First copy number variant in trans with single nucleotide variant in CCN6 causing progressive pseudorheumatoid dysplasia revealed by genome sequencing and deep phenotyping in monozygotic twins.

Biallelic pathogenic variants in CCN6 cause progressive pseudorheumatoid dysplasia (PPD), a rare skeletal dysplasia. The predominant features include noninflammatory progressive joint stiffness and enlargement, which are not unique to this condition. Nearly 100% of the reported variants are single nucleotide variants or small indels, and missing of a second variant has been reported. Genome sequencing (GS) covers various types of variants and deep phenotyping (DP) provides detailed and precise information facilitating genetic data interpretation. The combination of GS and DP improves diagnostic yield, especially in rare and undiagnosed diseases. We identified a novel compound heterozygote involving a disease-causing copy number variant (g.112057664_112064205del) in trans with a single nucleotide variant (c.624dup(p.Cys209MetfsTer21)) in CCN6 in a pair of monozygotic twins, through the methods of GS and DP. The twins had received three nondiagnostic results before. The g.112057664_112064205del variant was missed by all the tests, and the recorded phenotypes were inaccurate or even misleading. The twins were diagnosed with PPD, ending a 13-year diagnostic odyssey. There may be other patients with PPD experiencing underdiagnosis and misdiagnosis due to inadequate genetic testing or phenotyping methods. This case highlights the critical role of GS and DP in facilitating an accurate and timely diagnosis.

Interleukin-5 alleviates cardiac remodelling via the STAT3 pathway in angiotensin II-infused mice.

Interleukin-5 (IL-5) has been reported to be involved in cardiovascular diseases, such as atherosclerosis and cardiac injury. This study aimed to investigate the effects of IL-5 on cardiac remodelling. Mice were infused with angiotensin II (Ang II), and the expression and source of cardiac IL-5 were analysed. The results showed that cardiac IL-5 expression was time- and dose-dependently decreased after Ang II infusion, and was mainly derived from cardiac macrophages. Additionally, IL-5-knockout (IL-5-/-) mice were used to observe the effects of IL-5 knockout on Ang II-induced cardiac remodelling. We found knockout of IL-5 significantly increased the expression of cardiac hypertrophy markers, elevated myocardial cell cross-sectional areas and worsened cardiac dysfunction in Ang II-infused mice. IL-5 deletion also promoted M2 macrophage differentiation and exacerbated cardiac fibrosis. Furthermore, the effects of IL-5 deletion on cardiac remodelling was detected after the STAT3 pathway was inhibited by S31-201. The effects of IL-5 on cardiac remodelling and M2 macrophage differentiation were reversed by S31-201. Finally, the effects of IL-5 on macrophage differentiation and macrophage-related cardiac hypertrophy and fibrosis were analysed in vitro. IL-5 knockout significantly increased the Ang II-induced mRNA expression of cardiac hypertrophy markers in myocardial cells that were co-cultured with macrophages, and this effect was reversed by S31-201. Similar trends in the mRNA levels of fibrosis markers were observed when cardiac fibroblasts and macrophages were co-cultured. In conclusions, IL-5 deficiency promote the differentiation of M2 macrophages by activating the STAT3 pathway, thereby exacerbating cardiac remodelling in Ang II-infused mice. IL-5 may be a potential target for the clinical prevention of cardiac remodelling.

Efficacy and safety of multikinase inhibitors for patients with refractory thyroid cancer: Systematic review and network meta-analysis.

CONTEXT: Multikinase inhibitors (MKIs) improve the treatment of refractory thyroid cancer, included radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) and advanced medullary thyroid carcinoma (aMTC). OBJECTIVE: This study aims to compare the efficacy of MKIs in improving survival outcomes and safety. DATA SOURCES: Comprehensive database searches of MEDLINE via PubMed, EMBASE and Cochrane performed from inception to December 2023. STUDY SELECTION: Three independent authors selected these studies. Randomised-controlled trials that compared the use of a MKI to other MKIs or placebo were included. DATA EXTRACTION AND SYNTHESIS: This review followed PRISMA guidelines. Risk of bias was analyzed using the Cochrane RoB 2 tool. Bayesian network meta-analysis was performed. Treatments were grouped into common nodes based on the type of MKI. MAIN OUTCOMES AND MEASURES: Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate, disease control rate, clinical benefit rate, and adverse events. RESULTS: Cabozantinib 60 mg/d (CAB60) was associated with the highest prolonged PFS in RAIR-DTC patients, followed by lentivatinib 18 or 24 mg/d (LEN18 or LEN24), and apatinib. PFS was also improved in in aMTC patients received CAB 140 mg/d (CAB140), CAB60, or anlotinib. A significantly greater improvement on the performance of OS was seen in CAB60, LEN24, anlotinib, and sorafenib in RAIR-DTC patients, but which in aMTC patients were lack of statistical differences. Compared with the low-dose of MKIs, high-dose of MKIs such as CAB, LEN, and vandetanib increased the incidence of adverse events. CONCLUSION: CAB60, LEN, and apatinib are promising topical MKIs with statistically significant primary outcomes in RAIR-DTC patients, while CAB and anlotinib are effective in prolonging PFS in aMTC patients.

Relationships Between Chemotherapy-Related Cognitive Impairment, Self-Care Ability, and Quality of Life in Breast Cancer Survivors: A Cross-Sectional Study.

OBJECTIVES: It is not clear how chemotherapy-related cognitive impairment and self-care ability affect the quality of life of women with breast cancer. The purpose of this study was to explore the relationships between chemotherapy-related cognitive impairment, self-care ability, and quality of life in breast cancer patients, and test whether self-care ability plays a mediating role in the association between cognitive impairment and quality of life. METHODS: This study was a cross-sectional study, conducted in China in 2022. Self-reported scales were used to assess cognitive function, self-care ability, and quality of life. Data were analyzed using descriptive statistics, spearman correlation analysis and hierarchical multiple regression analyses, the SPSS Process program was used to explore the mediating effect of self-care ability. RESULTS: A total of 218 participants were investigated, and approximately 79.3% of patients experienced mild chemotherapy-related cognitive impairment, the mean quality of life score was 59.96 ± 14.15, and the mean self-care ability score was 107.4 ± 24.09. Significant correlations among cognitive impairment, self-care ability, and quality of life were observed (P < .05). Additionally, self-care ability played a partial mediating role between cognitive impairment and quality of life (P < .05), accounting for 24.3% and 22.3%, respectively. CONCLUSIONS: Chemotherapy-related cognitive impairment and self-care ability are factors affecting the quality of life of breast cancer survivors. Self-care ability mediates the relationship between cognitive impairment and quality of life. Enhancing patients' self-care ability can improve the quality of life of patients with cognitive impairment. IMPLICATIONS FOR NURSING PRACTICE: In the future, oncology nurses should not only pay attention to the severity of cognitive impairment, but also assess the level of patients' self-care ability, provide relevant medical and healthcare guidance, train self-management behavior and strengthen self-care ability by integrating multidisciplinary forces to improve the quality of life of breast cancer patients effectively.

Defect Passivation and Crystallization Regulation for Efficient and Stable Formamidinium Lead Iodide Solar Cells with Multifunctional Amidino Additive.

Amidino-based additives show great potential in high-performance perovskite solar cells (PSCs). However, the role of different functional groups in amidino-based additives have not been well elucidated. Herein, two multifunctional amidino additives 4-amidinobenzoic acid hydrochloride (ABAc) and 4-amidinobenzamide hydrochloride (ABAm) are employed to improve the film quality of formamidinium lead iodide (FAPbI3) perovskites. Compared with ABAc, the amide group imparts ABAm with larger dipole moment and thus stronger interactions with the perovskite components, i.e., the hydrogen bonds between N…H and I- anion and coordination bonds between C = O and Pb2+ cation. It strengthens the passivation effect of iodine vacancy defect and slows down the crystallization process of α-FAPbI3, resulting in the significantly reduced non-radiative recombination, long carrier lifetime of 1.7 µs, uniformly large crystalline grains, and enhances hydrophobicity. Profiting from the improved film quality, the ABAm-treated PSC achieves a high efficiency of 24.60%, and maintains 93% of the initial efficiency after storage in ambient environment for 1200 hours. This work provides new insights for rational design of multifunctional additives regarding of defect passivation and crystallization control toward highly efficient and stable PSCs.

Genome-Scale Multimodal Analysis of Cell-Free DNA Whole-Methylome Sequencing for Noninvasive Esophageal Cancer Detection.

PURPOSE: Simultaneous profiling of cell-free DNA (cfDNA) methylation and fragmentation features to improve the performance of cfDNA-based cancer detection is technically challenging. We developed a method to comprehensively analyze multimodal cfDNA genomic features for more sensitive esophageal squamous cell carcinoma (ESCC) detection. MATERIALS AND METHODS: Enzymatic conversion-mediated whole-methylome sequencing was applied to plasma cfDNA samples extracted from 168 patients with ESCC and 251 noncancer controls. ESCC characteristic cfDNA methylation, fragmentation, and copy number signatures were analyzed both across the genome and at accessible cis-regulatory DNA elements. To distinguish ESCC from noncancer samples, a first-layer classifier was developed for each feature type, the prediction results of which were incorporated to construct the second-layer ensemble model. RESULTS: ESCC plasma genome displayed global hypomethylation, altered fragmentation size, and chromosomal copy number alteration. Methylation and fragmentation changes at cancer tissue-specific accessible cis-regulatory DNA elements were also observed in ESCC plasma. By integrating multimodal genomic features for ESCC detection, the ensemble model showed improved performance over individual modalities. In the training cohort with a specificity of 99.2%, the detection sensitivity was 81.0% for all stages and 70.0% for stage 0-II. Consistent performance was observed in the test cohort with a specificity of 98.4%, an all-stage sensitivity of 79.8%, and a stage 0-II sensitivity of 69.0%. The performance of the classifier was associated with the disease stage, irrespective of clinical covariates. CONCLUSION: This study comprehensively profiles the epigenomic landscape of ESCC plasma and provides a novel noninvasive and sensitive ESCC detection approach with genome-scale multimodal analysis.

Novel PLCZ1 compound heterozygous mutations indicate gene dosage effect involved in TFF after ICSI.

Oocyte activation failure, one of the main factors of total fertilization failure (TFF) after ICSI, could be induced by abnormal calcium oscillations. Phospholipase C zeta (PLCζ), a sperm factor, was associated with Ca2+ oscillations in oocytes of mammals. To date, only a limited number of mutations in PLCZ1 (the gene encodes PLCζ) have been linked to TFF demonstrated by the observed reduction in protein levels or activity. In this study, males with normozoospermic sperm suffering TFF after ICSI and their families were recruited. Firstly, mutations in the PLCZ1 sequence were identified by Whole exome sequencing and validated by Sanger sequencing. Then the transcript and protein levels and locations of PLCZ1/PLCζ in sperms of patients were studied followed by in vitro function analysis and in silico analysis to investigate the function-structure correlation of mutations identified in PLCZ1 through Western blotting, Immunofluorescence, RT-qPCR and Molecular Simulation. Ca2+ oscillations were detected after cRNA microinjection with MⅡ mouse oocyte to investigate the calcium oscillations of abnormal PLCζ. Five variants in compound heterozygosity were identified including five new mutations and three-reported mutations which were located across the main domains of PLCζ, except the EF hands domain. The transcript and protein levels were decreased among all the mutations identified in PLCZ1 at different degrees when transfected with HEK293T cells. Among these mutations, M138V and R391* of PLCζ could not trigger normal Ca2+ oscillations. In case 5, an abnormal location in the head of sperm and a higher expression of PLCζ in the sperm were found.

c-FLIP facilitates ZIKV infection by mediating caspase-8/3-dependent apoptosis.

c-FLIP functions as a dual regulator of apoptosis and inflammation, yet its implications in Zika virus (ZIKV) infection remain partially understood, especially in the context of ZIKV-induced congenital Zika syndrome (CZS) where both apoptosis and inflammation play pivotal roles. Our findings demonstrate that c-FLIP promotes ZIKV infection in placental cells and myeloid-derived macrophages, involving inflammation and caspase-8/3-mediated apoptosis. Moreover, our observations reveal that c-FLIP augments ZIKV infection in multiple tissues, including blood cell, spleen, uterus, testis, and the brain of mice. Notably, the partial deficiency of c-FLIP provides protection to embryos against ZIKV-induced CZS, accompanied by a reduction in caspase-3-mediated apoptosis. Additionally, we have found a distinctive parental effect of c-FLIP influencing ZIKV replication in fetal heads. In summary, our study reveals the critical role of c-FLIP as a positive regulator in caspase-8/3-mediated apoptosis during ZIKV infection, significantly contributing to the development of CZS.

Safety and Efficiency of Anlotinib in Patients with Recurrent Grade 4 Glioma: A Single-Center Retrospective Analysis.

PURPOSE: Anlotinib is a multi-target TKI which has been used in different advanced tumors. However, its efficiency and safety in patients with glioblastoma are still not well discussed. This retrospective study aimed to discover the safety and efficiency of anlotinib in recurrent grade 4 glioma. METHODS: The clinical data of patients with recurrent grade 4 glioma treated with anlotinib in our center were collected and analyzed. The progression-free survival (PFS), overall survival (OS), and OS after recurrence were calculated by Kaplan-Meier method and compared by log-rank test. Sub-group analysis was used to find possible variables that affect survival. RESULTS: From October 2017 to December 2020, seventeen patients with recurrent grade 4 glioma treated with anlotinib were enrolled. The median age was 50 with 13 males. The median KPS was 70. All patients received standard STUPP mode treatment before recurrence. The median PFS was 7 months [95% confidence interval (CI) 5.3-8.6]. The median OS after first diagnosis was 17 months (95% CI 15.7-18.3). The median OS after recurrence was 10 months (95% CI 7.6-12.4). The objective response rate was 33.33% (5/15), and the disease control rate was 60% (9/15). The existence of target genes was identified as a variable affecting the survival after recurrence. The median OS after recurrence in patients with target genes was 12 months (95% CI 6.9-17.1), whereas for patients without targets, the median OS was 4 months (95% CI 1.9-6.1) and for patients with an unknown status, the median OS was 10 months (95% CI 8.4-11.6) (P = 0.013). CONCLUSION: For recurrent grade 4 glioma, anlotinib can be considered as a supplement to the standard STUPP treatment, especially for the patient with anlotinib target genes.

Spiritual needs of women with breast cancer: A structural equation model.

PURPOSE: The purpose of this study was to develop a structural equation model (SEM) to explore the factors influencing the spiritual needs of breast cancer patients. METHODS: A cross-sectional study was conducted in the breast surgery department of a tertiary hospital in China from September 2020 to December 2020; convenience sampling and questionnaires were used to facilitate sampling and data collection. A total of 220 female breast cancer patients were included in the study. The data were analysed using multiple linear regression and structural equation modelling. RESULTS: Compared with patients with other diseases, patients with breast cancer have greater spiritual needs (76.16 ± 13.19). Multivariate analysis revealed that religious beliefs, education level, social support, and resilience are important factors affecting the mental health of women with cancer (p < 0.05). The structural equation model fit well (RMSEA = 0.056, χ2p = 0.002). Social support directly affected spiritual needs (ß = 0.607, p < 0.001) and indirectly affected spiritual needs through resilience (ß = 0.353, p < 0.001). Resilience directly affected spiritual needs (ß = 0.386, p < 0.05). Education level indirectly affected spiritual needs through social support (ß = 0.307, p < 0.001). CONCLUSION: This study provides a theoretical basis for intervention measures to improve the spiritual needs of female breast cancer patients. Paying more attention to social support and resilience may help solve the problem of meeting the high spiritual needs of breast cancer patients. Further research is needed to develop interventions.

Methylprednisolone Modulates the Tfr/Tfh ratio in EAE-Induced Neuroinflammation through the PI3K/AKT/FoxO1 and PI3K/AKT/mTOR Signalling Pathways.

Methylprednisolone (MP) is a potent glucocorticoid that can effectively inhibit immune system inflammation and brain tissue damage in Multiple sclerosis (MS) patients. T follicular helper (Tfh) cells are a subpopulation of activated CD4 + T cells, while T follicular regulatory (Tfr) cells, a novel subset of Treg cells, possess specialized abilities to suppress the Tfh-GC response and inhibit antibody production. Dysregulation of either Tfh or Tfr cells has been implicated in the pathogenesis of MS. However, the molecular mechanism underlying the anti-inflammatory effects of MP therapy on experimental autoimmune encephalomyelitis (EAE), a representative model for MS, remains unclear. This study aimed to investigate the effects of MP treatment on EAE and elucidate the possible underlying molecular mechanisms involed. We evaluated the effects of MP on disease progression, CNS inflammatory cell infiltration and myelination, microglia and astrocyte activation, as well as Tfr/Tfh ratio and related molecules/inflammatory factors in EAE mice. Additionally, Western blotting was used to assess the expression of proteins associated with the PI3K/AKT pathway. Our findings demonstrated that MP treatment ameliorated clinical symptoms, inflammatory cell infiltration, and myelination. Furthermore, it reduced microglial and astrocytic activation. MP may increase the number of Tfr cells and the levels of cytokine TGF-ß1, while reducing the number of Tfh cells and the levels of cytokine IL-21, as well as regulate the imbalanced Tfr/Tfh ratio in EAE mice. The PI3K/AKT/FoxO1 and PI3K/AKT/mTOR pathways were found to be involved in EAE development. However, MP treatment inhibited their activation. MP reduced neuroinflammation in EAE by regulating the balance between Tfr/Tfh cells via inhibition of the PI3K/AKT/FoxO1 and PI3K/AKT/mTOR signalling pathways.

Mitigating the influence of multivalent ions on power density performance in a single-membrane capacitive reverse electrodialysis cell.

In recent years, the energy generated by the salinity gradient has become a subject of growing interest as a source of renewable energy. One of the most widely used processes is reverse electrodialysis (RED), based on the use of ion exchange membranes and Faradaic electrodes. However, the use of real salt solutions containing mixtures of divalent and monovalent ions in the RED process results in a significant loss of recovered power, compared with salt solutions containing only monovalent ions. From an original point of view, in this work we study and explain the influence of divalent ions and complex solutions in reverse electrodialysis devices equipped with capacitive electrodes with a single membrane (CREDSM). We show that CREDSM mitigates the impact of divalent ions. From a quantitative point of view, the power recovered in a Faradaic cell drops by more than 75 % when the solutions contain 50 % molar fraction of divalent ions and by 33 % when the solutions contain 10 % molar fraction of divalent ions. For similar low-cost membranes with fairly low selectivity, recovered power drops by only 34 % when solutions contain 60 % moles of divalent ions in CREDSM. We show that only the membrane potential, which makes up half of the cell's open circuit potential, is affected. The potential of capacitive electrodes which counts for half of the potential cell does not decrease in the presence of divalents. For the same membrane under the same conditions, we estimate a loss of 62 % in a RED device Furthermore, the membrane is not poisoned by divalent ions because we periodically change the electrical current direction, by means of switching the feed waters. CREDSM devices do not show any variation in membrane resistance or membrane selectivity. The techno-economic analysis suggests further valorization of salinity gradients in industrial operations.

Haploidentical Hematopoietic Stem Cell Transplantation for Paediatric Patients with X-linked Lymphoproliferative Syndrome.

The aim of this study was to investigate the prognostic factors of haploid hematopoietic stem cell transplantation in the treatment of X-linked lymphoproliferative syndrome. Seven children with X-linked lymphoproliferative syndrome diagnosed by XIAP gene analysis were enrolled. The conditioning regimens were tolerated in all seven patients, and the median time of neutrophil engraftment was 10 days (8-13 days), and that of platelet engraftment was 21 days (14-24 days). STR-PCR analysis on the peripheral blood cells showed complete donor origins. Four cases developed Grade I acute graft versus host disease (aGVHD), one developed Grade III aGVHD (intestinal tract), and two cases had limited chronic GVHD. Four cases had cytomegalovirus (CMV) reactivation, and two cases had Epstein-Barr virus (EBV) reactivation. One case was diagnosed as pneumocystosis, and thrombotic microangiopathy (TMA) occurred in three cases. During the follow-up period (median time of 42 months), one patient died of TMA and six patients survived. Statistical analysis showed that the status of disease remission and the positive result of virus in blood before transplantation were independent prognostic factors. Haplo-HSCT might be a curative option for children with refractory X-linked lymphoproliferative syndrome. Low-intensity conditioning regimens may reduce transplant-related mortality and improve overall survival.

Overexpression of MD1 ameliorates pathological myocardial remodeling in diabetic cardiomyopathy by TLR4/STAT3 signaling pathway.

Diabetic cardiomyopathy (DCM) is characterized by oxidative damage and inflammatory responses. Myeloid differentiation protein 1 (MD1) exhibits antioxidant and anti-inflammatory properties. However, the specific role of MD1 in DCM has yet to be elucidated. This study aims to investigate the role of MD1 in DCM and to elucidate the underlying mechanisms. We utilized a gain-of-function approach to explore the involvement of MD1 in DCM. Diabetes was induced in MD1-transgenic (MD1-TG) mice and their wild-type (WT) counterparts via streptozotocin (STZ) injection. Additionally, a diabetes cell model was established using H9c2 cells exposed to high glucose levels. We conducted comprehensive evaluations, including pathological analyses, echocardiography, electrocardiography, and molecular assessments, to elucidate the underlying mechanisms of MD1 in DCM. Notably, MD1 expression was reduced in the hearts of STZ-induced diabetic mice. Overexpression of MD1 significantly improved cardiac function and markedly inhibited ventricular pathological hypertrophy and fibrosis in these mice. Furthermore, MD1 overexpression resulted in a substantial decrease in myocardial reactive oxygen species (ROS) accumulation, mitigating myocardial oxidative stress and reducing the levels of inflammation-related markers such as IL-1ß, IL-6, and TNF-α. Mechanistically, MD1 overexpression inhibited the activation of the TLR4/STAT3 signaling pathway, as demonstrated in both in vivo and in vitro experiments. The overexpression of MD1 significantly impeded pathological cardiac remodeling and improved cardiac function in STZ-induced diabetic mice. This effect was primarily attributed to a reduction in ROS accumulation and mitigation of myocardial oxidative stress and inflammation, facilitated by the inhibition of the TLR4/STAT3 signaling pathway.

Diet Drives Gut Bacterial Diversity of Wild and Semi-Captive Common Cranes (Grus grus).

The gut microbiota of wild animals can regulate host physical health to adapt to the environment. High-throughput sequencing from fecal samples was used to analyze the gut microbiota communities in common cranes (Grus grus) without harming them. Herein, we compared the fecal microbiome of fifteen G. grus in Tianjin Tuanbo Bird Natural Reserve (wild group) and six G. grus sampled from Beijing Wildlife Park (semi-captive group) in China, using 16S amplicon sequencing and bioinformatic analysis. The results showed that microbiota diversity and composition varied in different groups, suggesting that the gut microbiota was interactively influenced by diet and the environment. A total of 38 phyla and 776 genera were analyzed in this study. The dominant phyla of the G. grus were Firmicutes and Proteobacteria. Meanwhile, the microbiota richness of the semi-captive group was higher than the wild group. Data on beta diversity highlighted significant differences based on different dietary compositions. Zea mays, Glycine max, and Phragmites australia showed a significant correlation with intestinal bacteria of G. grus. This study provides a comprehensive analysis of diet and microbiomes in semi-captive and wild G. grus living in different environments, thus helping us to evaluate the influence on animal microbiomes and improve conservation efforts for this species.

Transfection of entomopathogenic Metarhizium species with a mycovirus confers hypervirulence against two lepidopteran pests.

Although most known viruses infecting fungi pathogenic to higher eukaryotes are asymptomatic or reduce the virulence of their host fungi, those that confer hypervirulence to entomopathogenic fungus still need to be explored. Here, we identified and studied a novel mycovirus in Metarhizium flavoviride, isolated from small brown planthopper (Laodelphax striatellus). Based on molecular analysis, we tentatively designated the mycovirus as Metarhizium flavoviride partitivirus 1 (MfPV1), a species in genus Gammapartitivirus, family Partitiviridae. MfPV1 has two double-stranded RNAs as its genome, 1,775 and 1,575 bp in size respectively, encapsidated in isometric particles. When we transfected commercial strains of Metarhizium anisopliae and Metarhizium pingshaense with MfPV1, conidiation was significantly enhanced (t test; P-value < 0. 01), and the significantly higher mortality rates of the larvae of diamondback moth (Plutella xylostella) and fall armyworm (Spodoptera frugiperda), two important lepidopteran pests were found in virus-transfected strains (ANOVA; P-value < 0.05). Transcriptomic analysis showed that transcript levels of pathogenesis-related genes in MfPV1-infected M. anisopliae were obviously altered, suggesting increased production of metarhizium adhesin-like protein, hydrolyzed protein, and destruxin synthetase. Further studies are required to elucidate the mechanism whereby MfPV1 enhances the expression of pathogenesis-related genes and virulence of Metarhizium to lepidopteran pests. This study presents experimental evidence that the transfection of other entomopathogenic fungal species with a mycovirus can confer significant hypervirulence and provides a good example that mycoviruses could be used as a synergistic agent to enhance the biocontrol activity of entomopathogenic fungi.

Efficacy of a smartphone application assisting home-based rehabilitation and symptom management for patients with lung cancer undergoing video-assisted thoracoscopic lobectomy: a prospective, single-blinded, randomised control trial (POPPER study).

BACKGROUND: Video-assisted thoracoscopic (VATS) lobectomy can affect patients' pulmonary function and quality of life significantly. No optimal protocol combining patient-reported outcome-based symptom management and post-discharge rehabilitation programme has yet been established. This study aimed to assess the efficacy of a novel smartphone app designed for home-based symptom management and rehabilitation. METHODS: The app was developed based on three modules: a symptom reporting system with alerts, aerobic and respiratory training exercises, and educational material. Four core symptoms were selected based on a questionnaire survey of 201 patients and three rounds of Delphi voting by 30 experts. We screened 265 patients and randomly assigned 136 equally to the app group and usual care group. The primary outcome was pulmonary function recovery at 30 days postoperatively. Secondary outcomes included symptom burden and interference with daily living (both rated using the MD Anderson Symptom Inventory for Lung Cancer), aerobic exercise intensity, emergency department visits, app-related safety, and satisfaction with the app. FINDINGS: Of the 136 participants, 56.6% were women and their mean age was 61 years. The pulmonary function recovery ratio 1 month after surgery in the app group was significantly higher than that in the usual care group (79.32% vs. 75.73%; P=0.040). The app group also recorded significantly lower symptom burden and interference with daily living scores and higher aerobic exercise intensity after surgery than the usual care group. Thirty-two alerts were triggered in the app group. The highest pulmonary function recovery ratio and aerobic exercise intensity were recorded in those patients who triggered alerts in both groups. INTERPRETATION: Using a smartphone app is an effective approach to accelerate home-based rehabilitation after VATS lobectomy. The symptom alert mechanism of this app could optimise recovery outcomes, possibly driven by patients' increased self-awareness.

Enhancing diabetic wound healing with a pH/glucose dual-responsive hydrogel for ROS clearance and antibacterial activity.

Currently, the treatment of diabetic wounds in clinical practice is still unsatisfactory due to the risks of oxidative damage and bacterial infection during the healing process. An optimal wound dressing should exhibit robust capabilities in scavenging reactive oxygen species (ROS) and combatting bacterial growth. In this study, we utilized borax as a crosslinker and prepared a pH/glucose dual-responsive composite hydrogel based on poly(vinyl alcohol) (PVA), sodium alginate (SA), and tannic acid (TA). This hydrogel, loaded with cerium dioxide, serves as an effective ROS scavenger, promoting wound closure by reducing the level of ROS in the wound area. Additionally, the hydrogel can release the antibacterial drug ofloxacin in response to the low pH and high glucose microenvironment in infected wounds. Results from skin defect model in diabetic mice demonstrated this ROS-scavenging and antibacterial hydrogel can suppress inflammation and accelerate wound healing. In summary, our work provides a new perspective on a local and stimulus-responsive drug delivery strategy for treating diabetic wounds.

Genetic etiology study in a large cohort with congenital insensitivity to pain with anhidrosis.

ABSTRACT: Pathogenic variations in the NTRK1 can cause congenital insensitivity to pain with anhidrosis (CIPA), a rare autosomal recessive inherited neuropathy. The precise diagnosis of CIPA relies on the identification of pathogenic genotypes. Therefore, it is essential to expand the NTRK1 variation spectrum and improve molecular diagnosis methods. In this study, 74 probands with typical manifestations of CIPA but unknown genotypes were recruited. A comprehensive molecular genetic analysis was performed to identify variations in the NTRK1, using techniques including Sanger and next-generation sequencing, bioinformatic analysis, quantitative polymerase chain reaction (qPCR), gap-PCR, short tandem repeat (STR) genotyping, and reverse-transcription PCR. In addition, functional assays were conducted to determine the pathogenicity of variants of uncertain significance (VUS) and further characterized changes in glycosylation and phosphorylation of 14 overexpressed mutant vectors with variants at different domains in the TrkA protein, which is encoded by NTRK1. A total of 48 variations in the NTRK1 were identified, including 22 novel ones. When combined with data from another 53 CIPA patients examined in our previous work, this study establishes the largest genotypic and phenotypic spectra of CIPA worldwide, including 127 CIPA families. Moreover, functional studies indicated that the pathogenicity of VUS mainly affected insufficient glycosylation in the extracellular domain and abnormal phosphorylation in the intracellular domain. This study not only provides important evidence for precise diagnosis of CIPA but also further enriches our understanding of the pathogenesis of this disease.