of DMN in MDD but found reduced rather than increased FC within the DMN. Future studies should test whether decreased DMN FC mediates response to treatment. All R-fMRI indices of data contributed by the REST-meta-MDD consortium are being shared publicly via the R-fMRI Maps Project.
Abstract
SARS-CoV-2 infection causes a wide spectrum of clinical manifestations in humans, and olfactory dysfunction is one of the most predictive and common symptoms in COVID-19 patients. However, ...the underlying mechanism by which SARS-CoV-2 infection leads to olfactory disorders remains elusive. Herein, we demonstrate that intranasal inoculation with SARS-CoV-2 induces robust viral replication in the olfactory epithelium (OE), not the olfactory bulb (OB), resulting in transient olfactory dysfunction in humanized ACE2 (hACE2) mice. The sustentacular cells and Bowman’s gland cells in the OE were identified as the major target cells of SARS-CoV-2 before invasion into olfactory sensory neurons (OSNs). Remarkably, SARS-CoV-2 infection triggers massive cell death and immune cell infiltration and directly impairs the uniformity of the OE structure. Combined transcriptomic and quantitative proteomic analyses revealed the induction of antiviral and inflammatory responses, as well as the downregulation of olfactory receptor (OR) genes in the OE from the infected animals. Overall, our mouse model recapitulates olfactory dysfunction in COVID-19 patients and provides critical clues for understanding the physiological basis for extrapulmonary manifestations of COVID-19.
•A novel quantitative measure reflecting functional connectivity asymmetry of brain was employed.•The largest resting-state fMRI dataset of major depressive disorder in China was used.•Many brain ...networks contribute to broad clinical pathophysiology of MDD.•A lateralized, efficient and economical brain information processing system is disrupted in MDD.
: Functional specialization is a feature of human brain for understanding the pathophysiology of major depressive disorder (MDD). The degree of human specialization refers to within and cross hemispheric interactions. However, most previous studies only focused on interhemispheric connectivity in MDD, and the results varied across studies. Hence, brain functional connectivity asymmetry in MDD should be further studied.
: Resting-state fMRI data of 753 patients with MDD and 451 healthy controls were provided by REST-meta-MDD Project. Twenty-five project contributors preprocessed their data locally with the Data Processing Assistant State fMRI software and shared final indices. The parameter of asymmetry (PAS), a novel voxel-based whole-brain quantitative measure that reflects inter- and intrahemispheric asymmetry, was reported. We also examined the effects of age, sex and clinical variables (including symptom severity, illness duration and three depressive phenotypes).
: Compared with healthy controls, patients with MDD showed increased PAS scores (decreased hemispheric specialization) in most of the areas of default mode network, control network, attention network and some regions in the cerebellum and visual cortex. Demographic characteristics and clinical variables have significant effects on these abnormalities.
: Although a large sample size could improve statistical power, future independent efforts are needed to confirm our results.
: Our results highlight the idea that many brain networks contribute to broad clinical pathophysiology of MDD, and indicate that a lateralized, efficient and economical brain information processing system is disrupted in MDD. These findings may help comprehensively clarify the pathophysiology of MDD in a new hemispheric specialization perspective.
While gastrointestinal (GI) symptoms are very common in patients with major depressive disorder (MDD), few studies have investigated the neural basis behind these symptoms. In this study, we sought ...to elucidate the neural basis of GI symptoms in MDD patients by analyzing the changes in regional gray matter volume (GMV) and gray matter density (GMD) in brain structure.
Subjects were recruited from 13 clinical centers and categorized into three groups, each of which is based on the presence or absence of GI symptoms: the GI symptoms group (MDD patients with at least one GI symptom), the non-GI symptoms group (MDD patients without any GI symptoms), and the healthy control group (HCs). Structural magnetic resonance images (MRI) were collected of 335 patients in the GI symptoms group, 149 patients in the non-GI symptoms group, and 446 patients in the healthy control group. The 17-item Hamilton Depression Rating Scale (HAMD-17) was administered to all patients. Correlation analysis and logistic regression analysis were used to determine if there was a correlation between the altered brain regions and the clinical symptoms.
There were significantly higher HAMD-17 scores in the GI symptoms group than that of the non-GI symptoms group (P < 0.001). Both GMV and GMD were significant different among the three groups for the bilateral superior temporal gyrus, bilateral middle temporal gyrus, left lingual gyrus, bilateral caudate nucleus, right Fusiform gyrus and bilateral Thalamus (GRF correction, cluster-P < 0.01, voxel-P < 0.001). Compared to the HC group, the GI symptoms group demonstrated increased GMV and GMD in the bilateral superior temporal gyrus, and the non-GI symptoms group demonstrated an increased GMV and GMD in the right superior temporal gyrus, right fusiform gyrus and decreased GMV in the right Caudate nucleus (GRF correction, cluster-P < 0.01, voxel-P < 0.001). Compared to the non-GI symptoms group, the GI symptoms group demonstrated significantly increased GMV and GMD in the bilateral thalamus, as well as decreased GMV in the bilateral superior temporal gyrus and bilateral insula lobe (GRF correction, cluster-P < 0.01, voxel-P < 0.001). While these changed brain areas had significantly association with GI symptoms (P < 0.001), they were not correlated with depressive symptoms (P > 0.05). Risk factors for gastrointestinal symptoms in MDD patients (p < 0.05) included age, increased GMD in the right thalamus, and decreased GMV in the bilateral superior temporal gyrus and left Insula lobe.
MDD patients with GI symptoms have more severe depressive symptoms. MDD patients with GI symptoms exhibited larger GMV and GMD in the bilateral thalamus, and smaller GMV in the bilateral superior temporal gyrus and bilateral insula lobe that were correlated with GI symptoms, and some of them and age may contribute to the presence of GI symptoms in MDD patients.
•The present study is the first to investigate the GMV and GMD changes of the regional brain in MDD patients with GI symptoms through multicenter clinical data, based on the VBM of structural MRI.•The study found MDD patients with GI symptoms have more severe depressive symptoms.•The study pointed out that the dysfunction of CNS may be one of the important pathophysiologic mechanisms causing GI symptoms in MDD patients.
The pathological progression of non-alcoholic fatty liver disease (NAFLD) is driven by multiple factors, and non-alcoholic steatohepatitis (NASH) represents its progressive form. In our previous ...studies, we found that bicyclol had beneficial effects on NAFLD/ NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding.
A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. Data are available
Proteome X change with identifier PXD040233. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data.
Bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and GSTA1). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP3A11 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3).
These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.
Guiding by LC-MS/MS analysis and the GNPS Molecular Networking, five undescribed daphnane diterpenoids, tanguticanines A–E, and eleven known analogues were discovered from the whole plants of Daphne ...tangutica Maxim. Their structures and absolute configurations were determined via extensive NMR spectroscopic analysis, ECD calculations, and X-ray diffraction crystallography. Tanguticanine E (5) exhibited promising cytotoxicity against the HepG2 cell line with an IC50 value of 9.93 ± 0.10 μM. Further flow cytometry experiment was performed to detect cell apoptosis, and the results indicated that cytotoxic diterpenoids (tanguticanines B, D and E, altadaphnan C, gniditrin, hirsein A and simplexin) exert their effects through induction of apoptosis.
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•New daphnane diterpenoids were isolated from D. tangutica by LC-MS/MS analysis.•The structures were determined by NMR data, ECD calculations and X-ray diffraction.•Tanguticanine E exhibited the most prominent cytotoxicity against HepG2 cells.•Cytotoxic diterpenoids exert cytotoxic effects through induction of apoptosis.
Abrasive waterjet peening (AWJP) has become an essential surface treatment technique to improve the surface integrity and mechanical properties of metallic parts due to its high controllability and ...small thermal influence. However, since existing AWJP processes are based on straight nozzles, they are difficult for complex geometrical profiles and confined spaces treatment, such as dovetail slots. In the present work, a novel deflecting AWJP (DAWJP) process with a designed deflecting nozzle was proposed and verified by experiments on the nickel-based superalloy GH4169. First, the DAWJP's deflecting nozzle was designed based on the AWJP's straight nozzle and deflecting pin with deflection angle. Second, the internal and external flow field distribution and abrasive movement state of deflecting nozzles with different deflection angles (R = 0, 1, 1.5, 2 mm) were studied by using the FLUENT CFD software. Finally, the surface integrity of the GH4169 specimen treated by the proposed DAWJP with an optimized deflecting nozzle was investigated, including microstructure, height difference, surface roughness and microscopic morphology, surface and subsurface microhardness and compressive residual stress (CRS). The results of this study highlighted that the deflecting nozzle with a deflection angle of 1.5 mm could obtain relatively optimized jet flow velocities of the water and abrasive mixed phases. The GH4169 specimen treated by the DAWJP with different processing parameters using the optimized deflection angle formed a plastic deformation depth of 22–51 μm, a height difference between the as-received and DAWJP treated surface of 4–48 μm, and the surface roughness Ra and Sa of 0.199–0.503 μm and 0.535–0.953 μm. The surface microhardness and CRS of the DAWJP treated specimen were approximately 522–573 HV and 773–991 MPa, which is 7.6 %–18.1 % and 209 %–296 % times higher than the as-received specimen, respectively. The work-hardened layer and CRS depth of the near surface of the specimen induced by the DAWJP treatment were approximately 120–180 μm and 112–203 μm. This work presents a novel DAWJP method and investigates its effect on the surface integrity of the GH4169 material, which is expected to have applications in improving the surface integrity and mechanical properties of metallic parts with confined spaces.
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•Proposing a DAWJP method to improve surface integrity of metallic confined spaces•Optimizing the deflecting angle of the deflecting nozzle based on FLUENT software•Revealing the microstructure evolution of the DAWJP treated GH4169 material•Reducing the surface roughness of the as-received specimen by the DAWJP method•Inducing greater microhardness and CRS of GH4169 specimens through DAWJP treatment
Peripheral arterial disease (PAD) is a prevalent and debilitating disease that can be effectively treated by surgical revascularization. However, Medicare-Medicaid dual-eligible patients have ...experienced worse long-term outcomes, notably higher rates of amputation and mortality, relative to other insurance groups. In the present study, we investigated how insurance status can perpetuate health disparities in PAD outcomes.
The National Inpatient Sample was queried from 2000 to 2011 for patients aged ≥18 years with PAD who had undergone surgical revascularization with hospitalization. Patients were stratified by insurance status, and dual-eligible patients were compared with Medicare-only, Medicaid-only, private insurance, and self-pay patients. Multivariable regression analysis was performed to assess the effect of dual-eligible status on postoperative outcomes such as inpatient mortality, complications, and favorable discharge (home or home with services).
A total of 771,790 hospitalizations were included in the present analysis and stratified by insurance type. Dual-eligible patients had the highest rates of major (32%) and extreme (11%) severity of illness and the highest rates of major (19%) and extreme (6%) risk of mortality among all insurance groups (P < .001). Dual-eligibility status was independently associated with reduced odds of favorable discharge relative to all patients (P < .001) and increased length of stay relative to Medicare-only (P = .002) and private-payor groups (P < .001). Although dual-eligible patients had increased mortality odds relative to the Medicaid-only and self-pay groups, they did not have significantly different odds of perioperative complications relative to all other insurance groups.
Medicare-Medicaid dual-eligible patients with PAD had had more severe clinical presentations, a greater risk of extended hospitalizations, and a lower likelihood of discharge to home, relative to patients without dual eligibility. Further studies are needed to examine the link between discharge disposition and disparities in healthcare outcomes and to investigate the interventions that effectively address the increased severity of PAD in dual-eligible patients.
As a classic drug with several hydrate forms, Calcium Dobesilate is widely used in the treatment of diabetic retinopathy and chronic venous insufficiency, and Monohydrate is the medicinal form. The ...key impurity, hydroquinone, is an important synthetic raw material of Calcium Dobesilate, but has a potential genotoxicity, so the content of hydroquinone in the final product should be lower. In this paper, based on characterization results of different hydrates, the Dihydrate is found as the beneficial form for purification, thus a novel crystallization process for purification has been carried out. The Dihydrate is obtained by a recrystallization and then transformed into the Monohydrate. From the results of solid‐state characterization and process analysis of phase transformation, the transformation relationship between the two hydrates is determined, and it is found out that the transformation from Dihydrate to Monohydrate could only happen via solution‐mediated transformation in Ethanol or Isopropanol. The impurity content of the Monohydrate product prepared by the new crystallization process is far below the current standard in the Pharmacopoeia.
The impurity of Calcium Dobesilate, hydroquinone, is potential genotoxic, so its content in the final product should be lower. In this work, the Dihydrate is found as the beneficial form for purification, and the Monohydrate is obtained from the Dihydrate through solution‐mediated transformation in Ethanol or Isopropanol. The impurity content of the final product prepared in the work is far below the current standard.
This study aimed at investigating the correlation between estradiol and sleep apnea among women with major depressive disorders during the perimenopausal and postmenopausal periods.
A total of 84 ...perimenopausal and postmenopausal women diagnosed with depression, and who had been subjected to whole-night polysomnography (PSG) were retrospectively studied. They were assigned into two groups based on the presence of OSA (apnea-hypopnea index (AHI)≥5) (OSA vs non-OSA). The correlation between estradiol levels and apnea-hypopnea index were assessed by logistic regression models after adjusting for age, body mass index (BMI), Hamilton Depression Rating Scale (HAMD), Pittsburgh Sleep Quality Index (PSQI), apnea frequency and progesterone.
Among the 84 patients, 45.23% had OSA. Estradiol levels were significantly elevated in non-OSA than in OSA patients (
<0.05). Univariate analysis revealed that elevated estradiol levels are associated with reduced odds of OSA (odds ratio OR 0.92, 95% confidence interval CI 0.875-0.966,
= 0.001). Multivariate analyses showed that low estradiol levels (OR = 0.859, 95% CI 0.826-0.991, p = 0.031), higher HAMD scores (OR = 1.212, 95% CI 1.012-1.453, p = 0.037), higher apnea frequency (OR = 2.493, 95% CI 1.389-4.473, p = 0.002) and higher BMI (OR=1.635, 95% CI 1.136-2.353, p = 0.008) are correlated with OSA.
The ratio of depressed perimenopausal to postmenopausal women comorbid OSA was high. Higher BMI, low estradiol levels, high apnea frequency and high HAMD scores were correlated with OSA diagnosis and could be potential diagnostic markers for OSA in depressed perimenopausal and postmenopausal women. Reduced estradiol levels were correlated with an increased risk of OSA among depressed perimenopausal and postmenopausal women.
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