Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction.

Progenitor cells differentiate into specialized cell types through coordinated expression of lineage-specific genes and modification of complex chromatin configurations. We demonstrate that a histone deacetylase (Hdac3) organizes heterochromatin at the nuclear lamina during cardiac progenitor lineage restriction. Specification of cardiomyocytes is associated with reorganization of peripheral heterochromatin, and independent of deacetylase activity, Hdac3 tethers peripheral heterochromatin containing lineage-relevant genes to the nuclear lamina. Deletion of Hdac3 in cardiac progenitor cells releases genomic regions from the nuclear periphery, leading to precocious cardiac gene expression and differentiation into cardiomyocytes; in contrast, restricting Hdac3 to the nuclear periphery rescues myogenesis in progenitors otherwise lacking Hdac3. Our results suggest that availability of genomic regions for activation by lineage-specific factors is regulated in part through dynamic chromatin-nuclear lamina interactions and that competence of a progenitor cell to respond to differentiation signals may depend upon coordinated movement of responding gene loci away from the nuclear periphery.

ß-Hydroxybutyrate suppresses colorectal cancer.

Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed1. Here we identify a metabolite signalling pathway that provides actionable insights towards this goal. We perform a dietary screen in autochthonous animal models of CRC and find that ketogenic diets exhibit a strong tumour-inhibitory effect. These properties of ketogenic diets are recapitulated by the ketone body ß-hydroxybutyrate (BHB), which reduces the proliferation of colonic crypt cells and potently suppresses intestinal tumour growth. We find that BHB acts through the surface receptor Hcar2 and induces the transcriptional regulator Hopx, thereby altering gene expression and inhibiting cell proliferation. Cancer organoid assays and single-cell RNA sequencing of biopsies from patients with CRC provide evidence that elevated BHB levels and active HOPX are associated with reduced intestinal epithelial proliferation in humans. This study thus identifies a BHB-triggered pathway regulating intestinal tumorigenesis and indicates that oral or systemic interventions with a single metabolite may complement current prevention and treatment strategies for CRC.

Distinguishing homolytic vs heterolytic bond dissociation of phenylsulfonium cations with localized active space methods.

Modeling chemical reactions with quantum chemical methods is challenging when the electronic structure varies significantly throughout the reaction and when electronic excited states are involved. Multireference methods, such as complete active space self-consistent field (CASSCF), can handle these multiconfigurational situations. However, even if the size of the needed active space is affordable, in many cases, the active space does not change consistently from reactant to product, causing discontinuities in the potential energy surface. The localized active space SCF (LASSCF) is a cheaper alternative to CASSCF for strongly correlated systems with weakly correlated fragments. The method is used for the first time to study a chemical reaction, namely the bond dissociation of a mono-, di-, and triphenylsulfonium cation. LASSCF calculations generate smooth potential energy scans more easily than the corresponding, more computationally expensive CASSCF calculations while predicting similar bond dissociation energies. Our calculations suggest a homolytic bond cleavage for di- and triphenylsulfonium and a heterolytic pathway for monophenylsulfonium.

Methotrexate therapy for adult and paediatric moderate-to-severe atopic dermatitis: A PRISMA-compliant meta-analysis of data from daily practice.

Of the 15 eligible studies identified via electronic searches in MEDLINE, EMBASE and CENTRAL in November 2022 for methotrexate therapy of moderate-to-severe atopic dermatitis, 12 were non-randomized controlled trial (non-RCT) studies with data from 437 patients (235 adults and 202 children). The response rates for short-term therapy were 77% [95% CI 55-99] (four studies; adults) - comparable to 81% [54-100] of RCTs (two studies; adults) (p = 0.63) - and 61% [43-79] (two studies; children), and for medium/long-term therapy were 88.9% [74.3-100.0] (four studies; adults) and 77.7% [61.5-94.0] (three studies; children). Children had a markedly lower rate of treatment discontinuation due to side effects [2.0% (five studies; children) vs. 14.9% (six studies; adults)], but were more likely to experience gastrointestinal disorders {relative risk (RR) 2.0 [1.44-2.71]}, fatigue (RR 2.3 [1.35-3.72]), headache (RR 2.8 [1.23-5.61]), and infections (RR 2.9 [2.18-3.58]). Other adverse events (children vs. adults) included hepatic disorders (32/176 vs. 35/305) and blood and lymphatic system/bone marrow disorders (25/148 vs. 19/184). Four serious adverse events were reported (children). Evidence from daily practice was limited by bias in the selection of participants in the study.

Vicarious trauma in nursing: A hybrid concept analysis.

BACKGROUND: Vicarious trauma can significantly affect the physical and mental health of nurses, as well as their ability to provide quality of care. However, the concept of vicarious trauma has received limited attention and remains controversial in the nursing context. OBJECTIVE: The purpose of this study was to clarify and define the concept of vicarious trauma as it pertains to the nursing context. METHODS: The Schwartz and Kim's three-stage hybrid concept analysis method was used to define the concept. In the theoretical phase, PubMed, CINAHL, OVID, Medline, Embase, Web of Science, Scopus, ProQuest, PsycINFO, CNKI database, VIP database and Wanfang database were used using keywords "nurs*"and "vicarious trauma*", resulting in a total of 25 papers. In the fieldwork phase, we conducted participatory observations in three hospitals and semi-structured in-depth interviews with 18 clinical nurses from seven cities. In the analysis phase, the results of the previous two phases were integrated to develop a comprehensive concept of vicarious trauma in nursing. RESULTS: Based on the results of the theoretical and field phases, we propose the concept of vicarious trauma in nursing as follows: vicarious trauma is a psychological trauma impacting nurses' cognitive schema which they may experience in clinical settings or on social media, resulting from deeply empathize with the physical or emotional trauma of patients, family, or colleagues, such as patients' physical injuries or death, family's grieving feelings and colleagues' received threats and attacks. Positively, vicarious trauma can transform into vicarious post-trauma growth through repositioning and connection, nourishing nurses and promoting their personal and professional development. CONCLUSION: The concept of vicarious trauma in nursing is multidimensional and holistic. This study clarifies the concept of vicarious trauma in nursing using the hybrid concept analysis, providing a framework for future research and practice on vicarious trauma in the nursing field. PATIENT OR PUBLIC CONTRIBUTION: Nurses contributed to the conduct of the study by participating in the data collection via interviews.

Rituximab as maintenance therapy following remission induction in relapsing or refractory systemic lupus erythematosus.

OBJECTIVE: To investigate the efficacy and safety of rituximab (RTX) maintenance therapy compared with traditional immunosuppressive agent (ISA) maintenance therapy in patients with relapsing or refractory SLE. METHODS: It is a prospective observational non-randomized cohort study. The study enrolled SLE patients in four centres who had received at least one course of RTX induction treatment. Patients with a clinical response to RTX were divided into two groups based on their maintenance therapy in the first 12 months: the RTX group and the ISA group. The relapse-free survival times were compared between the two groups. Univariate and multivariate analyses were conducted to identify predictive factors for disease relapse. RESULTS: Among the 82 patients included in the cohort, 67 (81.7%) patients had a clinical response at 6 months. RTX maintenance therapy was applied in 34 (50.7%) patients and ISA maintenance therapy was applied in the remaining 33 (49.3%) patients. After a median follow-up of 24 months, a total of 13 (19.4%) patients had experienced disease relapse, comprising three in the RTX group and 10 in the ISA group. Patients in the RTX group had a higher relapse-free survival rate than patients in the ISA group. Multivariate analysis identified hydroxychloroquine use, RTX maintenance therapy and haematological system involvement as independent predictors for sustained remission. CONCLUSION: This multicentre prospective cohort study demonstrated that long-term RTX maintenance therapy has high efficacy and acceptable safety in relapsing or refractory SLE patients who had a clinical response to RTX induction therapy.

What is nursing professionalism? a concept analysis.

BACKGROUND: Nursing professionalism plays an important role in clinical nursing. However, a clear conceptual understanding of nursing professionalism is lacking. METHOD: Walker and Avant's strategy was used to analyse the concept of nursing professionalism. We searched electronic databases, including PubMed, Scopus, and CINAHL, for studies published from 1965 to 2021. Quantitative or qualitative studies published in English that focused on nursing professionalism were included in the study. RESULTS: The three attributes of nursing professionalism are multidimensional, dynamic, and culture oriented. Based on the analysis, nursing professionalism is defined as providing individuals care based on the principles of professionalism, caring, and altruism. CONCLUSIONS: This study offers a theoretical definition and conceptual model of nursing professionalism that may be applied to develop standardized assessment tools or nursing professionalism training programs.

Effect of low dose aspirin application during pregnancy on fetal congenital anomalies.

BACKGROUND: With the extensive use of aspirin in obstetrics and reproductive medicine, concerns of potentially related congenital anomalies have been raised in previous studies. However, there is a lack of evidence concerning the safety of application of aspirin during pregnancy in Chinese population, especially during the first trimester. PATIENTS AND METHODS: We retrospectively included a total of 2,763 patients with 2,856 fetuses (2670 singleton births and 93 pairs of twins), among whom 1,684 took low dose aspirin (LDA) during pregnancy (the LDA group) and the other 1,079 were not exposed to LDA (the control group). The primary outcome was the rate of fetal congenital anomalies, and was compared between the LDA group and the control group. We also conducted logistic regression to examine the potential risk factors of congenital abnormalities. RESULTS: The average daily dose of LDA taken was 67.6 mg. The rate of congenital anomalies was comparable between the two groups, suggesting low teratogenicity of LDA application during pregnancy (3.3% vs. 2.8%; P = 0.421). The duration of LDA exposure and the time of LDA exposure showed no association with congenital anomalies. A previous history of fetal congenital anomalies was associated with an increased risk of the recurrence of congenital anomalies in the siblings (adjusted OR = 3.00, 95% CI: 1.00-8.60; P = 0.041). CONCLUSION: Exposure to LDA during pregnancy did not increase the risk of congenital anomalies in the fetus, suggesting that it was safe to apply LDA during pregnancy. A history of previous fetal abnormalities was found to be an independent risk factor of congenital anomalies. Our study suggests that LDA can be safely applied during pregnancy without increasing risks of congenital anomalies.

The subjective experience of family caregivers of people living with Parkinson's disease: a meta-ethnography of qualitative literature.

BACKGROUND AND AIMS: Parkinson's disease patients (PwPD) rely heavily on their family caregivers. However, there remains uncertainty regarding the subjective experience of the family caregivers of PwPD. This study aims to provide an in-depth summary of the current knowledge about the subjective experiences of family caregivers caring for PwPD, to understand the factors that influence this experience and to provide the evidence for healthcare services. METHODS: We conducted a systematic review and meta-ethnography using Noblit and Hare's approach. The search strategy used MeSH terms in combination with free-text searching of 10 databases (from their inception until July 2021). Titles and abstracts were reviewed by two reviewers and, for the studies that met the eligibility criteria, full-text articles were obtained. The Critical Appraisal Skills Program (CASP) checklist was employed to assess the quality of studies. RESULTS: A total of 3318 studies were screened and 29 qualitative studies were included in this review. These studies recorded the experience of 399 participants across 12 countries, most were females. Five themes emerged: (a) feelings related to PD; (b) challenges to family life; (c) external challenges; (d) adjustment and adaptation; (e) external support. We propose a new conceptual model that highlights that the experiences of caregivers for PwPD are dynamic and influenced by a variety of internal and external factors. CONCLUSION: Our findings illustrate the complex and dynamic experiences of family caregivers for PwPD. It is necessary to explore how the influencing factors can be modified to improve the lived experience of family caregivers.

Early lineage specification defines alveolar epithelial ontogeny in the murine lung.

During the stepwise specification and differentiation of tissue-specific multipotent progenitors, lineage-specific transcriptional networks are activated or repressed to orchestrate cell specification. The gas-exchange niche in the lung contains two major epithelial cell types, alveolar type 1 (AT1) and AT2 cells, and the timing of lineage specification of these cells is critical for the correct formation of this niche and postnatal survival. Integrating cell-specific lineage tracing studies, spatially specific mRNA transcript and protein expression, and single-cell RNA-sequencing analysis, we demonstrate that specification of alveolar epithelial cell fate begins concomitantly with the proximal-distal specification of epithelial progenitors and branching morphogenesis earlier than previously appreciated. By using a newly developed dual-lineage tracing system, we show that bipotent alveolar cells that give rise to AT1 and AT2 cells are a minor contributor to the alveolar epithelial population. Furthermore, single-cell assessment of the transcriptome identifies specified AT1 and AT2 progenitors rather than bipotent cells during sacculation. These data reveal a paradigm of organ formation whereby lineage specification occurs during the nascent stages of development coincident with broad tissue-patterning processes, including axial patterning of the endoderm and branching morphogenesis.

BRD4 (Bromodomain-Containing Protein 4) Interacts with GATA4 (GATA Binding Protein 4) to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes.

BACKGROUND: Gene regulatory networks control tissue homeostasis and disease progression in a cell type-specific manner. Ubiquitously expressed chromatin regulators modulate these networks, yet the mechanisms governing how tissue specificity of their function is achieved are poorly understood. BRD4 (bromodomain-containing protein 4), a member of the BET (bromo- and extraterminal domain) family of ubiquitously expressed acetyl-lysine reader proteins, plays a pivotal role as a coactivator of enhancer signaling across diverse tissue types in both health and disease and has been implicated as a pharmacological target in heart failure. However, the cell-specific role of BRD4 in adult cardiomyocytes remains unknown. METHODS: We combined conditional mouse genetics, unbiased transcriptomic and epigenomic analyses, and classic molecular biology and biochemical approaches to understand the mechanism by which BRD4 in adult cardiomyocyte homeostasis. RESULTS: Here, we show that cardiomyocyte-specific deletion of Brd4 in adult mice leads to acute deterioration of cardiac contractile function with mutant animals demonstrating a transcriptomic signature characterized by decreased expression of genes critical for mitochondrial energy production. Genome-wide occupancy data show that BRD4 enriches at many downregulated genes (including the master coactivators Ppargc1a, Ppargc1b, and their downstream targets) and preferentially colocalizes with GATA4 (GATA binding protein 4), a lineage-determining cardiac transcription factor not previously implicated in regulation of adult cardiac metabolism. BRD4 and GATA4 form an endogenous complex in cardiomyocytes and interact in a bromodomain-independent manner, revealing a new functional interaction partner for BRD4 that can direct its locus and tissue specificity. CONCLUSIONS: These results highlight a novel role for a BRD4-GATA4 module in cooperative regulation of a cardiomyocyte-specific gene program governing bioenergetic homeostasis in the adult heart.

Effect of low-molecular-weight heparins on anti-Xa peak levels and adverse reactions in Chinese patients with recurrent spontaneous abortion: a single-center, observational study.

OBJECTIVE: To compare three commonly used low-molecular-weight heparins (LWMHs) in the treatment of recurrent spontaneous abortion (RSA) by evaluating the anti-Xa peak levels and adverse reactions. METHODS: In this single-center, observational study, we enrolled 310 patients with RSA in whom anti-Xa levels were measured during pregnancy. Patients were divided into three groups according to the LMWH they used: the nadroparin group, enoxaparin group and dalteparin group. We compared the peak anti-Xa levels and the coagulation status of each group, and analyzed the incidence of adverse reactions, including local allergy, liver and renal dysfunction, and the impact on platelet. RESULTS: Patients in the enoxaparin group had a higher anti-Xa peak level than those in the nadroparin group (0.80 ± 0.22 IU/ml vs. 0.61 ± 0.24 IU/ml; P <  0.0001), although most patients in the three groups reached the target concentration of anti-Xa. Furthermore, patients in the enoxaparin group had a more stable anti-Xa levels during pregnancy. In addition, patients in the nadroparin group had a higher rate of local allergy than those in the enoxaparin group (60.5% vs. 42.5%; P = 0.004) and those in the dalteparin group (60.5% vs. 33.3%; P = 0.002). Further examination by the type of local allergy indicated a dramatic difference in pruritus and induration between the nadroparin group and the other two groups. No difference was found in the incidence of liver and renal dysfunction and thrombocytopenia. CONCLUSION: Compared with nadroparin and daltepatin, enoxaparin showed a better performance regarding anti-Xa levels and the incidence of adverse reactions in the treatment of RSA.

Anti-angiogenesis therapy overcomes the innate resistance to PD-1/PD-L1 blockade in VEGFA-overexpressed mouse tumor models.

The effectual clinical benefits of immune checkpoint inhibitor (ICI) are hampered by a high rate of innate resistance, and VEGFA may contribute to ICI treatment resistance. In this study, we endeavored to assess the tumor microenvironment (TME) in VEGFA-overexpressed human tumors and mouse tumor models, and to explore whether anti-angiogenesis therapy can overcome the innate resistance to ICI in hyperangiogenesis mouse tumor models and the underlying mechanism. Effect of VEGFA on clinical prognosis and TME was analyzed using TCGA data. The VEGFA-overexpressed mouse breast and colon subcutaneous models were established. PD-1 mAb or apatinib alone and combination therapy were used. Immunohistochemistry and immunofluorescence were used to assess angiogenesis and hypoxia. Flow cytometry, RNA sequencing and MCP-counter were applied to detect tumor immunomicroenvironment. High level of VEGFA mRNA in human tumors is related to poor prognosis and hypoxic, angiogenic and immunosuppressive TME. Upregulation of VEGFA increased the degree of malignancy of tumor cells in vitro and in vivo. VEGFA-overexpressed models were characterized by hypoxic, hyperangiogenic and immunosuppressive TME and indicated innate resistance to ICI. In tumor-bearing mice without VEGFA overexpression, the combination therapy had no synergistic anti-tumor effect compared to monotherapy. However, apatinib alleviated hyperangiogenesis and hypoxia in TME and converted the immunosuppressive TME into an immunostimulatory one in VEGFA-overexpressed tumors. Thus, anti-angiogenesis therapy could improve the efficiency of ICI in VEGFA-overexpressed tumors. Revealing whether there is hypervascularization in tumor tissues may help to clarify the adoption of anti-angiogenesis and ICI combination therapy or ICI monotherapy in cancer treatment.

Decidua-derived granulocyte macrophage colony-stimulating factor induces polymorphonuclear myeloid-derived suppressor cells from circulating CD15+ neutrophils.

STUDY QUESTION: Do decidua-derived factors stimulate the conversion of circulating neutrophils to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in early human pregnancy? SUMMARY ANSWER: Circulating neutrophils can acquire PMN-MDSC-like phenotypes and function via phosphorylated signal transducer and activator of transcription 5/programmed death ligand 2 (pSTAT5/PD-L2) signalling after stimulation with decidua-derived granulocyte macrophage colony-stimulating factor (GM-CSF). WHAT IS KNOWN ALREADY: PMN-MDSCs are an important immunoregulatory cell type in early pregnancy. Neutrophils are of high heterogeneity and plasticity and can polarize to immunosuppressive PMN-MDSCs upon stimulation. STUDY DESIGN, SIZE, DURATION: For analysis of myeloid-derived suppressor cell (MDSC) subset proportions, 12 endometrium tissues and 12 peripheral blood samples were collected from non-pregnant women, and 40 decidua tissues and 16 peripheral blood samples were obtained from women with normal early pregnancy undergoing elective surgical pregnancy termination for nonmedical reasons with gestation age of 6-10 weeks. Twenty-nine decidua tissues were collected for isolation of CD15+ PMN-MDSCs. Twenty endometrium tissues and 30 decidua tissues were collected for cytokine analysis, immunohistochemistry or neutrophil stimulation. Peripheral blood samples were obtained from 36 healthy donors for isolation of CD3+ T cells and CD15+ neutrophils. PARTICIPANTS/MATERIALS, SETTING, METHODS: The proportion of MDSC subsets in the decidua and peripheral blood of normal early pregnancy, endometrium and peripheral blood of non-pregnant women was analysed by flow cytometry. The phenotypes and function of decidual PMN-MDSCs and circulating neutrophils were compared by flow cytometry. Circulating neutrophils were stimulated with decidual explant supernatant (DES) and the phenotypes were measured by flow cytometry and immunofluorescence. The suppressive capacity of decidual PMN-MDSCs and DES-conditioned neutrophils was analysed by flow cytometry with or without anti-programmed cell death-1 (PD-1) antibody. Cytokines from DES and endometrial explant supernatant (EES) were detected by a Luminex assay. GM-CSF expression was determined by ELISA and immunohistochemistry. Neutrophils were stimulated with DES, EES, DES with anti-GM-CSF antibody or EES with GM-CSF. CD11b, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), PD-L2 and pSTAT5 expression were measured by flow cytometry. MAIN RESULTS AND THE ROLE OF CHANCE: The frequency of PMN-MDSCs was significantly increased in the decidua of early pregnancy compared with peripheral blood of non-pregnant women, the endometrium of non-pregnant women or peripheral blood during early pregnancy. Decidual PMN-MDSCs suppressed T-cell proliferation and cytokine production. Phenotypes of decidual PMN-MDSCs were similar to mature activated neutrophils. DES-induced CD11b, LOX-1, PD-L2 expression and STAT5 phosphorylation in neutrophils. The PD-L2 expression in neutrophils was dependent on STAT5 phosphorylation. Both decidual PMN-MDSCs and DES-conditioned neutrophils suppressed T-cell proliferation via PD-1 signalling. GM-CSF was up-regulated in the decidua and induced CD11b, LOX-1 and PD-L2 expression on neutrophils. DES significantly induced CD11b, LOX-1, PD-L2 expression and STAT5 phosphorylation. Anti-GM-CSF antibody remarkably blocked such stimulation in neutrophils. EES did not induce CD11b, LOX-1, PD-L2 expression or STAT5 phosphorylation, while GM-CSF treatment sufficiently stimulated CD11b, LOX-1, PD-L2 expression and STAT5 phosphorylation in neutrophils. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The study was based on in vitro experiments and we were not able to evaluate neutrophils differentiation to PMN-MDSCs in other sites before entering the maternal-foetal interface due to the limited availability of human samples. This needs to be explored using murine models. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study demonstrating that decidual PMN-MDSCs are a group of immunoregulatory cells with mature status, and that neutrophils can be induced to a PMN-MDSC-like phenotype with decidua-derived GM-CSF via pSTAT5/PD-L2 signalling. This study indicates that GM-CSF can facilitate immune tolerance of early pregnancy through regulating PMN-MDSCs and further provides a potential role of GM-CSF in prevention and treatment for pregnancy complications. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Natural Science Foundation of China (81671481) and National Natural Science Foundation of China (81871179). All authors have no competing interests to declare.

Altered Amplitude of Low-Frequency Fluctuations in Inactive Patients with Nonneuropsychiatric Systemic Lupus Erythematosus.

Objective: This study is aimed at investigating the characteristics of the spontaneous brain activity in inactive patients with nonneuropsychiatric systemic lupus erythematosus (non-NPSLE). Methods: Thirty-one female inactive patients with non-NPSLE and twenty healthy controls were examined by resting-state functional magnetic resonance imaging (RS-fMRI). Three amplitude methods including amplitude of low-frequency fluctuations (ALFF), fractional amplitude of low-frequency fluctuations (fALFF), and percent amplitude of fluctuation (PerAF) (with and without standardization) were applied to evaluate the spontaneous brain activity. The correlation was performed between low-frequency oscillations and clinical and neuropsychological factors in inactive patients with non-NPSLE. Results: Compared to healthy controls, patients with non-NPSLE showed increased standardized ALFF (mALFF) in the left inferior temporal gyrus and left putamen, decreased PerAF in the right postcentral gyrus and bilateral precentral gyrus, and increased standardized PerAF (mPerAF) in the left putamen and decreased mPerAF in the right postcentral gyrus and bilateral precentral gyrus. By standardized fALFF (mfALFF), no significant brain regions were found between the two groups. Correlation analysis revealed significantly positive correlations between glucocorticoid dose and PerAF in the right precentral gyrus and mPerAF in the left putamen, and Complement 3 (C3) and mPerAF in the right postcentral gyrus. There was a significant negative correlation between C3 and mALFF in the left putamen. Conclusion: Abnormal low-frequency oscillations in multiple brain regions were found in inactive patients with non-NPSLE, indicating that the alteration of mALFF, PerAF, and mPerAF in specific brain regions might be an imaging biomarker of brain dysfunction in inactive patients with non-NPSLE.

Hopx expression defines a subset of multipotent hair follicle stem cells and a progenitor population primed to give rise to K6+ niche cells.

The mammalian hair follicle relies on adult resident stem cells and their progeny to fuel and maintain hair growth throughout the life of an organism. The cyclical and initially synchronous nature of hair growth makes the hair follicle an ideal system with which to define homeostatic mechanisms of an adult stem cell population. Recently, we demonstrated that Hopx is a specific marker of intestinal stem cells. Here, we show that Hopx specifically labels long-lived hair follicle stem cells residing in the telogen basal bulge. Hopx(+) cells contribute to all lineages of the mature hair follicle and to the interfollicular epidermis upon epidermal wounding. Unexpectedly, our analysis identifies a previously unappreciated progenitor population that resides in the lower hair bulb of anagen-phase follicles and expresses Hopx. These cells co-express Lgr5, do not express Shh and escape catagen-induced apoptosis. They ultimately differentiate into the cytokeratin 6-positive (K6) inner bulge cells in telogen, which regulate the quiescence of adjacent hair follicle stem cells. Although previous studies have suggested that K6(+) cells arise from Lgr5-expressing lower outer root sheath cells in anagen, our studies indicate an alternative origin, and a novel role for Hopx-expressing lower hair bulb progenitor cells in contributing to stem cell homeostasis.

Vertically oriented silica mesochannels as the template for electrodeposition of polyaniline nanostructures and their electrocatalytic and electroanalytical applications.

A mesoporous silica film (MSF) with vertically oriented mesochannels on a conductive substrate serves as a hard-template for electrodeposition of polyaniline (PANI). The PANI nanostructures thus prepared are orderly confined in silica mesochannels, eventually producing a robust hybrid film. The film displays a good electrocatalytic activity toward oxidation of ascorbic acid, and can be used for potentiometric pH sensing with a Nernstian response.

Differential pulse voltammetry detection of dopamine and ascorbic acid by permselective silica mesochannels vertically attached to the electrode surface.

A thin film consisting of highly ordered and vertically oriented silica mesochannels (SMCs) was prepared on the indium tin oxide (ITO) coated glass electrode surface by chronopotentiometry. The mesochannel has a uniform pore size of 2-3 nm in diameter and a positively charged surface due to grafted ammonium groups. The electrostatic and steric effects resulted from control of the surface charge and the ionic buffer concentration make the SMCs permselective, favoring the mass transport of oppositely charged species and repelling that of similarly charged ones. By using differential pulse voltammetry (DPV), the SMCs with this charge selectivity can be employed for permselective detection of ascorbic acid (AA) and dopamine (DA) that are oppositely charged compounds. The obtained linear detection range was 49-2651 µM for AA and 20-226 µM for DA, respectively. AA and DA in real samples were also determined by the SMC film modified electrode.

Decidual stromal cells-derived exosomes incurred insufficient migration and invasion of trophoblast by disturbing of ß-TrCP-mediated snail ubiquitination and degradation in unexplained recurrent spontaneous abortion.

BACKGROUND: Exosomes released from decidual stromal cells (DSC-exos) play a crucial role in facilitating the epithelial-mesenchymal transition (EMT) of trophoblasts and insufficient trophoblasts EMT are associated with URSA (unexplained recurrent spontaneous abortion). However, the mechanisms underlying DSC-exos inducing EMT is not completely understood. METHODS: DSC-exos of normal pregnant women (N-DSC-exos) and URSA patients (URSA-DSC-exos) were extracted and characterized. Characterization of the isolated DSC-exos was performed using with TEM (transmission electron microscopy), NTA (nanoparticle tracking analysis), and WB (western blot) techniques. Subsequently, these DSC-exos were co-cultured with trophoblasts cell lines (HTR-8/SVneo). The influence of both N-DSC-exos and URSA-DSC-exos on trophoblasts proliferation, invasion and migration, as well as on the expression of EMT-related proteins, was evaluated through a series of assays including CCK8 assays, wound healing assays, transwell assays, and western blot, respectively. Then rescue experiments were performed by ß-TrCP knockdown or ß-TrCP overexpressing trophoblasts with snail-siRNA transfection or ß-TrCP overexpressing Lentivirus infection, respectively. Finally, animal experiments were employed to explore the effect of N-DSC-exos on embryo absorption in mice. RESULTS: We found increased ß-TrCP expression in the villus of URSA patients when compared to the normal pregnant women, alongside reduction in the levels of both snail and N-cadherin within URSA patients. N-DSC-exos can promote the EMT of the trophoblast by inhibiting ß-TrCP-mediated ubiquitination and degradation of transcription factor snail. Moreover the capacity to promote EMT was found to be more potent in N-DSC-exos than URSA-DSC-exos. Down-regulation of snail or overexpression of ß-TrCP can reverse the effects of N-DSC-exos on trophoblast. Finally, in vivo experiment suggested that N-DSC-exos significantly reduced the embryo resorption rate of spontaneous abortion mouse model. CONCLUSIONS: Our findings indicate that URSA-DSC-exos caused insufficient migration and invasion of trophoblast because of disturbing of ß-TrCP-mediated ubiquitination and degradation of EMT transcription factor snail. Elucidating the underlying mechanism of this dysregulation may shed light on the novel pathways through which DSC-exos influence trophoblast function, thereby contributing to our understanding of their role in URSA.

Development and external validation of a prediction model for the premature circuit clotting of continuous renal replacement therapy in critically ill patients.

OBJECTIVE: This study aimed to develop and validate a prediction model for premature circuit clotting of continuous renal replacement therapy (CRRT) in critically ill patients. DESIGN: A retrospective cohort study was conducted on ICU patients undergoing CRRT. The Medical Information Mart for Intensive Care-III Clinical Database CareVue subset and Medical Information Mart for Intensive Care-IV were utilized for model development, while the eICU Collaborative Research Database was employed for external validation. Predictive factors were selected through Least Absolute Shrinkage and Selection Operator Regression and univariate logistic regression. A prediction model was then developed using binary logistic regression. Internal and external validations assessed the model's discrimination, calibration, and clinical net benefit. RESULTS: This study encompassed 2531 patients overall, with a premature circuit clotting rate of 31.88 %. The prediction model comprises five variables: body temperature, anticoagulation, mean arterial pressure, maximum transmembrane pressure change within two hours, and vasopressor. The model demonstrated robust predictive performance, achieving an area under the receiver operating characteristic curve of 0.897 (95 % CI: 0.879-0.915) in the training set and 0.877 (95 % CI: 0.852-0.902) in the external validation set. Internal validation yielded a Brier score of 0.087, while external validation showed a Brier score of 0.120. Calibration curves indicated good model calibration for both validations. The decision curve analysis indicates that the model yields a clinical net benefit across a wide range of decision thresholds. CONCLUSION: The model demonstrates robust discrimination, calibration, and clinical net benefit, with readily available variables indicating substantial potential for valuable clinical applications. IMPLICATIONS FOR CLINICAL PRACTICE: Healthcare providers in the ICU can leverage the model to evaluate the risk of premature circuit clotting in critically ill patients undergoing continuous renal replacement therapy, facilitating timely intervention to mitigate its incidence.