The Mitochondrial Unfolded Protein Response Is Mediated Cell-Non-autonomously by Retromer-Dependent Wnt Signaling.

The mitochondrial unfolded protein response (UPRmt) can be triggered in a cell-non-autonomous fashion across multiple tissues in response to mitochondrial dysfunction. The ability to communicate information about the presence of mitochondrial stress enables a global response that can ultimately better protect an organism from local mitochondrial challenges. We find that animals use retromer-dependent Wnt signaling to propagate mitochondrial stress signals from the nervous system to peripheral tissues. Specifically, the polyQ40-triggered activation of mitochondrial stress or reduction of cco-1 (complex IV subunit) in neurons of C. elegans results in the Wnt-dependent induction of cell-non-autonomous UPRmt in peripheral cells. Loss-of-function mutations of retromer complex components that are responsible for recycling the Wnt secretion-factor/MIG-14 prevent Wnt secretion and thereby suppress cell-non-autonomous UPRmt. Neuronal expression of the Wnt ligand/EGL-20 is sufficient to induce cell-non-autonomous UPRmt in a retromer complex-, Wnt signaling-, and serotonin-dependent manner, clearly implicating Wnt signaling as a strong candidate for the "mitokine" signal.

Immunogram defines four cancer-immunity cycle phenotypes with distinct clonal selection patterns across solid tumors.

BACKGROUND: The cancer-immunity cycle (CI cycle) provides a theoretical framework to illustrate the process of the anticancer immune response. Recently, the update of the CI cycle theory emphasizes the importance of tumor's immunological phenotype. However, there is lack of immunological phenotype of pan-cancer based on CI cycle theory. METHODS: Here, we applied a visualizing method termed 'cancer immunogram' to visualize the state of CI cycle of 8460 solid tumors from TCGA cohort. Unsupervised clustering of the cancer immunogram was performed using the nonnegative matrix factorization (NMF) analysis. We applied an evolutionary genomics approach (dN/dS ratio) to evaluate the clonal selection patterns of tumors with distinct immunogram subtypes. RESULTS: We defined four major CI cycle patterns across 32 cancer types using a cancer immunogram approach. Immunogram-I was characterized by 'hot' and 'exhausted' features, indicating a favorable prognosis. Strikingly, immunogram-II, immunogram-III, and immunogram-IV represented distinct immunosuppressive patterns of 'cold' tumor. Immunogram-II was characterized by 'cold' and 'radical' features, which represented increased expression of immune inhibitor molecules and high levels of positive selection, indicating the worst prognosis. Immunogram-III was characterized by 'cold' and 'recognizable' features and upregulated expression of MHC I molecules. Immunogram-IV was characterized by 'cold' and 'inert' features, which represented overall immunosuppression, lower levels of immunoediting and positive selection, and accumulation of more tumor neoantigens. In particular, favorable overall survival was observed in metastatic urothelial cancer patients with immunogram-I and immunogram-IV after immune checkpoint inhibitor (ICI) therapy. Meanwhile, a higher response rate to ICI therapy was observed in metastatic gastric cancer patients with immunogram-I phenotype. CONCLUSIONS: Our findings provide new insight into the interaction between immunity and cancer evolution, which may contribute to optimizing immunotherapy strategies.

Tuning the Topology of Two-Dimensional Covalent Organic Frameworks through Site-Selective Synthetic Strategy.

Tuning the topology of two-dimensional (2D) covalent organic frameworks (COFs) is of paramount scientific interest but remains largely unexplored. Herein, we present a site-selective synthetic strategy that enables the tuning of 2D COF topology by simply adjusting the molar ratio of an amine-functionalized dihydrazide monomer (NH2 -Ah) and 4,4',4''-(1,3,5-triazine-2,4,6-triyl)tribenzaldehyde (Tz). This approach resulted in the formation of two distinct COFs: a clover-like 2D COF with free amine groups (NH2 -Ah-Tz) and a honeycomb-like COF without amine groups (Ah-Tz). Both COFs exhibited good crystallinity and moderate porosity. Remarkably, the clover-shaped NH2 -Ah-Tz COF, with abundant free amine groups, displayed significantly enhanced adsorption capacities toward crystal violet (CV, 261 mg/g) and congo red (CR, 1560 mg/g) compared to the non-functionalized honeycomb-like Ah-Tz COF (123 mg/g for CV and 1340 mg/g for CR), underscoring the pivotal role of free amine functional groups in enhancing adsorption capacities for organic dyes. This work highlights that the site-selective synthetic strategy paves a new avenue for manipulating 2D COF topology by adjusting the monomer feeding ratio, thereby modulating their adsorption performances toward organic dyes.

Fascicular ventricular tachycardia arising from the left side His and its adjacent region: a subset of upper septal idiopathic left ventricular tachycardia.

AIMS: Fascicular ventricle tachycardia (FVT) arising from the proximal aspect of left His-Purkinje system (HPS) has not been specially addressed. Current study was to investigate its clinical, electrocardiographic, and electrophysiological characteristics. METHODS AND RESULTS: Eighteen patients who were identified as this rare FVT were consecutively enrolled, and their scalar electrocardiogram and electrophysiological data were collected and analysed. The ventricular tachycardia (VT) morphology was similar to sinus rhythm (SR) in eight patients, left bundle branch block type in one patient, right bundle branch block type in seven patients, and both narrow and wide QRS type in two patients. During VT, right-sided His potential preceded the QRS with His-ventricle (H-V) interval of 36.3 ± 12.4 ms, which was shorter than that during SR (-51.4 ± 8.6 ms) (P = 0.002). The earliest Purkinje potentials (PPs) were recorded within 7 ± 3 mm of left-side His and preceded the QRS by 49.1 ± 14.0 ms. Mapping along the left anterior fascicle and left posterior fascicle revealed an antegrade activation sequence in all with no P1 potentials recorded. In the two patients with two VT morphologies, the earliest PP was documented at the same site, and the activation sequence of HPS remained antegrade. Ablation at the earliest PP successfully eliminated the tachycardia, except one patient who developed complete atrial-ventricular block and two patients who abandoned ablations. After at least 12 months follow-up, 15 patients were free from any recurrences. CONCLUSIONS: Fascicular ventricle tachycardia arising from the proximal aspect of left HPS was featured by recording slightly shorter H-V interval and absence of P1 potentials. Termination of VT requires ablation at the left-sided His or its adjacent region.

Asymptomatic atrial fibrillation among hospitalized patients: clinical correlates and in-hospital outcomes in Improving Care for Cardiovascular Disease in China-Atrial Fibrillation.

AIMS: The clinical correlates and outcomes of asymptomatic atrial fibrillation (AF) in hospitalized patients are largely unknown. We aimed to investigate the clinical correlates and in-hospital outcomes of asymptomatic AF in hospitalized Chinese patients. METHODS AND RESULTS: We conducted a cross-sectional registry study of inpatients with AF enrolled in the Improving Care for Cardiovascular Disease in China-Atrial Fibrillation Project between February 2015 and December 2019. We investigated the clinical characteristics of asymptomatic AF and the association between the clinical correlates and the in-hospital outcomes of asymptomatic AF. Asymptomatic and symptomatic AF were defined according to the European Heart Rhythm Association score. Asymptomatic patients were more commonly males (56.3%) and had more comorbidities such as hypertension (57.4%), diabetes mellitus (18.6%), peripheral artery disease (PAD; 2.3%), coronary artery disease (55.5%), previous history of stroke/transient ischaemic attack (TIA; 17.9%), and myocardial infarction (MI; 5.4%); however, they had less prevalent heart failure (9.6%) or left ventricular ejection fractions ≤40% (7.3%). Asymptomatic patients were more often hospitalized with a non-AF diagnosis as the main diagnosis and were more commonly first diagnosed with AF (23.9%) and long-standing persistent/permanent AF (17.0%). The independent determinants of asymptomatic presentation were male sex, long-standing persistent AF/permanent AF, previous history of stroke/TIA, MI, PAD, and previous treatment with anti-platelet drugs. The incidence of in-hospital clinical events such as all-cause death, ischaemic stroke/TIA, and acute coronary syndrome (ACS) was higher in asymptomatic patients than in symptomatic patients, and asymptomatic clinical status was an independent risk factor for in-hospital all-cause death, ischaemic stroke/TIA, and ACS. CONCLUSION: Asymptomatic AF is common among hospitalized patients with AF. Asymptomatic clinical status is associated with male sex, comorbidities, and a higher risk of in-hospital outcomes. The adoption of effective management strategies for patients with AF should not be solely based on clinical symptoms.

Built environment factors moderate pandemic fatigue in social distance during the COVID-19 pandemic: A nationwide longitudinal study in the United States.

Non-pharmaceutical interventions (NPIs) remain some of the most effective measures for coping with the ever-changing coronavirus disease 2019 (COVID-19) pandemic. Pandemic fatigue, which manifests as the declined willingness to follow the recommended protective behaviors (e.g., keeping social distance policies, wearing masks), has commanded increasing attention from researchers and policymakers after the prolonged NPIs and COVID-19 worldwide. However, long-term changes in pandemic fatigue are not well understood, especially amidst the ever-changing pandemic landscape. Built environment factors have been shown to positively affect mental and physical health, but it is still unclear whether built environments can moderate pandemic fatigue. In this study, we used Google mobility data to investigate longitudinal trends of pandemic fatigue in social distance since the onset of NPIs enforcement in the United States. The results indicated that pandemic fatigue continuously worsened over nearly two years of NPIs implementation, and a sharp increase occurred after the vaccination program began. Additionally, we detected a significant moderation effect of greenspace and urbanicity levels on pandemic fatigue. People living in areas with high levels of greenness or urbanicity experienced lower levels of pandemic fatigue. These findings not only shed new light on the effects of greenness and urbanicity on COVID-19 pandemic fatigue, but also provide evidence for developing more tailored and effective strategies to cope with pandemic fatigue.

Self-Assembly of Helical Nanofibrous Chiral Covalent Organic Frameworks.

Despite significant progress on the design and synthesis of covalent organic frameworks (COFs), precise control over microstructures of such materials remains challenging. Herein, two chiral COFs with well-defined one-handed double-helical nanofibrous morphologies were constructed via an unprecedented template-free method, capitalizing on the diastereoselective formation of aminal linkages. Detailed time-dependent experiments reveal the spontaneous transformation of initial rod-like aggregates into the double-helical microstructures. We have further demonstrated that the helical chirality and circular dichroism signal can be facilely inversed by simply adjusting the amount of acetic acid during synthesis. Moreover, by transferring chirality to achiral fluorescent molecular adsorbents, the helical COF nanostructures can effectively induce circularly polarized luminescence with the highest luminescent asymmetric factor (glum ) up to ≈0.01.

Identification of genes associated with feather color in Liancheng white duck using FST analysis.

Liancheng white duck has two phenotypic traits: white feather and black beak-black foot, but the genes controlling these phenotypic traits are unknown. The objective of this study is to identify various candidate genes related to the plumage of Liancheng white duck. This study used F2 population construction generated between white Kaiya duck and Liancheng white duck and FST analysis between the dominant and recessive loci associated with the Liancheng white duck white feather in order to identify specific gene regions. As per the feather color statistics of the F2 population, it is estimated that there are about three or four genes controlling the white feather of Liancheng white ducks, and the FST results showed that four significant signals were found on chromosomes 4, 12, 13, and 21. Further annotation of these regions led to the identification of five genes involved in the melanin pathway, namely, KIT, CLOCK, MITF, CEBPA, and DOK5. Among them, CEBPA and DOK5 might be affecting the white feather traits of Liancheng white duck by regulating the melanin production and its transfer to the feather. The results provide insightful understanding into the genetic mechanisms of white feather in Liancheng white duck.

Green spaces, especially nearby forest, may reduce the SARS-CoV-2 infection rate: A nationwide study in the United States.

The coronavirus pandemic is an ongoing global crisis that has profoundly harmed public health. Although studies found exposure to green spaces can provide multiple health benefits, the relationship between exposure to green spaces and the SARS-CoV-2 infection rate is unclear. This is a critical knowledge gap for research and practice. In this study, we examined the relationship between total green space, seven types of green space, and a year of SARS-CoV-2 infection data across 3,108 counties in the contiguous United States, after controlling for spatial autocorrelation and multiple types of covariates. First, we examined the association between total green space and SARS-CoV-2 infection rate. Next, we examined the association between different types of green space and SARS-CoV-2 infection rate. Then, we examined forest-infection rate association across five time periods and five urbanicity levels. Lastly, we examined the association between infection rate and population-weighted exposure to forest at varying buffer distances (100 m to 4 km). We found that total green space was negative associated with the SARS-CoV-2 infection rate. Furthermore, two forest variables (forest outside park and forest inside park) had the strongest negative association with the infection rate, while open space variables had mixed associations with the infection rate. Forest outside park was more effective than forest inside park. The optimal buffer distances associated with lowest infection rate are within 1,200 m for forest outside park and within 600 m for forest inside park. Altogether, the findings suggest that green spaces, especially nearby forest, may significantly mitigate risk of SARS-CoV-2 infection.

Gene coexpression network approach to develop an immune prognostic model for pancreatic adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is a nonimmunogenic tumor, and very little is known about the relationship between the host immune response and patient survival. We aimed to develop an immune prognostic model (IPM) and analyze its relevance to the tumor immune profiles of patients with PAAD. METHODS: We investigated differentially expressed genes between tumor and normal tissues in the TCGA PAAD cohort. Immune-related genes were screened from highly variably expressed genes with weighted gene correlation network analysis (WGCNA) to construct an IPM. Then, the influence of IPM on the PAAD immune profile was comprehensively analyzed. RESULTS: A total of 4902 genes highly variably expressed among primary tumors were used to construct a weighted gene coexpression network. One hundred seventy-five hub genes in the immune-related module were used for machine learning. Then, we established an IPM with four core genes (FCGR2B, IL10RA, and HLA-DRA) to evaluate the prognosis. The risk score predicted by IPM was an independent prognostic factor and had a high predictive value for the prognosis of patients with PAAD. Moreover, we found that the patients in the low-risk group had higher cytolytic activity and lower innate anti-PD-1 resistance (IPRES) signatures than patients in the high-risk group. CONCLUSIONS: Unlike the traditional methods that use immune-related genes listed in public databases to screen prognostic genes, we constructed an IPM through WGCNA to predict the prognosis of PAAD patients. In addition, an IPM prediction of low risk indicated enhanced immune activity and a decreased anti-PD-1 therapeutic response.

Tripartite motif 31 alleviates IL-1ß secretion via promoting the ubiquitination of pyrin domain domains-containing protein 3 in human periodontal ligament fibroblasts.

Apical periodontitis (AP) is an inflammatory disease caused by bacteria infection and is regarded as a common disease in the world. In the progression of AP, the function of nucleotide-binding oligomerization, leucine-rich repeat and pyrin domain domains-containing protein 3 (NLRP3) inflammasome has been revealed. Although tripartite motif 31 (TRIM31) has been suggested to regulate many chronic inflammations by mediating NLRP3 inflammasome, such mechanism in AP remains unclear. In this study, co-treatment of human periodontal ligament fibroblasts (HPDLFs) with lipopolysaccharides (LPS) and adenosine triphosphate (ATP) were conducted to establish AP cell model. ELISA assay was used to measure the concentration of secretive interleukin 1 beta (IL-1ß). In addition, the expression levels of NLRP3 after TRIM31 up- or down-regulation were detected by real-time PCR and western blot. Immunoprecipitation was used to explore the interaction between TRIM31 and NLRP3. We found that co-treatment with LPS and ATP increased the secretion of IL-1ß and expression of NLRP3 in HPDLFs, while TRIM31 overexpression could reverse these effects caused by LPS and ATP. Furthermore, the interaction between TRIM31 and NLRP3 was observed, and TRIM31 was found to promote the ubiquitination of NLRP3. TRIM31 may alleviate IL-1ß secretion caused by LPS and ATP via promoting the ubiquitination of NLRP3 and may exert an influence on the development of AP.

Correction to: Tripartite motif 31 alleviates IL-1ß secretion via promoting the ubiquitination of pyrin domain domains-containing protein 3 in human periodontal ligament fibroblasts.

The article Tripartite motif 31 alleviates IL 1ß secretion via promoting the ubiquitination of pyrin domain domains containing protein 3 in human periodontal ligament fibroblasts, written by Xueying Wu, Mengmeng Lu, Sheng Ding and Qun Zhong, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 22 April 2020 with open access.

Immature monocytes contribute to cardiopulmonary bypass-induced acute lung injury by generating inflammatory descendants.

BACKGROUND: As immune regulatory and effector cells, monocytes play an important role in the blood-extracorporeal circuit contact-related acute lung injury in patients undergoing cardiopulmonary bypass (CPB). However, circulating monocytes are phenotypically and functionally heterogeneous, so we characterised how immature monocytes affect acute lung injury induced by CPB. METHODS: The identification and dynamic changes in monocyte subsets were monitored by flow cytometry in patients undergoing CPB and in a rat model of CPB. The differentiation and migration of monocyte subsets were explored by in vitro cultures and adoptive transfer in the CPB rat model. RESULTS: We observed a dramatic increase of two monocyte subsets in the peripheral blood of patients undergoing CPB, involving tumour necrosis factor (TNF)-α-producing, mature intermediate CD14highCD16+ monocytes and a novel immature CD14lowCD16- subset. The immature CD14lowCD16- monocytes possessed limited ability for TNF-α production, and failed to suppress T-cell proliferation mediated by T-cell receptor signalling. However, these immature cells were highly proliferative and could differentiate into TNF-α producing, mature CD14highCD16+ monocytes. In the rat model of CPB, we further demonstrated that CPB induced migration of immature monocytes into the lungs, either from the bone marrow or from the spleen. Moreover, we confirmed the hypothesis that immature subsets could contribute to CPB-induced acute lung injury by giving rise to TNF-α producing descendants. CONCLUSIONS: The immature CD14lowCD16- monocytes might contribute to blood-circuit contact-induced acute lung injury by generating TNF-α-producing, mature monocytes. New strategies based on monocyte manipulation could be a promising therapeutic approach for minimising CPB-related lung injury.

Evaluation of left atrial volume and function using single-beat real-time three-dimensional echocardiography in atrial fibrillation patients.

BACKGROUND: This study was aimed to evaluate the feasibility and accuracy of real-time three-dimensional echocardiography (RT-3DE) measurement of left atrial (LA) volume and function in comparison with two-dimensional echocardiography (2DE) measurements in atrial fibrillation (AF) patients. METHODS: A total of 50 pairs of AF patients and healthy controls were enrolled in this study. Indexed LA end-diastole volume (ILAEDV) and indexed LA end-systolic volume (ILAESV), as well as LA function indices such as segmental LA ejection fraction (LAEF), were assessed using 2DE Simpson's method and the RT-3DE method. RESULTS: The images showed that regional LA volume-time curves and LAEF were disordered in AF patients. ILAEDV and ILAESV were markedly increased and global LAEF was significantly decreased in AF patients compared with those in healthy controls (P < 0.01). No significant differences were found in ILAEDV, ILAESV, and LAEF levels as determined by the RT-3DE method or 2DE Simpson's method. Bland-Altman analysis showed that the two methods agreed well for measuring ILAEDV, ILAESV, and segmental LAEF. CONCLUSION: The RT-3DE method may be a feasible and accurate method for evaluating LA volume and function of AF patients in clinical practice.

Expansion of activated regulatory T cells by myeloid-specific chemokines via an alternative pathway in CSF of bacterial meningitis patients.

Previous studies have demonstrated that activation/expansion by certain cytokines as well as recruitment by specific chemokines is involved in enrichment of regulatory T (Treg) cells in local tissues or organs under pathological conditions. Recent evidence indicates that human Treg cells are a heterogeneous population that comprises three distinct subpopulations: CD25⁺CD45RA⁺ resting Treg (rTreg) cells, CD25(hi)CD45RA⁻ activated Treg (aTreg) cells, which are both suppressive, and CD25⁺CD45RA⁻ cytokine-secreting T cells with proinflammatory capacity. Moreover, rTreg cells can proliferate and convert to aTreg cells. Here, we found an increase in aTreg-cell frequency in the cerebrospinal fluid (CSF) of patients with postneurosurgery bacterial meningitis. We revealed that such an increased aTreg-cell frequency in the CSF was not due to enhanced chemotaxis. Instead of a classic conversion pathway from rTreg to aTreg cells, we identified an alternative route of Treg-cell conversion from cytokine-secreting cells to aTreg cells induced by myeloid-specific chemokine CXC chemokine receptor (CXCR) ligand 5 via CXCR1 and CXCR2 receptors, or by CSF myeloid cells in a cell-cell contact manner. Our results reveal a different view of how the immune system controls overwhelming local immune responses during infection, and provide evidence of how innate immunity negatively regulates adaptive immunity.

Efficient preparation of (R)-2-chloromandelic acid via a recycle process of resolution.

Efficient preparation of (R)-2-chloromandelic acid based on a recycle process of resolution is described. In the process, the desired was obtained by coordination-mediated resolution with D-O,O'-di-(p-toluoyl)-tartaric acid in the presence of Ca(2+) . Meanwhile, the undesired could be racemized in the presence of sodium hydroxide and the product was suitable for further resolution. A carbanion mechanism for the racemization of is proposed.

The quality of written instructions for dental prostheses in China.

PURPOSE: To investigate the quality of written instructions for dental prostheses in China, including metal-ceramic fixed restorations and removable partial dentures (RPDs). MATERIALS AND METHODS: A total of 1600 prepiloted questionnaires were distributed to five major commercial dental laboratories in different regions in China. The opinions of dental technicians on the written instructions provided by dentists were investigated. In addition, this study also revealed the technicians' responses to poorly written instructions. RESULTS: Seven percent of the written instructions clarified the disinfection status of the impressions or casts, while 32% of the instructions provided general patient information (e.g., gender and age). In cases of metal-ceramic fixed restorations, percentages of written instructions specifying shade, ceramic veneering area, and margin design were 72%, 20%, and 9%, respectively. In fixed partial denture cases, 60% of written instructions provided the number of pontics, while 22% specified the pontic design. In the case of RPDs, 90% of instructions showed the type and position of clasps, 88% provided connector design, while 68% mentioned information regarding the artificial teeth. Dental technicians claimed that 78% of the written instructions involved were inadequately prescribed to some extent, but only about one-third of them would contact dentists for clarification. CONCLUSIONS: Written instructions are not well prescribed in many cases. This situation may jeopardize the quality of prosthodontic treatment. It is necessary to shape responsible policy and mandatory professional guidelines for prosthodontic treatment procedures including dental laboratory services.

Anti-Wound Dehiscence and Antibacterial Dressing with Highly Efficient Self-Healing Feature for Guided Bone Regeneration Wound Closure.

Guided bone regeneration (GBR) is a well-established technique for preserving and enhancing alveolar ridge structures. Success in GBR relies on fulfilling the Primary wound closure, Angiogenesis, Space maintenance, and Stability (PASS) principles. Conventional methods, involving titanium meshes and sutures, have drawbacks, including the need for secondary removal and customization challenges. To address these issues, an innovative multifunctional GBR dressing (MGD) based on self-healing elastomer (PUIDS) is introduced. MGD provides sutureless wound closure, prevents food particle accumulation, and maintains a stable environment for bone growth. It offers biocompatibility, bactericidal properties, and effectiveness in an oral GBR model. In summary, MGD provides a reliable, stable osteogenic environment for GBR, aligning with PASS principles and promoting superior post-surgery bone regeneration.

Comparison of tacrolimus with or without prednisone therapy in primary membranous nephropathy: a retrospective clinical study.

Previous studies showed tacrolimus monotherapy and dual therapy with tacrolimus and prednisone as effective treatment modalities in managing membranous nephropathy. However, few studies have compared these therapeutic regimens. The patients were divided into two groups based on the treatment regimen: (1) tacrolimus and prednisone dual therapy (T + P group, n = 67) treatment group; and (2) tacrolimus monotherapy (T group, n = 65) or the control group. Propensity matching method and subgroup analysis to eliminate the bias in the relationship between the treatment regimen and the outcomes. The mean remission times were 20.33 ± 2.75 weeks at T group and 9.50 ± 1.81 weeks at T + P group. The T group had a remission rates of 73.33, 76.66 and 66.66% at 12weeks, 24weeks and 48weeks, while the T + P group had a remission rate of 81.66, 86.66, 91.66%; At the follow-up of 48 weeks, the relapse rate for the T group was 21.66%, and that for the T + P group was 5%. The anti-PLA2R ab is positive and therapy may be the independent risk factors for predicting remission. Tacrolimus and low-dose prednisone dual therapy is efficacious in managing MN and lowers the recurrence rate in clinical practice.