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Abstract Purpose To report two-year survival after scheduled extubation in patients with pneumonia or acute respiratory distress syndrome (ARDS). Methods This was a prospective observational study performed in a respiratory ICU of a teaching hospital. Pneumonia or ARDS patients who successfully completed a spontaneous breathing trial were enrolled. Data were collected before extubation. Patients were followed up to two years by phone every 3 months. Results A total of 230 patients were enrolled in final analysis. One-, 3-, 6-, 12-, and 24-month survival was 77.4%, 63.8%, 61.3%, 57.8%, and 47.8%, respectively. Cox regression shows that Charlson comorbidity index (hazard ratio: 1.20, 95% confidence interval: 1.10–1.32), APACHE II score before extubation (1.11, 1.05–1.17), cough peak flow before extubation (0.993, 0.986–0.999), and extubation failure (3.96, 2.51–6.24) were associated with two-year mortality. To predict death within two years, the area under the curve of receiver operating characteristic was 0.79 tested by Charlson comorbidity index, 0.75 tested by APACHE II score, and 0.75 tested by cough peak flow. Two-year survival was 31% and 77% in patients with Charlson comorbidity index ≥ 1 and 58 and ≤ 58 L/min, respectively. Conclusions Comorbidity, disease severity, weak cough and extubation failure were associated with increased two-year mortality in pneumonia or ARDS patients who experienced scheduled extubation. It provides objective information to caregivers to improve decision-making process during hospitalization and post discharge.

Over the past decades, increasing evidence has indicated that multiple mechanical signals with different magnitude and pattern, including fluid flow-derived shear stress, topology of extracellular matrix (ECM), substrate stiffness, tension or compression, are now emerging as important orchestrators of immune response under physiological and pathophysiological conditions. Correspondingly, the extrinsic mechanical signals may confer the unique mechanophenotypes on cells, which coupled with their immunophenotypes, determines the ultimate type of immune response. Therefore, the concept of mechano-immunological checkpoints is proposed, which concerns the featured mechanical signals and the typical mechanophenotypes of immune cells, making it possible to elucidate and treat immune-associated disease from the mechanical viewpoint.

Abstract Objective To explore the association between PaCO2 and noninvasive ventilation (NIV) failure in patients with hypoxemic respiratory failure. Methods A retrospective study was performed in a respiratory ICU of a teaching hospital. Patients admitted to ICU between 2011 and 2019 were screened. We enrolled the patients with hypoxemic respiratory failure. However, patients who used NIV due to acute-on-chronic respiratory failure or heart failure were excluded. Data before the use of NIV were collected. Requirement of intubation was defined as NIV failure. Results A total of 1029 patients were enrolled in final analysis. The rate of NIV failure was 45% (461/1029). A nonlinear relationship between PaCO2 and NIV failure was found by restricted cubic splines (p = 0.03). The inflection point was 32 mmHg. The rate of NIV failure was 42% (224/535) in patients with PaCO2 >32 mmHg. However, it increased to 48% (237/494) in those with PaCO2 ≤ 32 mmHg. The crude and adjusted hazard ratio (HR) for NIV failure was 1.36 (95%CI:1.13–1.64) and 1.23(1.01–1.49), respectively, if the patients with PaCO2 >32 mmHg were set as reference. In patients with PaCO2 ≤ 32 mmHg, one unit increment of PaCO2 was associated with 5% reduction of NIV failure. However, it did not associate with NIV failure in patients with PaCO2 >32 mmHg. Conclusions PaCO2 and NIV failure was nonlinear relationship. The inflection point was 32 mmHg. Below the inflection point, lower PaCO2 was associated with higher NIV failure. However, it did not associate with NIV failure above this point.

Abstract Background The efficacy of palliative primary tumor resection (PTR) in improving prognosis for patients with unresectable metastatic colorectal neuroendocrine neoplasms (NENs) has not been fully explored. Methods We performed one retrospective cohort study and recruited 68 patients with unresectable metastatic colorectal NENs from two Chinese medical centers between 2000 and 2022. All patients were assigned to PTR group and no PTR group. The clinicopathological manifestation data were carefully collected, and the survival outcomes were compared between the two groups using Kaplan–Meier methods. Propensity score matching (PSM) was conducted to minimize confounding bias. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify prognostic factors. Results A total of 32 patients received PTR, and the other 36 patients did not. The median progression-free survival (PFS) and overall survival (OS) times were 4 and 22 months in the whole cohort, respectively. For patients who received no PTR, the median OS was 16 months, and the 1-year OS rate and 3-year OS rate were 56.4% and 39.6%, respectively. For patients who received PTR, the median OS was 24 months, and the 1-year OS rate and 3-year OS rate were 67.9% and 34.1%, respectively. However, the Kaplan–Meier survival curves and log-rank test demonstrated no significant survival difference between the two groups (P = 0.963). Moreover, palliative PTR was also not confirmed as a prognostic factor in subsequent univariable and multivariable Cox proportional hazards regression analyses in both the original and matched cohorts. Only histological differentiation was identified as an independent prognostic factor affecting PFS [hazard ratio (HR) = 1.86, 95% confidence interval (CI): 1.02–3.41, P = 0.043] and OS [HR = 3.70, 95% CI: 1.09–12.48, P = 0.035] in the original cohort. Conclusions Palliative PTR may not offer survival benefits for patients with unresectable metastatic colorectal NENs.

In this study, we observed worsening metabolic crosstalk in mouse models with concomitant metabolic disorders such as hyperhomocysteinemia (HHcy), hyperlipidemia, and hyperglycemia and in human coronary artery disease by analyzing metabolic profiles. We found that HHcy worsening is most sensitive to other metabolic disorders. To identify metabolic genes and metabolites responsible for the worsening metabolic crosstalk, we examined mRNA levels of 324 metabolic genes in Hcy, glucose-related and lipid metabolic systems. We examined Hcy-metabolites (Hcy, SAH and SAM) by LS-ESI-MS/MS in 6 organs (heart, liver, brain, lung, spleen, and kidney) from C57BL/6J mice. Through linear regression analysis of Hcy-metabolites and metabolic gene mRNA levels, we discovered that SAH-responsive genes were responsible for most metabolic changes and all metabolic crosstalk mediated by Serine, Taurine, and G3P. SAH-responsive genes worsen glucose metabolism and cause upper glycolysis activation and lower glycolysis suppression, indicative of the accumulation of glucose/glycogen and G3P, Serine synthesis inhibition, and ATP depletion. Insufficient Serine due to negative correlation of PHGDH with SAH concentration may inhibit the folate cycle and transsulfurarion pathway and consequential reduced antioxidant power, including glutathione, taurine, NADPH, and NAD+. Additionally, we identified SAH-activated pathological TG loop as the consequence of increased fatty acid (FA) uptake, FA β-oxidation and Ac-CoA production along with lysosomal damage. We concluded that HHcy is most responsive to other metabolic changes in concomitant metabolic disorders and mediates worsening metabolic crosstalk mainly via SAH-responsive genes, that organ-specific Hcy metabolism determines organ-specific worsening metabolic reprogramming, and that SAH, acetyl-CoA, Serine and Taurine are critical metabolites mediating worsening metabolic crosstalk, redox disturbance, hypomethylation and hyperacetylation linking worsening metabolic reprogramming in metabolic syndrome.

In recent years, researchers have become focused on the relationship between lipids and bone metabolism balance. Moreover, many diseases related to lipid metabolism disorders, such as nonalcoholic fatty liver disease, atherosclerosis, obesity, and menopause, are associated with osteoporotic phenotypes. It has been clinically observed in humans that these lipid metabolism disorders promote changes in osteoporosis-related indicators bone mineral density and bone mass. Furthermore, similar osteoporotic phenotype changes were observed in high-fat and high-cholesterol-induced animal models. Abnormal lipid metabolism (such as increased oxidized lipids and elevated plasma cholesterol) affects bone microenvironment homeostasis via cross-organ communication, promoting differentiation of mesenchymal stem cells to adipocytes, and inhibiting commitment towards osteoblasts. Moreover, disturbances in lipid metabolism affect the bone metabolism balance by promoting the secretion of cytokines such as receptor activator of nuclear factor-kappa B ligand by osteoblasts and stimulating the differentiation of osteoclasts. Conclusively, this review addresses the possible link between lipid metabolism disorders and osteoporosis and elucidates the potential modulatory mechanisms and signaling pathways by which lipid metabolism affects bone metabolism balance. We also summarize the possible approaches and prospects of intervening lipid metabolism for osteoporosis treatment.

Abstract Background Hyperhomocysteinemia (HHcy) has been linked to development of Alzheimer’s disease (AD) neuropathologically characterized by the accumulation of amyloid β (Aβ). Microglia (MG) play a crucial role in uptake of Aβ fibrils, and its dysfunction worsens AD. However, the effect of HHcy on MG Aβ phagocytosis remains unstudied. Methods We isolated MG from the cerebrum of HHcy mice with genetic cystathionine-β-synthase deficiency (Cbs −/− ) and performed bulk RNA-seq. We performed meta-analysis over transcriptomes of Cbs −/− mouse MG, human and mouse AD MG, MG Aβ phagocytosis model, human AD methylome, and GWAS AD genes. Results HHcy and hypomethylation conditions were identified in Cbs −/− mice. Through Cbs −/− MG transcriptome analysis, 353 MG DEGs were identified. Phagosome formation and integrin signaling pathways were found suppressed in Cbs −/− MG. By analyzing MG transcriptomes from 4 AD patient and 7 mouse AD datasets, 409 human and 777 mouse AD MG DEGs were identified, of which 37 were found common in both species. Through further combinatory analysis with transcriptome from MG Aβ phagocytosis model, we identified 130 functional-validated Aβ phagocytic AD MG DEGs (20 in human AD, 110 in mouse AD), which reflected a compensatory activation of Aβ phagocytosis. Interestingly, we identified 14 human Aβ phagocytic AD MG DEGs which represented impaired MG Aβ phagocytosis in human AD. Finally, through a cascade of meta-analysis of transcriptome of AD MG, functional phagocytosis, HHcy MG, and human AD brain methylome dataset, we identified 5 HHcy-suppressed phagocytic AD MG DEGs (Flt1, Calponin 3, Igf1, Cacna2d4, and Celsr) which were reported to regulate MG/MΦ migration and Aβ phagocytosis. Conclusions We established molecular signatures for a compensatory response of Aβ phagocytosis activation in human and mouse AD MG and impaired Aβ phagocytosis in human AD MG. Our discoveries suggested that hypomethylation may modulate HHcy-suppressed MG Aβ phagocytosis in AD.

Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-associated enzyme-CAS holds great promise for treating many uncured human diseases and illnesses by precisely correcting harmful point mutations and disrupting disease-causing genes. The recent Food and Drug Association (FDA) approval of the first CRISPR-based gene therapy for sickle cell anemia marks the beginning of a new era in gene editing. However, delivering CRISPR specifically into diseased cells in vivo is a significant challenge and an area of intense research. The identification of new CRISPR/Cas variants, particularly ultra-compact CAS systems with robust gene editing activities, paves the way for the low-capacity delivery vectors to be used in gene therapies. CRISPR/Cas technology has evolved beyond editing DNA to cover a wide spectrum of functionalities, including RNA targeting, disease diagnosis, transcriptional/epigenetic regulation, chromatin imaging, high-throughput screening, and new disease modeling. CRISPR/Cas can be used to engineer B-cells to produce potent antibodies for more effective vaccines and enhance CAR T-cells for the more precise and efficient targeting of tumor cells. However, CRISPR/Cas technology has challenges, including off-target effects, toxicity, immune responses, and inadequate tissue-specific delivery. Overcoming these challenges necessitates the development of a more effective and specific CRISPR/Cas delivery system. This entails strategically utilizing specific gRNAs in conjunction with robust CRISPR/Cas variants to mitigate off-target effects. This review seeks to delve into the intricacies of the CRISPR/Cas mechanism, explore progress in gene therapies, evaluate gene delivery systems, highlight limitations, outline necessary precautions, and scrutinize the ethical considerations associated with its application.

Hydraulic fracturing plays a vital role in the development of coalbed methane (CBM). Coal seam structures can, however, affect the fracturing operations, further affecting gas and water production from the coal seam. Within the research area—the Shizhuangnan Block, Southern Qinshui Basin, China—three types of coal body textures are relevant, including original, cataclastic, and granulated structure. This research describes the impacts of different coal seam types on fracturing operations and gas and water production. The results show that different types of coal seams have different impacts on hydraulic fracturing and the resultant production of gas and water. The coal seams are classified according to the vertical variation characteristics of the coal seam structures. The first type of coal seam (Type I) only develops the original and cataclastic coal structure. The effects of fracturing reconstruction for Type I are good. A high degree of coal breakage and fracture formation is observed. Gas production from CBM wells in Type I coalbeds is usually high because the water in the coal reservoir can be discharged smoothly at an early stage. The second type of coal seam (Type II) develops an additional layer of granulated coal compared with Type I. During the fracturing process, breakage of the coal seam is obvious, and the granulated coal can easily produce fine-grained coal that can block the pores and fractures, which causes an increase and fluctuation of oil pressure and can affect the effectiveness of fracturing. The gas production curve from CBM wells in Type II coal seams is mostly bimodal and water production depends on whether the pulverized coal blocks the pores and fractures. The third type of coal seam (Type III) develops two additional layers of granulated coal compared with Type I, with a greater proportion of granulated coal present. A low degree of coal breakage and fracture formation is observed, and fractures are easily blocked by pulverized coal. The effects of fracturing reconstruction for Type III are bad. Forming an effective seepage channel in this type of coal seam and extending the fracture to the far end is difficult. The gas production from CBM wells in Type III coal seams is usually low, and water production is generally low during the whole drainage period.

In metal-wall EAST superconducting tokamak, H-mode operation with plasma density close to the Greenwald density limit nGW has been achieved with radio frequency and NBI heating for the first time. Both gas puffing from horizontal plane and HFS pellet fueling were used for density ramp-up during the experiment. The confinement of H-mode gradually deteriorates with plasma density increasing. And the H-L transition can be observed after heating power dropping or pellet injection. In the density range of (0.6–1)×nGW, the divertor detachment occurs and causes an obvious confinement degradation. The maximum accessible density ne, max in H-mode phase deviates from the Greenwald scaling. It has been observed that the fraction ne, max/nGW is almost independent of the total heating power, but a high heating power is helpful to extend the duration of high density H-mode. And ne,max/nGW has an increase relation with the safety factor q95 varied by changing plasma current. Besides, it is also found that the discharges with low plasma current have a higher ne, max/nGW than those with high plasma current. All these findings will provide a good reference to the high density plasma operation for future metal-wall fusion devices.

Reactive oxygen burst in articular chondrocytes is a major contributor to osteoarthritis progression. Although selenium is indispensable role in the antioxidant process, the narrow therapeutic window, delicate toxicity margins, and lack of an efficient delivery system have hindered its translation to clinical applications. Herein, transcriptomic and biochemical analyses revealed that osteoarthritis was associated with selenium metabolic abnormality. A novel injectable hydrogel to deliver selenium nanoparticles (SeNPs) was proposed to intervene selenoprotein expression for osteoarthritis treatment. The hydrogels based on oxidized hyaluronic acid (OHA) cross-linked with hyaluronic acid-adipic acid dihydrazide (HA-ADH) was formulated to load SeNPs through a Schiff base reaction. The hydrogels were further incorporated with SeNPs, which exhibited minimal toxicity, mechanical properties, self-healing capability, and sustained drug release. Encapsulated with SeNPs, the hydrogels facilitated cartilage repair through synergetic effects of scavenging reactive oxygen species (ROS) and depressing apoptosis. Mechanistically, the hydrogel restored redox homeostasis by targeting glutathione peroxidase-1 (GPX1). Therapeutic outcomes of the SeNPs-laden hydrogel were demonstrated in an osteoarthritis rat model created by destabilization of the medial meniscus, including cartilage protection, subchondral bone sclerosis improvement, inflammation attenuation, and pain relief were demonstrated. These results highlight therapeutic potential of OHA/HA-ADH@SeNPs hydrogels, providing fundamental insights into remedying selenium imbalance for osteoarthritis biomaterial development.

Background & Aims: Liver paracrine signaling from liver sinusoid endothelial cells to hepatocytes in response to mechanical stimuli is crucial in highly coordinated liver regeneration. Interstitial flow through the fenestrated endothelium inside the space of Disse potentiates the role of direct exposure of hepatocytes to fluid flow in the immediate regenerative responses after partial hepatectomy, but the underlying mechanisms remain unclear. Methods: Mouse liver perfusion was used to identify the effects of interstitial flow on hepatocyte proliferation ex vivo. Isolated hepatocytes were further exposed to varied shear stresses directly in vitro. Knockdown and/or inhibition of mechanosensitive proteins were used to unravel the signaling pathways responsible for cell proliferation. Results: An increased interstitial flow was visualized and hepatocytes' regenerative response was demonstrated experimentally by ex vivo perfusion of mouse livers. In vitro measurements also showed that fluid flow initiated hepatocyte proliferation in a duration- and amplitude-dependent manner. Mechanistically, flow enhanced β1 integrin expression and nuclear translocation of YAP (yes-associated protein), via the Hippo pathway, to stimulate hepatocytes to re-enter the cell cycle. Conclusions: Hepatocyte proliferation was initiated after direct exposure to interstitial flow ex vivo or shear stress in vitro, which provides new insights into the contributions of mechanical forces to liver regeneration. Impact and implications: By using both ex vivo liver perfusion and in vitro flow exposure tests, we identified the roles of interstitial flow in the space of Disse in stimulating hepatocytes to re-enter the cell cycle. We found an increase in shear flow-induced hepatocyte proliferation via β1 integrin-YAP mechanotransductive pathways. This serves as a useful model to potentiate hepatocyte expansion in vitro using mechanical forces.

Abstract Background The ratio of SpO2/FiO2 to respiratory rate (ROX) index is commonly used to predict the failure of high-flow nasal cannula. However, its predictive power for noninvasive ventilation (NIV) failure is unclear. Methods This was a secondary analysis of a multicenter prospective observational study, intended to update risk scoring. Patients with de novo acute respiratory failure were enrolled, but hypercapnic patients were excluded. The ROX index was calculated before treatment and after 1–2, 12, and 24 h NIV. Differences in predictive power for NIV failure using the ROX index, PaO2/FiO2, and PaO2/FiO2/respiratory rate were tested. Results A total of 1286 patients with de novo acute respiratory failure were enrolled. Of these, 568 (44%) experienced NIV failure. Patients with NIV failure had a lower ROX index than those with NIV success. The rates of NIV failure were 92.3%, 70.5%, 55.3%, 41.1%, 35.1%, and 29.5% in patients with ROX index values calculated before NIV of ≤ 2, 2–4, 4–6, 6–8, 8–10, and > 10, respectively. Similar results were found when the ROX index was assessed after 1–2, 12, and 24 h NIV. The area under the receiver operating characteristics curve was 0.64 (95% CI 0.61–0.67) when the ROX index was used to predict NIV failure before NIV. It increased to 0.71 (95% CI 0.68–0.74), 0.74 (0.71–0.77), and 0.77 (0.74–0.80) after 1–2, 12, and 24 h NIV, respectively. The predictive power for NIV failure was similar for the ROX index and for the PaO2/FiO2. Likewise, no difference was found between the ROX index and the PaO2/FiO2/respiratory rate, except at the time point of 1–2 h NIV. Conclusions The ROX index has moderate predictive power for NIV failure in patients with de novo acute respiratory failure.

Abstract Background Heart rate, acidosis, consciousness, oxygenation, and respiratory rate (HACOR) have been used to predict noninvasive ventilation (NIV) failure. However, the HACOR score fails to consider baseline data. Here, we aimed to update the HACOR score to take into account baseline data and test its predictive power for NIV failure primarily after 1–2 h of NIV. Methods A multicenter prospective observational study was performed in 18 hospitals in China and Turkey. Patients who received NIV because of hypoxemic respiratory failure were enrolled. In Chongqing, China, 1451 patients were enrolled in the training cohort. Outside of Chongqing, another 728 patients were enrolled in the external validation cohort. Results Before NIV, the presence of pneumonia, cardiogenic pulmonary edema, pulmonary ARDS, immunosuppression, or septic shock and the SOFA score were strongly associated with NIV failure. These six variables as baseline data were added to the original HACOR score. The AUCs for predicting NIV failure were 0.85 (95% CI 0.84–0.87) and 0.78 (0.75–0.81) tested with the updated HACOR score assessed after 1–2 h of NIV in the training and validation cohorts, respectively. A higher AUC was observed when it was tested with the updated HACOR score compared to the original HACOR score in the training cohort (0.85 vs. 0.80, 0.86 vs. 0.81, and 0.85 vs. 0.82 after 1–2, 12, and 24 h of NIV, respectively; all p values 14 after 1–2 h of NIV, the rate of NIV failure was 12.4%, 38.2%, 67.1%, and 83.7%, respectively. Conclusions The updated HACOR score has high predictive power for NIV failure in patients with hypoxemic respiratory failure. It can be used to help in decision-making when NIV is used.

Abstract Background Cough strength is associated with short-term outcome in patients with scheduled extubation who successfully complete a spontaneous breathing trial (SBT). However, the long-term outcome is unclear. Methods This was a prospective observational study performed in a respiratory ICU of a teaching hospital. COPD patients who successfully completed a SBT were candidates. We enrolled the case who assessed the cough strength by cough peak flow (CPF) or semiquantitative cough strength score (SCSS, ranging from 0 = weak to 5 = strong). Patients were followed up to two years by phone every 3 months. Results A total of 215 patients were enrolled in current study. Among them, CPF and SCSS were measured in 214 and 208 cases, respectively. Strong cough was associated with a 16% decrease in the risk of two-year mortality (adjusted hazard ratio [HR] 0.84, 95%CI: 0.78–0.91) per 10 L/min increment of CPF. When it was tested by SCSS, decrease in the risk of two-year mortality per unit increment was 27% (adjusted HR 0.73, 95%CI: 0.62–0.86). Similar results were confirmed in the discharged patients. In all patients, the two-year mortality was 75%, 53%, and 38% in patients with CPF 90 L/min; and 85%, 70%, and 40% in patients with SCSS of 0–1, 2–3, and 4–5, respectively. Similar trend was found among the discharged patients whether it was assessed by CPF or SCSS. Conclusions In COPD patients, weak cough is associated with increased two-year mortality after a scheduled extubation. It provides objective information to caregivers to improve decision-making process during hospitalization and after discharge.

Background: Pin1 is a member of the evolutionarily conserved peptidyl-prolyl isomerase (PPIase) family of proteins. Following phosphorylation, Pin1-catalyzed prolyl-isomerization induces conformational changes, which serve to regulate the function of many phosphorylated proteins that play important roles during oncogenesis. Thus, the inhibition of Pin1 provides a unique means of disrupting oncogenic pathways and therefore represents an appealing target for novel anticancer therapies.Methods: As Pin1 is conserved between yeast and humans, we employed budding yeast to establish a high-throughput screening method for the primary screening of Pin1 inhibitors. This effort culminated in the identification of the compounds HWH8-33 and HWH8-36. Multifaceted approaches were taken to determine the inhibition profiles of these compounds against Pin1 activity in vitro and in vivo, including an isomerization assay, surface plasmon resonance (SPR) technology, virtual docking, MTT proliferation assay, western blotting, cell cycle analysis, apoptosis analysis, immunofluorescence analysis, wound healing, migration assay, and nude mouse assay.Results:In vitro, HWH8-33 and HWH8-36 could bind to purified Pin1 and inhibited its enzyme activity; showed inhibitory effects on cancer cell proliferation; led to G2/M phase arrest, dysregulated downstream protein expression, and apoptosis; and suppressed cancer cell migration. In vivo, HWH8-33 suppressed tumor growth in the xenograft mice after oral administration for 4 weeks, with no noticeable toxicity. Together, these results show the anticancer activity of HWH8-33 and HWH8-36 against Pin1 for the first time.Conclusion: In summary, we identified two hit compounds HWH8-33 and HWH8-36, which after further structure optimization have the potential to be developed as antitumor drugs.

In this work, high-frequency forced vibrations of lateral field excitation (LFE) devices with stepped electrodes based on monoclinic crystals GdCOB are modeled, and the influence laws of the device parameters (the step number, size, and thickness of the stepped electrodes) on the energy-trapping effects of the device are revealed. The results show that the step number has a significant effect on the energy-trapping effect of the device: with the increase in the step number, the stronger energy-trapping effect of the device can be obtained; with the increase in the thickness difference of two layers of electrodes, the energy-trapping effect of the device becomes stronger; with the increase in the difference of the electrode radius, the energy-trapping effect of the device is enhanced gradually. The results of this work can provide an important theoretical basis for the design of stepped-electrode LFE resonators and sensors with high-quality factors based on monoclinic crystals.

IntroductionNon-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% of the population and is a leading cause of cirrhosis and hepatocellular carcinoma. NAFLD ranges from simple steatosis (non-alcoholic fatty liver) to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs) and monocyte-derived macrophages, act as key players in the progression of NAFLD. Caspases are a family of endoproteases that provide critical connections to cell regulatory networks that sense disease risk factors, control inflammation, and mediate inflammatory cell death (pyroptosis). Caspase-11 can cleave gasdermin D (GSDMD) to induce pyroptosis and specifically defends against bacterial pathogens that invade the cytosol. However, it’s still unknown whether high fat diet (HFD)-facilitated gut microbiota-generated cytoplasmic lipopolysaccharides (LPS) activate caspase-11 and promote NAFLD.MethodsTo examine this hypothesis, we performed liver pathological analysis, RNA-seq, FACS, Western blots, Seahorse mitochondrial stress analyses of macrophages and bone marrow transplantation on HFD-induced NAFLD in WT and Casp11–/– mice.Results and DiscussionOur results showed that 1) HFD increases body wight, liver wight, plasma cholesterol levels, liver fat deposition, and NAFLD activity score (NAS score) in wild-type (WT) mice; 2) HFD increases the expression of caspase-11, GSDMD, interleukin-1β, and guanylate-binding proteins in WT mice; 3) Caspase-11 deficiency decreases fat liver deposition and NAS score; 4) Caspase-11 deficiency decreases bone marrow monocyte-derived macrophage (MDM) pyroptosis (inflammatory cell death) and inflammatory monocyte (IM) surface GSDMD expression; 5) Caspase-11 deficiency re-programs liver transcriptomes and reduces HFD-induced NAFLD; 6) Caspase-11 deficiency decreases extracellular acidification rates (glycolysis) and oxidative phosphorylation (OXPHOS) in inflammatory fatty acid palmitic acid-stimulated macrophages, indicating that caspase-11 significantly contributes to maintain dual fuel bioenergetics—glycolysis and OXPHOS for promoting pyroptosis in macrophages. These results provide novel insights on the roles of the caspase-11-GSDMD pathway in promoting hepatic macrophage inflammation and pyroptosis and novel targets for future therapeutic interventions involving the transition of NAFLD to NASH, hyperlipidemia, type II diabetes, metabolic syndrome, metabolically healthy obesity, atherosclerotic cardiovascular diseases, autoimmune diseases, liver transplantation, and hepatic cancers.

Nanoscale/microscale metal–organic frameworks (nano/microscale MOFs) are considered kinds of nanomaterials with profound application potentials in many fields due to the high specific surface area, permanent porosity, and multiple chemical functions. This review focuses on the specific synthesis strategies of nano/microscale MOFs, such as controlled mediation, template, one‐pot, and interface growth methods, through which the shape and size of the crystal can be regulated during the nucleation process. After these targeted design and synthesis strategies, nano/microscale MOFs are optimized for energy storage, catalysis, and biomedical applications based on several merits, including a large specific surface area with more active sites, smaller ion transfer resistance, and structural stability. In addition, challenges and prospects of nano/microscale MOF materials are summarized for advanced energy storage and conversion applications.

In this work, we report the effect of axial ligation on the excited state dynamics of Cobalt phthalocyanines (CoPc) using the combination of X-ray absorption spectroscopy (XAS), transient absorption (TA) spectroscopy, and density functional theory (DFT) calculation. The formation of six coordinated Co center was unambiguously confirmed by XAS when pyridine was used as the solvent, which leads to the prominent blue shift of its Q-band transition with respect to that in weak-ligating solvent (DMF). This is further supported by DFT calculation, which predicted that axial coordination by two pyridine molecules leads to blue shift of Q band. More interestingly, using TA spectroscopy, we observed the formation of a new intermediated state, which is likely due to the further axial ligation of pyridine to CoPc upon photoexcitation, resulting in the quenching of the CoPc excited state and shorter lifetime.

Since deterministic prediction errors of wind power cannot be avoided, probabilistic prediction can adequately describe the uncertainty of wind power and, thus, provide further guidance to dispatching authorities for decision making. Current probabilistic prediction methods for wind power are still incomplete in mining its physical variation process. Therefore, this study constructs a new framework for short-term wind power probabilistic forecasting considering the spatio-temporal dependence of errors by mining the spatio-temporal characteristics of historical wind power data and numerical weather forecasts at numerical weather prediction (NWP). First, the deterministic prediction results are obtained by an improved deep belief network (DBN); then, a multi-location NWP is introduced to propose a multi-level error scenario partitioning method considering the spatio-temporal dependence property. Finally, a new error sample set is formed by reconstructing the kernel density estimation method to adapt the model, and the short-term wind power probability prediction at different confidence levels is carried out. It is, thus, concluded that the effectiveness of the overall framework under the probabilistic prediction considering spatio-temporal dependence is verified in a wind farm in Jilin, China, and the prediction accuracy is effectively and significantly improved compared with the same confidence level, and the coverage of the evaluation index prediction interval is improved by 1.23, 0.72, and 0.80%, and the average bandwidth of the prediction interval is reduced by 2.14, 1.40, and 0.63%, which confirms the proposed effectiveness and feasibility of the method.

Abstract Background As the COVID-19 pandemic rages on, the new SARS-CoV-2 variants have emerged in the different regions of the world. These newly emerged variants have mutations in their spike (S) protein that may confer resistance to vaccine-elicited immunity and existing neutralizing antibody therapeutics. Therefore, there is still an urgent need of safe, effective, and affordable agents for prevention/treatment of SARS-CoV-2 and its variant infection. Results We demonstrated that green tea beverage (GTB) or its major ingredient, epigallocatechin gallate (EGCG), were highly effective in inhibiting infection of live SARS-CoV-2 and human coronavirus (HCoV OC43). In addition, infection of the pseudoviruses with spikes of the new variants (UK-B.1.1.7, SA-B.1.351, and CA-B.1.429) was efficiently blocked by GTB or EGCG. Among the 4 active green tea catechins at noncytotoxic doses, EGCG was the most potent in the action against the viruses. The highest inhibitory activity was observed when the viruses or the cells were pre-incubated with EGCG prior to the infection. Mechanistic studies revealed that EGCG blocked infection at the entry step through interfering with the engagement of the receptor binding domain (RBD) of the viral spikes to angiotensin-converting enzyme 2 (ACE2) receptor of the host cells. Conclusions These data support further clinical evaluation and development of EGCG as a novel, safe, and cost-effective natural product for prevention/treatment of SARS-CoV-2 transmission and infection.

In order to determine the optimum lithofacies for continental shale, the reservoir characteristics of different lithofacies types were studied based on a series of experiments. The lacustrine organic-rich shale of the Shahezi Formation is divided into siliceous (ORS), argillaceous (ORA), calcareous (ORC), and mixed (ORM) shales. The ORS, ORA, ORC, and ORM shales all carried out comprehensive reservoir comparative analysis. The results showed that the moderate content of clay minerals (45%) can significantly improve porosity, and high and low clay mineral contents are not conducive to the improvement of porosity. The ORM shale tends to have better pore connectivity than the ORS and ORA shales, and the ORC shale has the poorest pore-throat connectivity in micron-size. Internal pores in bitumen and clay shrinkage cracks are the dominant pore type and are well developed in ORS and ORM shales. The two types of pores are less developed in the ORA shale; however, dissolution pores are better developed than those of ORS and ORM shales. Inorganic pores are well-developed in the ORC shale, but organic pores are not. Organic and inorganic pores tend to be better connected in the ORM shale than those of the other three types, which could help improve the gas storage capacity. The ORM shale may have more irregular surfaces and lower liquid/gas surface tension. The higher capillary condensation on pore surfaces is more likely to occur in the ORA shale. The ORS shale offers fewer adsorption sites for CH4 and has lower adsorption capacity. The ORC shale has weak heterogeneity of the pore structure. Therefore, the ORM shale may be the most favorable lithofacies for shale gas enrichment and development, which has high porosity, good pore connectivity, moderate brittleness, and strong gas adsorption and storage capacity, followed by the ORS and ORA shales. The ORC shale is the worst.

Abstract Background Smooth endoplasmic reticulum aggregation (SERa, SER+) has been reported to increase the risk of birth malformations and other abnormal outcomes, miscarriage, and perinatal complications. Other studies, however, suggest that SER+ embryos may develop into healthy infants. One report indicates that 25% of in vitro fertilization (IVF) centers discard SER+ oocytes. Thus, we investigated the effect of SER+ on birth outcomes in IVF and intracytoplasmic sperm injection. Methods We performed a literature search using PubMed, ScienceDirect, Cochrane, Embase, Ovid, and Scopus. We found a total of 1500 relevant studies between 1978 and 2020 and conducted a meta-analysis to study the effects of SER+ on live births, birth weight, and the number of metaphase II (MII) oocytes retrieved per cycle. Results Eleven eligible studies were included. If the SER+ zygote was evaluated again at the embryo transfer (ET) stage, SER+ did not affect birth or infant body weight. Stimulated ovaries producing too many oocytes per cycle were positively correlated with SER+ (OR = 1.28, 95% CI = 0.41–2.15; p = 0.004). SER+ was positively correlated with oocyte maturation rate, and observed heterogeneity in a previous meta-analysis was likely due to maternal age. Our data also showed that SER+ cycles produced more oocytes but achieved the same number of births from ET. Conclusions The use of SER+ MII oocytes is rare, with the collection of many oocytes in 1 cycle potentially inducing SER+. SER+ may be more common than we originally thought, as some SER+ is found in all oocytes. Although SER+ positively affected oocyte maturation rate, it did not affect births. We hypothesized that this is because the best embryos are chosen at every step of the process, and the oocytes with the poorest characteristics are removed. We therefore suggest a standard method for measuring SER+. Although embryos produced from SER+ cycles can be used, they should only be transferred when no other suitable embryos are available over several cycles.

During the last decade, substance use disorders (SUDs) have been increasingly recognized as neuroinflammation-related brain diseases. Various types of abused drugs (cocaine, methamphetamine, alcohol, opiate-like drugs, marijuana, etc.) can modulate the activation status of microglia and neuroinflammation levels which are involved in the pathogenesis of SUDs. Several neuroimmune signaling pathways, including TLR/NF-кB, reactive oxygen species, mitochondria dysfunction, as well as autophagy defection, etc., have been implicated in promoting SUDs. Recently, inflammasome-mediated signaling has been identified as playing critical roles in the microglia activation induced by abused drugs. Among the family of inflammasomes, NOD-, LRR-, and pyrin-domain-containing protein 3 (NLRP3) serves the primary research target due to its abundant expression in microglia. NLRP3 has the capability of integrating multiple external and internal inputs and coordinately determining the intensity of microglia activation under various pathological conditions. Here, we summarize the effects of abused drugs on NLRP3 inflammasomes, as well as others, if any. The research on this topic is still at an infant stage; however, the readily available findings suggest that NLRP3 inflammasome could be a common downstream effector stimulated by various types of abused drugs and play critical roles in determining abused-drug-mediated biological effects through enhancing glia–neuron communications. NLRP3 inflammasome might serve as a novel target for ameliorating the development of SUDs.

The relaxor ferroelectric single crystal (1−x)Pb(Mg1/3Nb2/3)O3-xPbTiO3 (PMN-PT) has high piezoelectric constants, and thus has a good application prospect in the field of highly sensitive piezoelectric sensors. In this paper, for relaxor ferroelectric single crystal PMN-PT, the bulk acoustic wave characteristics on pure- and pseudo-lateral-field-excitation (pure- and pseudo-LFE) modes are investigated. LFE piezoelectric coupling coefficients and acoustic wave phase velocities for PMN-PT crystals in different cuts and electric field directions are calculated. On this basis, the optimal cuts of pure-LFE and pseudo-LFE modes of relaxor ferroelectric single crystal PMN-PT are obtained, namely, (zxt)45° and (zxtl)90°/90°, respectively. Finally, finite element simulations are carried out to verify the cuts of pure-LFE and pseudo-LFE modes. The simulation results show that the PMN-PT acoustic wave devices in pure-LFE mode have good energy-trapping effects. For PMN-PT acoustic wave devices in pseudo-LFE mode, when the device is in air, no obvious energy-trapping emerges; when the water (as a virtual electrode) is added to the surface of the crystal plate, an obvious resonance peak and the energy-trapping effect appears. Therefore, the PMN-PT pure-LFE device is suitable for gas-phase detections. While the PMN-PT pseudo-LFE device is suitable for liquid-phase detections. The above results verify the correctness of the cuts of the two modes. The research results provide an important basis for the development of highly sensitive LFE piezoelectric sensors based on relaxor ferroelectric single crystal PMN-PT.

Vascular smooth muscle cell (VSMC) phenotypic transformation, proliferation, and migration play a pivotal role in developing neointimal hyperplasia after vascular injury, including percutaneous transluminal angioplasty and other cardiovascular interventions. Anemoside B4 (B4) is a unique saponin identified from the Pulsatilla chinensis (Bge.) Regel, which has known anti-inflammatory activities. However, its role in modulating VSMC functions and neointima formation has not been evaluated. Herein, we demonstrate that B4 administration had a potent therapeutic effect in reducing neointima formation in a preclinical mouse femoral artery endothelium denudation model. Bromodeoxyuridine incorporation study showed that B4 attenuated neointimal VSMC proliferation in vivo. Consistent with the in vivo findings, B4 attenuated PDGF-BB-induced mouse VSMC proliferation and migration in vitro. Moreover, quantitative RT-PCR and Western blot analysis demonstrated that B4 suppressed PDGF-BB-induced reduction of SM22α, SMA, and Calponin, suggesting that B4 inhibited the transformation of VSMCs from contractile to the synthetic phenotype. Mechanistically, our data showed B4 dose-dependently inhibited the activation of the phosphatidylinositol 3-kinase (PI3K)/AKT and p38 mitogen-activated protein kinase MAPK signaling pathways. Subsequently, we determined that B4 attenuated VSMC proliferation and migration in a p38 MAPK and AKT dependent manner using pharmacological inhibitors. Taken together, this study identified, for the first time, Anemoside B4 as a potential therapeutic agent in regulating VSMC plasticity and combating restenosis after the vascular intervention.

AimsTo explore the predictors of mucosal healing (MH) for short- and long-term after exclusive enteral nutrition (EEN) in pediatric Crohn’s disease (CD) patients.MethodsA retrospective analysis was performed for newly diagnosed active CD patients admitted to our center from January 2017 to 30 December 2020, who were treated with EEN for induction therapy with a minimum of 12 months of follow-up post-EEN. According to the simple endoscopic score for CD (SES-CD), at 1-year post-EEN, 17 patients with an SES-CD < 3 were classified into the sustained MH group (sMH), and 33 patients with an SES-CD ≥ 3 were classified into the sustained non-MH group (sNMH). Statistical methods were used to compare the differences between the two groups and explore the predictors of MH at the end of EEN and 1-year post-EEN.ResultsThe SES-CD in the sMH group was lower than that in the sNMH group both at baseline and the end of EEN [sMH vs. sNMH: 8.7 ± 1.2 vs. 16.2 ± 1.0, respectively, p < 0.001 at baseline; 1.0 (3.5) vs. 4.0 (2.0), respectively, p < 0.01 at the end of EEN]. The weighted Pediatric Crohn’s Disease Activity Index and erythrocyte sedimentation rate in the sMH group were lower than those in the sNMH group at baseline (both p < 0.05), but showed no difference at the end of EEN. From baseline to 1-year post-EEN, compared with patients in the sNMH group, there were more patients classified with L1 in the sMH group at each time point (all p < 0.001) and fewer patients classified with L3 in the sMH group at baseline and 1-year post-EEN. After EEN, fewer patients received infliximab and had a longer exposure time to infliximab in the sMH group than in the sNMH group. Only the SES-CD at baseline was negatively associated with MH at the end of EEN (OR = 1.40 95% CI = 1.12–1.67, p = 0.00) and 1-year post-EEN (OR = 1.33, 95% CI = 1.12–1.58, p = 0.001), and the cut off value was 11.5.ConclusionThe SES-CD could predict both short- and long-term MH for EEN. Patients with an SES-CD < 11.5 had a high probability of reaching MH by EEN-inducing therapy and maintaining sustained MH at 1-year post-EEN. Patients with an SES-CD greater than 11.5 at baseline should be treated more aggressively with biologics.

Although recent decades have witnessed the synthesis of 1,3,4-thiadiazoles via phosphorus POCl3-promoted cyclization reaction, simultaneous access to 2-amino-1,3,4-thiadiazole and 2-amino-1,3,4-oxadiazole analogs remains unexpected and elusive. Herein, a detailed regiocontrolled synthesis of 2-amino-1,3,4-thiadiazoles in good to high yields with good regioselectivities from readily available thiosemicarbazides using POCl3 was disclosed. Meantime, to establish a comprehensive structure–activity relationship, 2-amino-1,3,4-oxadiazole derivatives as single regioisomers were prepared via EDCI·HCl-triggered cyclization of the thiosemicarbazide intermediates. The in vitro anti-influenza assays proved that the selected compounds with the pyrazine/pyridine ring exhibited certain inhibitory activities against influenza A virus strains A/HK/68 (H3N2) and A/PR/8/34 (H1N1) in MDCK cells. Among them, N-(adamantan-1-yl)-5-(5-(azepan-1-yl)pyrazin-2-yl)-1,3,4-thiadiazol-2-amine (4j) was the most active compound, and exhibited favorable activity with EC50 values of 3.5 μM and 7.5 μM, respectively. In addition, the molecular docking results explained the reason why compound 4j had dual inhibitory activity and revealed the reasonable binding mode of this compound with the M2-S31N and M2-WT ion channels. This compound had the potential to be further developed as an anti-influenza drug.

Inflammatory arthritis is a major cause of disability in the elderly. This condition causes joint pain, loss of function, and deterioration of quality of life, mainly due to osteoarthritis (OA) and rheumatoid arthritis (RA). Currently, available treatment options for inflammatory arthritis include anti-inflammatory medications administered via oral, topical, or intra-articular routes, surgery, and physical rehabilitation. Novel alternative approaches to managing inflammatory arthritis, so far, remain the grand challenge owing to catastrophic financial burden and insignificant therapeutic benefit. In the view of non-targeted systemic cytotoxicity and limited bioavailability of drug therapies, a major concern is to establish stimuli-responsive drug delivery systems using nanomaterials with on-off switching potential for biomedical applications. This review summarizes the advanced applications of triggerable nanomaterials dependent on various internal stimuli (including reduction-oxidation (redox), pH, and enzymes) and external stimuli (including temperature, ultrasound (US), magnetic, photo, voltage, and mechanical friction). The review also explores the progress and challenges with the use of stimuli-responsive nanomaterials to manage inflammatory arthritis based on pathological changes, including cartilage degeneration, synovitis, and subchondral bone destruction. Exposure to appropriate stimuli induced by such histopathological alterations can trigger the release of therapeutic medications, imperative in the joint-targeted treatment of inflammatory arthritis.

The performance of implanted biomaterials is largely determined by their interaction with the host immune system. As a fibrous-like 3D network, fibrin matrix formed at the interfaces of tissue and material, whose effects on dendritic cells (DCs) remain unknown. Here, a bone plates implantation model was developed to evaluate the fibrin matrix deposition and DCs recruitment in vivo. The DCs responses to fibrin matrix were further analyzed by a 2D and 3D fibrin matrix model in vitro. In vivo results indicated that large amount of fibrin matrix deposited on the interface between the tissue and bone plates, where DCs were recruited. Subsequent in vitro testing denoted that DCs underwent significant shape deformation and cytoskeleton reorganization, as well as mechanical property alteration. Furthermore, the immune function of imDCs and mDCs were negatively and positively regulated, respectively. The underlying mechano-immunology coupling mechanisms involved RhoA and CDC42 signaling pathways. These results suggested that fibrin plays a key role in regulating DCs immunological behaviors, providing a valuable immunomodulatory strategy for tissue healing, regeneration and implantation.

To determine whether aorta becomes immune organ in pathologies, we performed transcriptomic analyses of six types of secretomic genes (SGs) in aorta and vascular cells and made the following findings: 1) 53.7% out of 21,306 human protein genes are classified into six secretomes, namely, canonical, caspase 1, caspase 4, exosome, Weibel–Palade body, and autophagy; 2) Atherosclerosis (AS), chronic kidney disease (CKD) and abdominal aortic aneurysm (AAA) modulate six secretomes in aortas; and Middle East Respiratory Syndrome Coronavirus (MERS-CoV, COVID-19 homologous) infected endothelial cells (ECs) and angiotensin-II (Ang-II) treated vascular smooth muscle cells (VSMCs) modulate six secretomes; 3) AS aortas upregulate T and B cell immune SGs; CKD aortas upregulate SGs for cardiac hypertrophy, and hepatic fibrosis; and AAA aorta upregulate SGs for neuromuscular signaling and protein catabolism; 4) Ang-II induced AAA, canonical, caspase 4, and exosome SGs have two expression peaks of high (day 7)-low (day 14)-high (day 28) patterns; 5) Elastase induced AAA aortas have more inflammatory/immune pathways than that of Ang-II induced AAA aortas; 6) Most disease-upregulated cytokines in aorta may be secreted via canonical and exosome secretomes; 7) Canonical and caspase 1 SGs play roles at early MERS-CoV infected ECs whereas caspase 4 and exosome SGs play roles in late/chronic phases; and the early upregulated canonical and caspase 1 SGs may function as drivers for trained immunity (innate immune memory); 8) Venous ECs from arteriovenous fistula (AVF) upregulate SGs in five secretomes; and 9) Increased some of 101 trained immunity genes and decreased trained tolerance regulator IRG1 participate in upregulations of SGs in atherosclerotic, Ang-II induced AAA and CKD aortas, and MERS-CoV infected ECs, but less in SGs upregulated in AVF ECs. IL-1 family cytokines, HIF1α, SET7 and mTOR, ROS regulators NRF2 and NOX2 partially regulate trained immunity genes; and NRF2 plays roles in downregulating SGs more than that of NOX2 in upregulating SGs. These results provide novel insights on the roles of aorta as immune organ in upregulating secretomes and driving immune and vascular cell differentiations in COVID-19, cardiovascular diseases, inflammations, transplantations, autoimmune diseases and cancers.

Adeno-associated virus (AAV)-mediated genetic targeting of microglia remains a challenge. Overcoming this hurdle is essential for gene editing in the central nervous system (CNS). Here, we characterized the minimal/native promoter of the HEXB gene, which is known to be specifically and stably expressed in the microglia during homeostatic and pathological conditions. Dual reporter and serial deletion assays identified the critical role of the natural 5’ untranslated region (−97 bp related to the first ATG) in driving transcriptional activity of the mouse Hexb gene. The native promoter region of mouse, human, and monkey HEXB are located at −135, −134, and −170 bp to the first ATG, respectively. These promoters were highly active and specific in microglia with strong cross-species transcriptional activities, but did not exhibit activity in primary astrocytes. In addition, we identified a 135 bp promoter of CD68 gene that was highly active in microglia but not in astrocytes. Considering that HEXB is specifically expressed in microglia, these data suggest that the newly characterized microglia-specific HEXB minimal/native promoter can be an ideal candidate for microglia-targeting AAV gene therapy in the CNS.

BackgroundClarithromycin resistance reduces the eradication rate of Helicobacter pylori (H. pylori). Cultures with susceptibility testing and molecular determination of genotypes are recommended to guide-tailored therapy.MethodsWe retrospectively enrolled patients aged 6 and 18 years with H. pylori infection, who underwent an endoscopy and agreed to undergo both culture and genetic testing for clarithromycin resistance. Patients receiving tailored therapy based on traditional culture results (phenotype-guided therapy) or genetic testing results (genotype-guided therapy) were included in the study. 13C-urea breath test was used to evaluate the success of eradication at least 4 weeks after the completion of treatment. We aimed to determine whether the eradication rate of phenotype- or genotype-guided therapy based on clarithromycin resistance is greater than 90% in children.ResultsBetween September 2017 and October 2020, 226 eligible patients were enrolled. There were 71 with clarithromycin-sensitive strains in the phenotype-guided therapy group and 87 without 23S rRNA point mutations (A2142G, A2142C, and A2143G) in the genotype-guided therapy group. Eradication rates were 70.4% (50/71, [95% CI: 58.4–80.7%] for phenotype-guided therapy and 92.0% (80/87, [95% CI: 84.1–96.7%]) for genotype-guided therapy (P < 0.01). The incidence of side effects was 4.2% (3/71) and 10.3% (9/87), with no major differences between these two groups (P = 0.15), respectively. The compliance rate was also similar (97.2 vs. 95.4%, P = 0.87).ConclusionTailored therapy according to genetic testing results achieved eradication rates of 92% and was superior to tailored therapy guided by traditional culture results.

While single atom catalysis combines heterogeneous materials with molecular understanding, the role of the single atoms remains vague. Here, authors examine single Ni on MoS2 via in situ X-ray absorption spectroscopy to reveal the intermediate and catalytically active species.

There are multiple diseases or conditions such as hereditary hemochromatosis, hemophilia, thalassemia, sickle cell disease, aging, and estrogen deficiency that can cause iron overload in the human body. These diseases or conditions are frequently associated with osteoarthritic phenotypes, such as progressive cartilage degradation, alterations in the microarchitecture and biomechanics of the subchondral bone, persistent joint inflammation, proliferative synovitis, and synovial pannus. Growing evidences suggest that the conditions of pathological iron overload are associated with these osteoarthritic phenotypes. Osteoarthritis (OA) is an important complication in patients suffering from iron overload-related diseases and conditions. This review aims to summarize the findings and observations made in the field of iron overload-related OA while conducting clinical and basic research works. OA is a whole-joint disease that affects the articular cartilage lining surfaces of bones, subchondral bones, and synovial tissues in the joint cavity. Chondrocytes, osteoclasts, osteoblasts, and synovial-derived cells are involved in the disease. In this review, we will elucidate the cellular and molecular mechanisms associated with iron overload and the negative influence that iron overload has on joint homeostasis. The promising value of interrupting the pathologic effects of iron overload is also well discussed for the development of improved therapeutics that can be used in the field of OA.

Background: Infliximab is an effective therapy for Crohn's disease (CD). Early non-invasive predictors of disease remission allow for modification of treatments. The aim of this study was to investigate the associations between genetic variants, pharmacokinetics, and infliximab efficacy in pediatric patients with CD.Methods: This retrospective observational study included CD patients under infliximab therapy between August 2015 and December 2020. Information on demographics, laboratory tests, medication data, and disease activity index was collected. The trough levels of infliximab (TLI) and antibodies to infliximab (ATI) were measured at week 14, and reactive drug monitoring was performed during follow-up. Ten single-nucleotide polymorphisms involved in the NF-κB-mediated inflammatory response, pharmacokinetics, and therapeutic response to infliximab were genotyped.Results: A total of 62 pediatric CD patients were enrolled. The clinical remission (CR) rate was 69.4 and 63.2% at week 14 and week 30, respectively. TLI at week 14 was significantly independently associated with CR at week 14 and mucosal healing (MH) at week 30 (p = 0.007 and p = 0.025, respectively). The optimal TLI threshold level capable of distinguishing between the CR and non-CR groups was 2.62 μg/ml (p < 0.001, area under the curve = 0.79, sensitivity = 69.2%, specificity = 78.9%), while that capable of distinguishing between the MH and non-MH groups was 3.34 μg/ml (p < 0.001, area under the curve = 0.85, sensitivity = 78.6%, specificity = 79.4%). Rs3397 in TNFRSF1B was associated with time to ATI production in CD patients (p < 0.001).Conclusions: Higher TLI contributed to achieving MH. Genotyping rs3397 in TNFRSF1B may identify patients who are prone to generating immunogenicity to drugs.

Osteoporosis is a common aging-related metabolic disease that mainly occurs in older adults and postmenopausal women. Despite advances in anti-osteoporosis treatment, outcomes remain unsatisfactory due to detrimental side effects. BCI hydrochloride (BCI), a selective dual-specificity phosphatase 6 (DUSP6) inhibitor, is associated with multiple cellular functions, including inhibiting tumor growth and macrophage inflammation; however, its role in regulating osteoclast differentiation remains unknown. Here, we revealed that treatment with BCI attenuated RANKL-mediated osteoclast differentiation in vitro and alleviated ovariectomy-induced osteoporosis without obvious toxicity. Specifically, BCI disrupted F-actin ring formation and bone-resorption activity and decreased osteoclast-specific gene and protein levels in a dose-dependent manner. KEGG pathway analysis, GSEA based on transcriptome sequencing, and western blot results suggested that BCI inhibited RANKL-induced osteoclastogenesis by restraining STAT3 and NF-κB signaling and attenuating NF-κB/p65 interaction with NFATc1. These results revealed that BCI treatment prevented postmenopausal osteoporosis and might represent an effective approach for treating osteoporosis.

Clubroot caused by Plasmodiophora brassicae is a devastating disease of cabbage (Brassica oleracea). To identify quantitative trait loci (QTLs) for clubroot resistance (CR) in B. oleracea, genomic resequencing was carried out in two sets of extreme pools, group I and group II, which were constructed separately from 110 and 74 F2 cloned lines derived from the cross between clubroot-resistant (R) cabbage “GZ87” (against race 4) and susceptible (S) cabbage “263.” Based on the QTL-sequencing (QTL-Seq) analysis of group I and group II, three QTLs (i.e., qCRc7-2, qCRc7-3, and qCRc7-4) were determined on the C07 chromosome. RNA-Seq and qRT-PCR were conducted in the extreme pools of group II before and after inoculation, and two potential candidate genes (i.e., Bol037115 and Bol042270), which exhibiting upregulation after inoculation in the R pool but downregulation in the S pool, were identified from the three QTLs on C07. A functional marker “SWU-OA” was developed from qCRc7-4 on C07, exhibiting ∼95% accuracy in identifying CR in 56 F2 lines. Our study will provide valuable information on resistance genes against P. brassicae and may accelerate the breeding process of B. oleracea with CR.

ObjectiveHepatocellular carcinoma (HCC) is one of the most common malignant tumors endangering human health and life in the 21st century. Chromatin licensing and DNA replication factor 1 (CDT1) is an important regulator of DNA replication licensing, which is essential for initiation of DNA replication. CDT1 overexpression in several human cancers reportedly leads to abnormal cell replication, activates DNA damage checkpoints, and predisposes malignant transformation. However, the abnormal expression of CDT1 in HCC and its diagnostic and prognostic value remains to be elucidated.MethodsTCGA, ONCOMINE, UALCAN, HCCDB, HPA, Kaplan-Meier plotter, STRING, GEPIA, GeneMANIA, and TIMER were conducted for bioinformatics analysis. CDT1 protein expression was evaluated by immunohistochemistry in HCC tissues through a tissue microarray. qRT-PCR, western blot and a cohort of functional experiments were performed for in vitro validation.ResultsIn this study, we discovered remarkably upregulated transcription of CDT1 in HCC samples relative to normal liver samples through bioinformatic analysis, which was further verified in clinical tissue microarray samples and in vitro experiments. Moreover, the transcriptional level of CDT1 in HCC samples was positively associated with clinical parameters such as clinical tumor stage. Survival, logistic regression, and Cox regression analyses revealed the significant clinical prognostic value of CDT1 expression in HCC. The receiver operating characteristic curve and nomogram analysis results demonstrated the strong predictive ability of CDT1 in HCC. Kyoto Encyclopedia of Genes and Genomes and gene set enrichment analyses indicated that CDT1 was mainly associated with the cell cycle, DNA repair, and DNA replication. We further demonstrated the significant correlation between CDT1 and minichromosome maintenance (MCM) family genes, revealing abnormal expression and prognostic significance of MCMs in HCC. Immune infiltration analysis indicated that CDT1 was significantly associated with immune cell subsets and affected the survival of HCC patients. Finally, knockdown of CDT1 decreased, whereas overexpression of CDT1 promoted the proliferation, migration, invasion of HCC cells in vitro.ConclusionsOur study findings demonstrate the potential diagnostic and prognostic significance of CDT1 expression in HCC, and elucidate the potential molecular mechanism underlying its role in promoting the occurrence and development of liver cancer. These results may provide new opportunities and research paths for targeted therapies in HCC.

Human cerebral organoid (CO) is a three-dimensional (3D) cell culture system that recapitulates the developing human brain. While CO has proved an invaluable tool for studying neurological disorders in a more clinically relevant matter, there have still been several shortcomings including CO variability and reproducibility as well as lack of or underrepresentation of certain cell types typically found in the brain. As the technology to generate COs has continued to improve, more efficient and streamlined protocols have addressed some of these issues. Here we present a novel scalable and simplified system to generate microglia-containing CO (MCO). We characterize the cell types and dynamic development of MCOs and validate that these MCOs harbor microglia, astrocytes, neurons, and neural stem/progenitor cells, maturing in a manner that reflects human brain development. We introduce a novel technique for the generation of embryoid bodies (EBs) directly from induced pluripotent stem cells (iPSCs) that involves simplified steps of transitioning directly from 3D cultures as well as orbital shaking culture in a standard 6-well culture plate. This allows for the generation of MCOs with an easy-to-use system that is affordable and accessible by any general lab.

To examine whether the expressions of 260 organelle crosstalk regulators (OCRGs) in 16 functional groups are modulated in 23 diseases and 28 tumors, we performed extensive -omics data mining analyses and made a set of significant findings: (1) the ratios of upregulated vs. downregulated OCRGs are 1:2.8 in acute inflammations, 1:1 in metabolic diseases, 1:1.2 in autoimmune diseases, and 1:3.8 in organ failures; (2) sepsis and trauma-upregulated OCRG groups such as vesicle, mitochondrial (MT) fission, and mitophagy but not others, are termed as the cell crisis-handling OCRGs. Similarly, sepsis and trauma plus organ failures upregulated seven OCRG groups including vesicle, MT fission, mitophagy, sarcoplasmic reticulum–MT, MT fusion, autophagosome–lysosome fusion, and autophagosome/endosome–lysosome fusion, classified as the cell failure-handling OCRGs; (3) suppression of autophagosome–lysosome fusion in endothelial and epithelial cells is required for viral replications, which classify this decreased group as the viral replication-suppressed OCRGs; (4) pro-atherogenic damage-associated molecular patterns (DAMPs) such as oxidized low-density lipoprotein (oxLDL), lipopolysaccharide (LPS), oxidized-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (oxPAPC), and interferons (IFNs) totally upregulated 33 OCRGs in endothelial cells (ECs) including vesicle, MT fission, mitophagy, MT fusion, endoplasmic reticulum (ER)–MT contact, ER– plasma membrane (PM) junction, autophagosome/endosome–lysosome fusion, sarcoplasmic reticulum–MT, autophagosome–endosome/lysosome fusion, and ER–Golgi complex (GC) interaction as the 10 EC-activation/inflammation-promoting OCRG groups; (5) the expression of OCRGs is upregulated more than downregulated in regulatory T cells (Tregs) from the lymph nodes, spleen, peripheral blood, intestine, and brown adipose tissue in comparison with that of CD4+CD25− T effector controls; (6) toll-like receptors (TLRs), reactive oxygen species (ROS) regulator nuclear factor erythroid 2-related factor 2 (Nrf2), and inflammasome-activated regulator caspase-1 regulated the expressions of OCRGs in diseases, virus-infected cells, and pro-atherogenic DAMP-treated ECs; (7) OCRG expressions are significantly modulated in all the 28 cancer datasets, and the upregulated OCRGs are correlated with tumor immune infiltrates in some tumors; (8) tumor promoter factor IKK2 and tumor suppressor Tp53 significantly modulate the expressions of OCRGs. Our findings provide novel insights on the roles of upregulated OCRGs in the pathogenesis of inflammatory diseases and cancers, and novel pathways for the future therapeutic interventions for inflammations, sepsis, trauma, organ failures, autoimmune diseases, metabolic cardiovascular diseases (CVDs), and cancers.

We performed a transcriptomic analyses using the strategies we pioneered and made the following findings: 1) Normal lymphoid Tregs, diseased kidney Tregs, splenic Tregs from mice with injured muscle have 3, 17 and 3 specific (S-) pathways, respectively; 2) Tumor splenic Tregs share 12 pathways with tumor Tregs; tumor splenic Tregs and tumor Tregs have 11 and 8 S-pathways, respectively; 3) Normal and non-tumor disease Tregs upregulate some of novel 2641 canonical secretomic genes (SGs) with 24 pathways, and tumor Tregs upregulate canonical secretomes with 17 pathways; 4) Normal and non-tumor disease tissue Tregs upregulate some of novel 6560 exosome SGs with 56 exosome SG pathways (ESP), tumor Treg ESP are more focused than other Tregs; 5) Normal, non-tumor diseased Treg and tumor Tregs upregulate some of novel 961 innate immune caspase-1 SGs and 1223 innate immune caspase-4 SGs to fulfill their tissue/SG-specific and shared functions; 6) Most tissue Treg transcriptomes are controlled by Foxp3; and Tumor Tregs had increased Foxp3 non-collaboration genes with ROS and 17 other pathways; 7) Immune checkpoint receptor PD-1 does, but CTLA-4 does not, play significant roles in promoting Treg upregulated genes in normal and non-tumor disease tissue Tregs; and tumor splenic and tumor Tregs have certain CTLA-4-, and PD-1-, non-collaboration transcriptomic changes with innate immune dominant pathways; 8) Tumor Tregs downregulate more immunometabolic and innate immune memory (trained immunity) genes than Tregs from other groups; and 11) ROS significantly regulate Treg transcriptomes; and ROS-suppressed genes are downregulated more in tumor Tregs than Tregs from other groups. Our results have provided novel insights on the roles of Tregs in normal, injuries, regeneration, tumor conditions and some of canonical and innate immune non-canonical secretomes via ROS-regulatory mechanisms and new therapeutic targets for immunosuppression, tissue repair, cardiovascular diseases, chronic kidney disease, autoimmune diseases, transplantation, and cancers.

Abstract Background Inflammatory osteolysis is a severe infectious bone disorder that occurs during orthopaedic surgery and is caused by disruptions in the dynamic balance of bone matrix homeostasis, which makes this condition a burden on surgical procedures. Developing novel therapeutic drugs about inhibiting excessive osteoclastogenesis acts as an efficient approach to preventing inflammatory bone destruction. Methods To study this, we explored the potential effects and mechanisms of compound 17 on inflammatory osteolysis in vitro. Meanwhile, a lipopolysaccharide (LPS)‐induced calvarial osteolysis mouse model was used to evaluate the protective effect of compound 17 on inflammatory bone destruction in vivo. Results In our study, we found that compound 17 could inhibit osteoclast (OC) differentiation and bone resorption during RANKL and LPS stimulation in a time‐ and dose‐dependent manner, while compounds 5 and 13 did not have the same effects. Mechanistically, compound 17 promoted phosphatase and tensin homologue (PTEN) activity by reducing PTEN ubiquitination, thereby restraining the RANKL‐induced NF‐κB pathway, resulting in the inhibition of the expression of osteoclastogenesis‐related genes and the formation of the NLRP3 inflammasome. Additionally, we also investigated whether compound 17 could negatively modulate macrophage polarization and repolarization due to its anti‐inflammatory effects. Moreover, compound 17 also plays an important role in osteoblast differentiation and mineralization. In vivo experiments showed that compound 17 could effectively protect mice from LPS‐induced inflammatory bone destruction by inhibiting osteoclastogenesis and inflammation. Conclusions Taken together, these results show that compound 17 might play protective role in inflammatory bone destruction through inhibiting osteoclastogenesis and inflammation. These findings imply a possible role of compound 17 in inflammatory osteolysis‐related diseases.

Interleukin (IL) 35 is a novel immunosuppressive heterodimeric cytokine in IL-12 family. Whether and how IL-35 regulates ischemia-induced angiogenesis in peripheral artery diseases are unrevealed. To fill this important knowledge gap, we used loss-of-function, gain-of-function, omics data analysis, RNA-Seq, in vivo and in vitro experiments, and we have made the following significant findings: i) IL-35 and its receptor subunit IL-12RB2, but not IL-6ST, are induced in the muscle after hindlimb ischemia (HLI); ii) HLI-induced angiogenesis is improved in Il12rb2−/− mice, in ApoE−/−/Il12rb2−/− mice compared to WT and ApoE−/− controls, respectively, where hyperlipidemia inhibits angiogenesis in vivo and in vitro; iii) IL-35 cytokine injection as a gain-of-function approach delays blood perfusion recovery at day 14 after HLI; iv) IL-35 spares regenerative angiogenesis at the late phase of HLI recovery after day 14 of HLI; v) Transcriptome analysis of endothelial cells (ECs) at 14 days post-HLI reveals a disturbed extracellular matrix re-organization in IL-35-injected mice; vi) IL-35 downregulates three reactive oxygen species (ROS) promoters and upregulates one ROS attenuator, which may functionally mediate IL-35 upregulation of anti-angiogenic extracellular matrix proteins in ECs; and vii) IL-35 inhibits human microvascular EC migration and tube formation in vitro mainly through upregulating anti-angiogenic extracellular matrix-remodeling proteins. These findings provide a novel insight on the future therapeutic potential of IL-35 in suppressing ischemia/inflammation-triggered inflammatory angiogenesis at early phase but sparing regenerative angiogenesis at late phase.

ObjectivesUmbilical cord blood transplantation (UCBT) is associated with a relatively high rate of engraftment failure. This study aimed at exploring whether any fecal microbiota could be associated with engraftment failure following UCBT in Crohn’s disease patients with IL10RA deficiency.MethodsThirteen patients were recruited and their 230 fecal samples were collected longitudinally from immediately before conditioning chemotherapy to 8 weeks post the UCBT. The V3-V4 regions of the bacterial 16S rRNA gene were amplified by PCR and sequenced, followed by bioinformatics analyses.ResultsFollowing the UCBT, 7 out of 13 patients achieved neutrophil and platelet engraftment with a median of 21 and 28 days, respectively (S group), while 6 patients failed to achieve engraftment (F group). In comparison with that in the S group, significantly lower Shannon diversity values on the UCBT day (P = 0.0176) and less abundance of Bifidobacterium longum, Bifidobacterium pseudolongum, Enterobacteriaceae_538000, and one taxon of Lachnospiraceae family was detected in the F group, accompanied by significantly higher abundances of four taxa including Lautropia, Pseudomonas, and species Microvirgula aerodenitrificans during the chemotherapy period as well as UCBT. The abundances of thirty OTUs were correlated significantly with clinical indices.ConclusionsMicrobial indicators of reduced diversity of microbiota and signatures of specific bacterial abundances, such as a lower abundance of Bifidobacterium longum, for engraftment failure would require validation. These indicators may help for the risk stratification in patients with IL10RA deficiency undergoing UCBT.