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Numerous magnetic resonance spectroscopy (MRS) studies have reported metabolic abnormalities in the brains of patients with depression, although inconsistent results have been reported. The aim of this study was to explore changes in neurometabolite levels in patients with depression across large-scale MRS studies.A total of 307 differential metabolite entries associated with depression were retrieved from 180 MRS studies retrieved from the Metabolite Network of Depression Database. The vote-counting method was used to identify consistently altered metabolites in the whole brain and specific brain regions of patients with depression.Only few differential neurometabolites showed a stable change trend. The levels of total choline (tCho) and the tCho/N-acetyl aspartate (NAA) ratio were consistently higher in the brains of patients with depression, and that the levels of NAA, glutamate and glutamine (Glx), and gamma-aminobutyric acid (GABA) were lower. For specific brain regions, we found lower Glx levels in the prefrontal cortex and lower GABA concentrations in the occipital cortex. We also found lower concentrations of NAA in the anterior cingulate cortex and prefrontal cortex. The levels of tCho were higher in the prefrontal cortex and putamen.Our results revealed that most altered neurometabolites in previous studies lack of adequate reproducibility. Through vote-counting method with large-scale studies, downregulation of glutamatergic neurometabolites, impaired neuronal integrity, and disturbed membrane metabolism were found in the pathobiology of depression, which contribute to existing knowledge of neurometabolic changes in depression. Further studies based on a larger dataset are needed to confirm our findings.

To investigate the imaging findings and clinical time course of COVID-19 pneumonia. A total of 113 baseline and follow-up CT scans from 24 January 2020 to 18 February 2020 were longitudinally collected from 29 confirmed COVID-19 patients in a single center. The changes in the clinical and laboratory characteristics, imaging features, lesion-to-muscle ratio (LMR), and pulmonary inflammation index (PII) at baseline, 1–6 days, 7–13 days, and ≥ 14 days were compared. Of the 29 COVID-19 patients enrolled, the baseline chest CT scan was obtained 3 ± 2 (0–9) days after the onset of symptoms, and each patient had an average of 4 ± 1 (3–5) CT scans with a mean interval of 5 ± 2 (1–14) days. The percentage of patients with fever, cough, shortness of breath, and myalgia obviously decreased at 7–13 days with regular treatment (p < 0.05). The lymphocyte count, C-reactive protein, interleukin-6, and oxygenation index worsened within 1–6 days but improved sharply at 7–13 days. Compared with those at the other three time points, the LMR, PII, and number of involved lobes at 1–6 days were the highest, and gradually improved after 7–13 days. Lung lesion development on chest CT reflects the clinical time course of COVID-19 progression over 1–6 days, followed by clinical improvement and the resorption of lesions. CT imaging may be indicated when patients fail to improve within a week of treatment, but repeated chest CT may be unnecessary when the patients show improvements clinically. • Chest CT reflects the development of coronavirus disease 2019 pneumonia (COVID-19). • COVID-19 usually shows progressive lesions over up to 9 days with subsequent resorption. • Unusual clinical time course of COVID-19 may indicate repeated chest CT.

BACKGROUND: Pulmonary artery sling (PAS) is associated with tracheal stenosis and left pulmonary artery (LPA) dysplasia in infants, both developmental abnormalities that may lead to pulmonary hypoplasia and lung volume changes. As such, we aimed to monitor the effects of tracheal stenosis and pulmonary vascular malformation on lung volumes in infants with PAS and their correlation with lung volumes in infants with PAS using dual-source computed tomography (DSCT). METHODS: A case-control study was performed. From May 2009 to June 2017, we retrospectively enrolled patients with surgically confirmed PAS and compared them to matched normal controls (A healthy control group comprising age- and gender-matched patients with adequate imaging data was used for the comparisons.). All the patients underwent DSCT examinations. We measured and compared the diameters of the trachea, main bronchus, and main pulmonary artery (MPA) and its branches, and both lung volumes on the axial, and reconstructed CT images. RESULTS: There were no statistical differences in the diameters of the MPA or right pulmonary artery (RPA) between patients (N=15) and controls (N=28). The diameter of the main bronchus, the bilateral trachea and the left pulmonary artery were all smaller in the PAS group than in the control group, and significant differences were evident in the left lung volume the right lung volume, and the right-to-left lung volume ratio between the 2 groups. Pearson’s correlation and linear regression analyses between the diameters of the trachea and MPA, total lung volume, ipsilateral bronchial and pulmonary artery branches, and ipsilateral lung volume ranged from 0.71 to 0.87 and 0.57 to 0.77 for the control and PAS groups, respectively. CONCLUSIONS: Tracheal stenosis and LPA dysplasia in infants with PAS cause alterations in lung tissue morphology and physiological development, resulting in reduced bilateral lung volumes.

Here we report on the design, synthesis, and assembly of an enzymatic programmable peptide system inspired by endocytic processes to induce molecular assemblies formation spatiotemporally in living cancer cells, resulting in glioblastoma cell death mainly in necroptosis. Our results indicate the stability and glycosylation of molecules play an essential role in determining the final bioactivity. Detailed mechanistic studies by CLSM, Flow cytometry, western blot, and Bio-EM suggest the site-specific formation of assemblies, which could induce the LMP and activate the downstream cell death pathway. Moreover, we also demonstrate that our strategy can boost the activity of commercial chemotherapy drug by escaping lysosome sequestration. We expected this work would be expanded towards artificial intelligent biomaterials for cancer therapy and imaging precisely.

Existing treatments for intracerebral hemorrhage (ICH) are unable to satisfactorily prevent development of secondary brain injury after ICH and multiple pathological mechanisms are involved in the development of the injury. In this study, we aimed to identify novel genes and proteins and integrated their molecular alternations to reveal key network modules involved in ICH pathology. A total of 30 C57BL/6 male mice were used for this study. The collagenase model of ICH was employed, 3 days after ICH animals were tested neurological. After it, animals were euthanized and perihematomal brain tissues were collected for transcriptome and TMT labeling-based quantitative proteome analyses. Protein-protein interaction (PPI) network, Gene Set Enrichment Analysis (GSEA), and regularized Canonical Correlation Analysis (rCCA) were performed to integrated multiomics data. For validation of hub genes and proteins, qRT-PCR and Western blot were carried out. The candidate biomarkers were further measured by ELISA in the plasma of ICH patients and the controls. A total of 2218 differentially expressed genes (DEGs) and 353 differentially expressed proteins (DEPs) between the ICH model group and control group were identified. GSEA revealed that immune-related gene sets were prominently upregulated and significantly enriched in pathways of inflammasome complex, negative regulation of interleukin-12 production, and pyroptosis during the ICH process. The rCCA network presented two highly connective clusters which were involved in the sphingolipid catabolic process and inflammatory response. Among ten hub genes screened out by integrative analysis, significantly upregulated Itgb2, Serpina3n, and Ctss were validated in the ICH group by qRT-PCR and Western blot. Plasma levels of human SERPINA3 (homologue of murine Serpina3n) were elevated in ICH patients compared with the healthy controls (SERPINA3: 13.3 ng/mL vs. 11.2 ng/mL, p = 0.015 ). Within the ICH group, higher plasma SERPINA3 levels with a predictive threshold of 14.31 ng/mL ( sensitivity = 64.3 % ; specificity = 80.8 % ; AUC = 0.742 , 95% CI: 0.567-0.916) were highly associated with poor outcome (mRS scores 4-6). Taken together, the results of our study exhibited molecular changes related to ICH-induced brain injury by multidimensional analysis and effectively identified three biomarker candidates in a mouse ICH model, as well as pointed out that Serpina3n/SERPINA3 was a potential biomarker associated with poor functional outcome in ICH patients.

Background: Pulmonary spherical ground-glass opacities (GGOs) are commonly detected on initial chest CT scan in patients with coronavirus disease 2019 (COVID-19).We aimed to investigate the evolution of spherical GGOs to better understand their clinical significance.Materials and Methods:A retrospective study of 33 consecutive patients with confirmed COVID-19 and pulmonary spherical GGOs was performed from January 21, 2020, to March 6, 2020. The initial and follow-up CT images and clinical data were reviewed. The initial CT manifestations of spherical GGOs and their subsequent changes were mainly evaluated. Results:A total of 101 pulmonary spherical GGOs, including 38 with and 63 without consolidation, were found in 33 patients. Of the 101 spherical GGOs, 71 (70.3%) and 30 (29.7%) showed progression and direct absorption on follow-up CT images, respectively. GGOs with consolidation were more likely to progress than those without (84.2% vs. 61.9%, p = 0.017). The 71 progressed lesions mainly showed an increase in size and/or density and most (70.4%) of them extended toward the pleura and developed from spherical to patchy. Internal consolidation appeared and increased in 18 (25.4%) and 22 (31.0%) lesions, respectively. During absorption, all the previous progressed and directly absorbed lesions exhibited a simultaneous decrease in size and density. On each patient’s final CT, more lesions with progression had a residual mixed GGO (40.8% vs. 6.7%, p = 0.002) and fewer had pure GGO (39.4% vs. 60.0%, p = 0.016) than those with direct absorption.Conclusion: In patients with COVID-19, most pulmonary spherical ground-glass opacities would progress, especially those with consolidation, and develop into patchy, subpleural lesions.

Purpose To determine whether new pulmonary lesions will develop in COVID-19 patients with negative initial chest CT findings and to investigate their CT features and outcome during treatment. Patients and Methods Data were collected retrospectively from 29 patients who had tested positive for COVID-19 by reverse-transcription polymerase chain reaction testing but negative by initial chest CT from January 22 to February 17, 2020. Clinical manifestations, laboratory indicators, and follow-up CT data were evaluated. Results Among 317 confirmed COVID-19 patients, 29 (9.1%) (mean ± SD, 38.5 ± 20.5 years; 12 women) with negative initial chest CT findings were evaluated. New pulmonary lesions developed in 10 (34.5%) patients on follow-up CT. Mean time from onset of new lesions to initial CT was 5.8 ± 3.0 days (range: 2–12 days). New lesions (mean involved lobes and segments: 2.5 ± 1.6 [range: 1–5] and 4.5 ± 4.5 [range: 1–13]) were mainly spherical/patchy ground-glass opacities frequently located in the left lower lobe (9, 90.0%). Among the 10 patients, lesions in 6 (60.0%) indicated progression after occurrence, and those in 10 (100.0%) indicated significant absorption on latest CT. When new lesions developed, 6 (60.0%) patients developed new symptoms or had aggravated symptoms and 3 (30.0%) had decreased lymphocyte count. Patients with worsening symptoms had higher involvement of lung segments (mean: 6.5 ± 5.0, range: 1–13) than asymptomatic patients (mean: 1.5 ± 0.6, range: 1–2) (P = 0.057). Conclusion In COVID-19 patients with negative initial chest CT findings, new pulmonary lesions may develop during treatment. Repeat CT is necessary for monitoring the disease, especially when patients have worsening symptoms or laboratory indicators.

TER94 is a multifunctional AAA+ ATPase crucial for diverse cellular processes, especially protein quality control and chromatin dynamics in eukaryotic organisms. Many viruses, including coronavirus, herpesvirus, and retrovirus, coopt host cellular TER94 for optimal viral invasion and replication. Previous proteomics analysis identified the association of TER94 with the budded virions (BVs) of baculovirus, an enveloped insect large DNA virus. Here, the role of TER94 in the prototypic baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) life cycle was investigated. In virus-infected cells, TER94 accumulated in virogenic stroma (VS) at the early stage of infection and subsequently partially rearranged in the ring zone region. In the virions, TER94 was associated with the nucleocapsids of both BV and occlusion-derived virus (ODV). Inhibition of TER94 ATPase activity significantly reduced viral DNA replication and BV production. Electron/immunoelectron microscopy revealed that inhibition of TER94 resulted in the trapping of nucleocapsids within cytoplasmic vacuoles at the nuclear periphery for BV formation and blockage of ODV envelopment at a premature stage within infected nuclei, which appeared highly consistent with its pivotal function in membrane biogenesis. Further analyses showed that TER94 was recruited to the VS or subnuclear structures through interaction with viral early proteins LEF3 and helicase, whereas inhibition of TER94 activity blocked the proper localization of replication-related viral proteins and morphogenesis of VS, providing an explanation for its role in viral DNA replication. Taken together, these data indicated the crucial functions of TER94 at multiple steps of the baculovirus life cycle, including genome replication, BV formation, and ODV morphogenesis. IMPORTANCE TER94 constitutes an important AAA+ ATPase that associates with diverse cellular processes, including protein quality control, membrane fusion of the Golgi apparatus and endoplasmic reticulum network, nuclear envelope reformation, and DNA replication. To date, little is known regarding the role(s) of TER94 in the baculovirus life cycle. In this study, TER94 was found to play a crucial role in multiple steps of baculovirus infection, including viral DNA replication and BV and ODV formation. Further evidence showed that the membrane fission/fusion function of TER94 is likely to be exploited by baculovirus for virion morphogenesis. Moreover, TER94 could interact with the viral early proteins LEF3 and helicase to transport and further recruit viral replication-related proteins to establish viral replication factories. This study highlights the critical roles of TER94 as an energy-supplying chaperon in the baculovirus life cycle and enriches our knowledge regarding the biological function of this important host factor.

Computational fluid dynamics (CFD) simulations, verified against test data, were undertaken to quantify ventilation dilution requirements needed for mitigating flammability risks during leaks of mi...

Biomolecular condensates have been demonstrated as a ubiquitous phenomenon in biological systems and play a crucial role in controlling cellular functions. However, the spatiotemporal construction of artificial biomolecular condensates with functions remains challenging and has been less explored. Herein, a general approach is reported to construct biomolecular condensates (e.g., hydrogel) in the lysosome of living cells for cancer therapy and address multiple drug resistance induced by lysosome sequestration. Aromatic-motif-appended pH-responsive hexapeptide (LTP) derived from natural insulin can be uptaken by cancer cells mainly through caveolae-dependent endocytosis, ensuring the proton-triggered phase transformation (solution to hydrogel) of LTP inside the lysosome specifically. Lysosomal hydrogelation further leads to enlargement of the lysosome in cancer cells and increases the permeability of the lysosome, resulting in cancer cell death. Importantly, lysosomal assemblies can significantly improve the efficiency of current chemotherapy drugs toward multidrug resistance (MDR) cells in vitro and in xenograft tumor models. As an example of functional artificial condensates in lysosomes, this work provides a new strategy for controlling functional condensates formation precisely in the organelles of living cells and addressing MDR in cancer therapy.

Karst groundwater is one of the primary water resources in most provinces of Southwestern China where karst topography is strongly featured. In Guizhou Province, a prominent geologic sedimentary formation is the dolomite stratum which exists as the restricted platform facies and potentially provides a large reservoir for drinking water. A proper understanding and evaluation of its hydrogeochemical characteristics and water quality is the key to ensuring the drinking water safety. In the present study, groundwater samples were collected from 25 locations of the dolomite aquifer across Guizhou to determine their major chemical compounds, including the cations (K+, Na+, Ca2+, Mg2+) and the anions (HCO3&minus, F&minus, Cl&minus, NO3&minus, SO42&minus, ), as well as the pH, total hardness, and total dissolved solids. HCO3&minus, and Ca2+ were found to be the dominant anion and cation, respectively, which is characteristic of typical karst groundwater and supports the overall observation of a slightly weak acid to weak alkaline environment in the studied groundwater, as the pH measurements ranged from 6.80 to 8.37. Fuzzy comprehensive evaluation method is used to evaluate the groundwater quality based on typical drinking water safety standard. The results show that the groundwater in most of the studied aquifers is of reasonably good quality. However, in some aquifers, concentrations of NO3&minus, and/or SO42&minus, were found to be excessively high. Overall, the studied dolomite aquifer in its natural environment as investigated in the present study can be considered as a potential geological stratum for water resources exploitation in Guizhou.

Baculoviruses, although they infect insects in nature, can transduce a wide variety of mammalian cells and are therefore promising gene therapy vectors. However, baculovirus transduction into many mammalian cells is very inefficient, and the limiting stages and factors remain unknown. An important finding is that a short-duration trigger with low pH can significantly enhance virus transduction efficiency, but the mechanism is poorly understood. Herein, we performed a detailed comparative study on entry mechanisms of the prototypical baculovirus Autographa californica multiple nucleopolyhedrovirus (AcMNPV) into insect and mammalian cells. The results showed that AcMNPV could be internalized into mammalian cells efficiently, but fusion in early endosomes (EEs) appeared to be the major obstacle. Measurement of endosomal pH suggested that virus fusion might be restricted under relatively high-pH conditions in mammalian cells. Interestingly, mutations of the major viral fusion protein GP64 that conferred decreased fusogenicity did not affect virus infection of insect cells, whereas virus transduction into mammalian cells was severely impaired, suggesting a more stringent dependence on GP64 fusogenicity for AcMNPV entry into mammalian cells than into insect cells. An increase in the fusogenicity of GP64 mutants resulting from low pH triggered the rescue of fusion-deficient recombinant virus transduction efficiency. Based on the above-described findings, the pH of EEs was specifically reduced with a Na(+)/K(+)-ATPase inhibitor, and the AcMNPV transduction of many mammalian cells indeed became highly efficient. This study not only revealed the roadblocks to mammalian cell entry of baculovirus but also provides a new strategy for improving baculovirus-based gene delivery and therapy. IMPORTANCE Baculoviruses can transduce a wide variety of mammalian cells but do so with low efficiency, which greatly limits their practical application as potential gene delivery vectors. So far, the understanding of baculovirus entry into mammalian cells is obscure, and the limiting stages and factors are unclear. In this study, by comparatively analyzing the mechanisms of baculovirus entry into mammalian and insect cells, virus fusion during the early stage of endocytosis was revealed as the major obstacle for efficient baculovirus transduction into mammalian cells. A higher fusogenicity of the major viral fusion protein GP64 was found to be required for virus entry into mammalian cells than for entry into insect cells. Interestingly, by decreasing the pH of early endosomes with a specific agent, virus transduction of a wide range of mammalian cells was greatly enhanced. This study uncovers the roadblocks to mammalian cell entry of baculoviruses and presents mechanisms to overcome the roadblocks.

gp41 , one of the baculovirus core genes, encodes the only recognized tegument (O-glycosylated) protein of the occlusion-derived virion (ODV) phenotype so far. A previous study using a temperature-sensitive Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) mutant showed that GP41 plays a crucial role in budded virion (BV) formation. However, the precise function of GP41 in the baculovirus replication cycle remains unclear. In this study, AcMNPV GP41 was found to accumulate around the ring zone (RZ) region within the infected nucleus and finally assembled into both BVs and ODVs. Deletion of gp41 from the AcMNPV genome showed that BVs were no longer formed and ODVs were no longer assembled, suggesting the essential role of this gene in baculovirus virion morphogenesis. In infected cells, besides the 42-kDa monomers, dimers and trimers were detected under nonreducing conditions, whereas only trimeric GP41 forms were selectively incorporated into BVs or ODVs. Mutations of all five cysteines in GP41 individually had minor effects on GP41 oligomer formation, albeit certain mutations impaired infectious BV production, suggesting flexibility in the intermolecular disulfide bonding. Single mutations of key leucines within two predicted leucine zipper-like motifs did not interfere with GP41 oligomerization or BV and ODV formation, but double leucine mutations completely blocked oligomerization of GP41 and progeny BV production. In the latter case, the usual subcellular localization, especially RZ accumulation, of GP41 was abolished. The above findings clearly point out a close correlation between GP41 oligomerization and function and therefore highlight the oligomeric state as the functional form of GP41 in the baculovirus replication cycle. IMPORTANCE The tegument, which is sandwiched between the nucleocapsid and the virion envelope, is an important substructure of many enveloped viruses. It is composed of one or more proteins that have important functions during virus entry, replication, assembly, and egress. Unlike another large DNA virus (herpesvirus) that encodes an extensive set of tegument components, baculoviruses very likely exploit the major tegument protein, GP41, to execute functions in baculovirus virion morphogenesis and assembly. However, the function of this O-glycosylated baculovirus tegument protein remains largely unknown. In this study, we identified trimers as the functional structure of GP41 in baculovirus virion morphogenesis and showed that both disulfide bridging and protein-protein interactions via the two leucine zipper-like domains are involved in the formation of different oligomeric states. This study advances our understanding of the unique viral tegument protein GP41 participating in the life cycle of baculoviruses.

Objective The aim of this study is to clarify the association between subventricular zone (SVZ) involvement and velocity of diametric expansion(VDE) in patients with low-grade astrocytoma and also assessed the clinical outcome of those patients. Materials and Methods A total of 168 adult patients with newly diagnosed supratentorial low-grade astrocytoma were studied retrospectively. Results There were 73 patients had SVZ involvement. Patients with SVZ involvement(7.16 ± 6.53 mm/y) had a higher VDE than patients without SVZ involvement(4.38 ± 5.35 mm/y). VDE was modeled as a categorical variable(＜4, ≥4 and, ＜8, ≥8 and, ＜12, ≥12 mm/y). Logistic regression showed that SVZ involvement was associated with high VDE after adjusting by confounding variables. On the univariate analysis, the results showed that tumor involved with SVZ, VDE ≥ 4 mm/y, VDE ≥ 8 mm/y, and VDE ≥ 8 mm/y were significant predictors of a shorter OS, progression-free survival (PFS) and malignant progression-free survival (MFS)(all p ＜0.05). The categorical variables of VDE (＜4 mm/y, ≥4 mm/y and, ＜8 mm/y, ≥8 mm/y and, ＜12 mm/y, ≥12 mm/y) were adjusted by confounding variables in multivariate analysis, respectively. The results indicated that VDE ≥ 8 mm/y, VDE ≥ 12 mm/y were worse prognostic factors for OS, while VDE ≥ 4 mm/y, VDE ≥ 8 mm/y and VDE ≥ 12 mm/y were related to shorter PFS and MFS. In addition, SVZ involvement was prognostic factors in predicting OS and PFS except MFS. Conclusion Our results demonstrated that SVZ involvement predicted high VDE and worse clinical outcome, and high VDE was associated with poor prognosis in patients with low-grade astrocytoma.

Quantification of the association between selenium and risk of oesophageal adenocarcinoma (OAC) is still conflicting. The purpose of this meta-analysis is to explore the relationship between selenium levels and OAC risk. PubMed and Web of Knowledge were searched for the related articles. Pooled relative risks (RRs) with 95% confidence intervals (CIs) from random effects models were calculated. Sensitivity analysis and publication bias were conducted. Dose–response relationship was assessed by restricted cubic spline and variance-weighted least squares regression analysis. Five articles involving 748 OAC cases were included in this meta-analysis. Pooled results suggest that higher selenium level was not significantly associated with the risk of OAC (summary RRs=1.08, 95% CIs=0.84–1.39, I2=0%). Besides, no significant association was found in case-control studies (summary RRs=1.13, 95% CIs=0.84–1.52, I2=0%) or cohort studies (summary RRs=0.99, 95% CIs=0.55–1.78, I2=32.6%). A linear dose–response relationship was attested that an increase in dietary selenium intake of 10 μg/day is marginally associated with 1% increase in the risk of developing OAC (summary RRs=1.01, 95% CIs=0.99–1.03), but not statistically significant. No publication bias was found. In conclusion, our analysis indicated that a higher selenium level was not significantly associated with the risk of OAC. The relevant further studies are warranted.

The Bunyavirales is one of the largest groups of RNA viruses, which encompasses many strains that are highly pathogenic to animals and humans. Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus that causes severe disease in humans, with a high fatality rate of up to 30%. To date, the entry process of bunyavirus infection remains obscure. Here, using quantum dot (QD)-based single-particle tracking and multicolor imaging, the dynamic molecular process of SFTSV entry and penetration is systematically dissected. The results show that internalization of SFTSV into host cells is initiated by recruiting clathrin onto the cell membrane for the formation of clathrin-coated pits and further pinching off from the plasma membrane to form discrete vesicles. These vesicular carriers further deliver virions to Rab5+ early endosomes, and then to Rab7+ late endosomes. The intracellular transport of virion-carrying endocytic vesicles is dependent first on actin filaments at the cell periphery, and then on microtubules toward the cell interior. The final fusion events occur at ≈15-60 min post-entry, and are triggered by the acidic environment at ≈pH5.6 within the late endosomes. These results reveal the multistep SFTSV entry process and the dynamic virus-host interactions involved.