Mitigating Strain Accumulation in Li2RuO3 via Fluorine Doping.

Lithium ruthenium oxide (Li2RuO3) is an archetypal lithium rich cathode material (LRCM) with both cation and anion redox reactions (ARRs). Commonly, the instability of oxygen redox activities has been regarded as the root cause of its performance degradation in long-term operation. However, we find that not triggering ARRs does not improve and even worsens its cyclability due to the detrimental strain accumulation induced by Ru redox activities. To solve this problem, we demonstrate that F-doping in Li2RuO3 can alter its preferential orientation and buffer interlayer repulsion upon Ru redox, both of which can mitigate the strain accumulation along the c-axis and improve its structural stability. This work highlights the importance of optimizing cation redox reactions in LRCMs and provides a new perspective for their rational design.

Exploration of new models for primary dysmenorrhea treatment: low-power visible-light-activated photodynamic therapy and oral contraceptives.

Background: Primary dysmenorrhea (PD) is one of the most common reasons that affect the life quality of women during childbearing age. This research aims to explore the efficacy and curative effect characteristics of oral contraceptives and low-power visible-light-activated photodynamic therapy (PDT). Besides investigating the possible mechanism of PDT, we expected to find a treatment model with better efficacy and fewer side effects. Method: It was a multicenter, randomized, parallel-controlled study. Eligible participants were randomly assigned to three groups: placebo group, oral contraceptive (Marvelon) group, and the PDT group. They were treated continuously for three menstrual cycles and followed up for two cycles after treatment. The scores of the visual analog scale (VAS) and the concentration of pain-related small molecules in blood before and after treatment were recorded in each group, which can evaluate the therapeutic characteristics of different treatments. Result: Both Marvelon and PDT were effective. The effect of Marvelon appears quickly which can significantly relieve symptoms at the beginning, while PDT shows a relatively slow role. There was no significant difference in the final efficacy two cycles after treatment. The therapeutic effect was achieved by reducing the concentrations of prostaglandin 2 (PGE2) and endothelin (ET) in the blood. Conclusion: Marvelon and PDT are effective methods for the treatment of PD. The long-term efficacy of the two is similar, while the therapeutic characteristics and the side effects are different. Patients can choose the suitable way according to their individual needs.

Prenatal diagnosis of interrupted aortic arch using high-definition flow render mode and spatiotemporal image correlation.

OBJECTIVES: To evaluate the clinical utility of two dimensional (2D) ultrasound combined with spatiotemporal image correlation (STIC) in diagnosing interrupted aortic arch (IAA) in fetal life. METHODS: A total of 53 cases of fetal IAA were diagnosed using 2D ultrasound combined with STIC, and 53 normal fetuses of the same gestational week were selected. These cases were retrospectively analyzed to assess the utility of employing 2D ultrasound combined with STIC in the diagnosis of IAA. RESULTS: 2D ultrasound combined with STIC detected 22 cases of type A IAA, 24 cases of type B IAA, and seven cases of type C IAA. Furthermore, combining 2D ultrasound with STIC enabled dynamic visualization of the IAA, aiding in prenatal diagnosis. The diagnostic coincidence rate of IAA was found to be higher in the HD-flow combined with STIC than that in the 2D combined with HD-flow. CONCLUSION: HD-flow combined with STIC can assist in diagnosing fetal IAA, and this technique has important clinical value.

Effect of Consultation Number on the Assessment and Treatment of Polycystic Ovary Syndrome.

Background: The basic medical education stage is not enough to support physicians to fully diagnose and evaluate polycystic ovary syndrome (PCOS). The study aims to discover the difference in treatment choice between participants with different annual consultation number of PCOS, to promote lifelong learning, and drive balanced development within healthcare. Methods: This is a multicenter cross-sectional survey. Participants' basic information, knowledge of PCOS and treatment options were collected online. According to the annual consultation number of patients with PCOS, physicians were divided into three groups: 0-50 people/yr, 50-200 people/yr, and >200 people/yr, and the results were derived from χ2 test, Fisher exact test, and multivariate logistic regression analysis. Results: The study analyzed 1689 questionnaires, and 1206 physicians (71.4%) received less than 50 women per year, 388 physicians (30.0%) with an annual number of 50-200 women, and 95 physicians (5.6%) with patient turnover for more than 200 people. Reproductive endocrinologists generally have higher access to the clinic. As the number of visits increases, more and more physicians would perceive patients as more likely to have abnormal blood glucose and heavy weight. Physicians with large numbers of consultations are more likely to use Asian or Chinese standards to assess obesity. The multivariate analysis involved variables such as age, hospital level, specialty, and patient turnover annually, and more young doctors actively assessed lipid profile (odds ratio (OR) 1.56, 95% confidence interval (CI) (1.16, 2.16)), and primary hospitals (OR 0.65 CI (0.44, 0.89)) chose OGTT for blood glucose assessment less than tertiary hospitals. Physicians in secondary hospitals are more aggressive in evaluating androgens. Conclusion: Our survey found differences in endocrine assessment, metabolic screening, and treatment in PCOS women in terms of the number of obstetrician-gynecologists who received different patient consultation numbers. The importance of continuing education for physicians is emphasized, to promote lifelong learning.

On-site detection and differentiation of African swine fever virus variants using an orthogonal CRISPR-Cas12b/Cas13a-based assay.

The African swine fever virus (ASFV) and its variants have induced substantial economic losses in China, prompting a critical need for efficient detection methods. Several PCR-based methods have been developed to discriminate between wild-type ASFV and gene-deleted variants. However, the requirement for sophisticated equipment and skilled operators limits their use in field settings. Here, we developed a CRISPR-Cas12b/Cas13a-based detection assay that can identify ASFV variants with minimal equipment requirements and a short turnaround time. The assay utilizes the distinct DNA/RNA collateral cleavage preferences of Cas12b/Cas13a to detect two amplified targets from multiplex recombinase polymerase amplification (RPA) in a single tube, and the results can be visualized through fluorescent or lateral-flow readouts. When tested with clinical samples in field settings, our assay successfully detected all ASFV-positive samples in less than 60 min. This assay provides a rapid on-site surveillance tool for detecting ASFV and its emerging variants.

Emerging non-antibody‒drug conjugates (non-ADCs) therapeutics of toxins for cancer treatment.

The non-selective cytotoxicity of toxins limits the clinical relevance of the toxins. In recent years, toxins have been widely used as warheads for antibody‒drug conjugates (ADCs) due to their efficient killing activity against various cancer cells. Although ADCs confer certain targeting properties to the toxins, low drug loading capacity, possible immunogenicity, and other drawbacks also limit the potential application of ADCs. Recently, non-ADC delivery strategies for toxins have been extensively investigated. To further understand the application of toxins in anti-tumor, this paper provided an overview of prodrugs, nanodrug delivery systems, and biomimetic drug delivery systems. In addition, toxins and their combination strategies with other therapies were discussed. Finally, the prospect and challenge of toxins in cancer treatment were also summarized.

Bone Morphogenetic Protein 2 Enhances Porcine Beige Adipogenesis via AKT/mTOR and MAPK Signaling Pathways.

Bone morphogenetic protein 2 (BMP2) has been reported to regulate adipogenesis, but its role in porcine beige adipocyte formation remains unclear. Our data reveal that BMP2 is significantly induced at the early stages of porcine beige adipocyte differentiation. Additionally, supplementing rhBMP2 during the early stages, but not the late stages of differentiation, significantly enhances porcine SVF adipogenesis, thermogenesis, and proliferation. Furthermore, compared to the empty plasmid-transfected-SVFs, BMP2-overexpressed SVFs had the enhanced lipid accumulation and thermogenesis, while knockdown of BMP2 in SVFs exhibited the opposite effect. The RNA-seq of the above three types of cells revealed the enrichment of the annotation of thermogenesis, brown cell differentiation, etc. In addition, the analysis also highlights the significant enrichment of cell adhesion, the MAPK cascade, and PPARγ signaling. Mechanistically, BMP2 positively regulates the adipogenic and thermogenic capacities of porcine beige adipocytes by activating PPARγ expression through AKT/mTOR and MAPK signaling pathways.

Protective effects of ginsenoside F2 on isoproterenol-induced myocardial infarction by activating the Nrf2/HO-1 and PI3K/Akt signaling pathways.

BACKGROUND: Ginsenoside F2 (GF2) serves as the principal intestinal metabolite resulting from the oral intake of Panax ginseng and Panax quinquefolius, exhibiting antioxidative, hypolipidemic, antitumor, and anti-inflammatory properties. Nevertheless, its effect on myocardial infarction (MI) is still unknown. PURPOSE: The purpose of this study is to investigate the protective effect and the underlying mechanisms of GF2 against isoproterenol (ISO)-induced MI. METHODS: ISO-induced H9c2 cardiomyocytes and MI rat models were utilized as in vitro and in vivo models to evaluate the impact of anti-MI of GF2. The underlying mechanisms were investigated using a variety of methodologies, including electrocardiography, Western blot analysis, histopathological examination, immunofluorescence, immunohistochemistry, and ELISA techniques. RESULTS: In vivo experiments, our results indicated that GF2 significantly ameliorated ISO-induced electrocardiographic (ECG) abnormalities, myocardial fiber necrosis, rupture, fibrosis of myocardial tissues, and suppressed cardiac enzyme activities. Meanwhile, GF2 notably raised the activity of antioxidant enzymes like CAT, GSH, and SOD. Furthermore, it downregulated Keap1 expression level while upregulating NQO1, Nrf2, and HO-1 expression levels. Additionally, GF2 suppressed the expression of the cleaved caspase-3 and pro-apoptotic protein Bax while promoting the expression of anti-apoptotic proteins Bcl-2, p-PI3K, and p-Akt. TUNEL fluorescence results also demonstrated that GF2 effectively inhibited cardiomyocyte apoptosis. Furthermore, consistent with the results of animal experiments, GF2 considerably attenuated ROS generation, changed apoptosis and mitochondrial function, and reduced oxidative stress in ISO-induced H9c2 cardiomyocytes through activating Nrf2/HO-1 and PI3K/Akt signaling pathways. CONCLUSION: Taken together, GF2 ameliorated MI by preventing cardiocyte apoptosis, oxidative stress, and mitochondrial dysfunction via modulating the Nrf2/HO-1 and PI3K/Akt signaling pathways, showing potential as a treatment strategy for treating MI.

Relationship between changes in late-life blood pressure and the risk of frailty and mortality among older population in China: a cohort study based on CLHLS.

The evidence regarding the effects of blood pressure changes on older individuals remains inconclusive, and the impact of frailty throughout the life course is not known. We investigated the associations of different change patterns of blood pressure during 3-year intervals with frailty and mortality. Participants included 7335 persons from 2008 to 2014 of the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Change in blood pressure was calculated as the difference between follow-up and baseline. Frailty was evaluated using a 40-item frailty index. Mortality status was ascertained up to December 31, 2014. The mean age of participants was 82.6 ± 10.7 years. The optimal blood pressure level (SBP, 130-150 mmHg; DBP, 70-90 mmHg) was associated with the lowest risk of frailty while decreasing follow-up SBP and DBP were significantly correlated with frailty. Lower baseline blood pressure levels (SBP < 130 mmHg; DBP < 70 mmHg) were associated with decreased mortality risk when participants increased their blood pressure to optimal levels during follow-up SBP and DBP (0.78, 0.63-0.98), compared to maintaining a steady low SBP (< 130 mmHg) and DBP (< 70 mmHg). For those with DBP around 70-90 mmHg, decreasing follow-up DBP (< 70 mmHg) was associated with higher mortality (1.23, 1.07-1.42) compared to maintaining stable follow-up DBP (70-90 mmHg). These results remain significant after adjusting for frailty. Optimal blood pressure levels were associated with the lowest risk of frailty. The association between lower blood pressure and increased mortality risk persisted even after accounting for frailty. We used a nationally representative longitudinal cohort study by using 2008-2014 of the Chinese Longitudinal Healthy Longevity in China. Change in blood pressure was calculated as the difference between follow-up and baseline. We investigated the associations of different change patterns of blood pressure during 3-year intervals with frailty and mortality.

Innovation or introduction? Impacts of the low-carbon city pilot policy on the pathways toward green technology progress.

To examine whether the low-carbon city pilot (LCCP) policy influences the green technology innovation (GTI) or embodied technology introduction (ETI), two different pathways to green technology progress, in manufacturing enterprises in China, this study employs a staggered difference-in-difference (DID) model to evaluate the effects of the policy. The findings suggest that the LCCP policy has stimulated an increase in the quantity of GTI and ETI among enterprises, but reduced the quality of innovation. Large, high-carbon-intensity, and state-owned enterprises are more likely to engage in GTI, while small, low-carbon-intensity, and non-state-owned enterprises prefer ETI. The policy is effective in alleviating financing constraints and improving environmental concerns. Both GTI and ETI play a crucial role in economic performance, while the latter also promotes environmental and ESG performance. Accordingly, we recommend establishing a policy-compatible evaluation system, strengthening mandatory and incentive measures, and cultivating a green innovation ecosystem, etc., to improve the performance of the LCCP policy.

Genetically modified pigs: Emerging animal models for hereditary hearing loss.

Hereditary hearing loss (HHL), a genetic disorder that impairs auditory function, significantly affects quality of life and incurs substantial economic losses for society. To investigate the underlying causes of HHL and evaluate therapeutic outcomes, appropriate animal models are necessary. Pigs have been extensively used as valuable large animal models in biomedical research. In this review, we highlight the advantages of pig models in terms of ear anatomy, inner ear morphology, and electrophysiological characteristics, as well as recent advancements in the development of distinct genetically modified porcine models of hearing loss. Additionally, we discuss the prospects, challenges, and recommendations regarding the use pig models in HHL research. Overall, this review provides insights and perspectives for future studies on HHL using porcine models.

Lyophilized lymph nodes for improved delivery of chimeric antigen receptor T cells.

Lymph nodes are crucial organs of the adaptive immune system, orchestrating T cell priming, activation and tolerance. T cell activity and function are highly regulated by lymph nodes, which have a unique structure harbouring distinct cells that work together to detect and respond to pathogen-derived antigens. Here we show that implanted patient-derived freeze-dried lymph nodes loaded with chimeric antigen receptor T cells improve delivery to solid tumours and inhibit tumour recurrence after surgery. Chimeric antigen receptor T cells can be effectively loaded into lyophilized lymph nodes, whose unaltered meshwork and cytokine and chemokine contents promote chimeric antigen receptor T cell viability and activation. In mouse models of cell-line-derived human cervical cancer and patient-derived pancreatic cancer, delivery of chimeric antigen receptor T cells targeting mesothelin via the freeze-dried lymph nodes is more effective in preventing tumour recurrence when compared to hydrogels containing T-cell-supporting cytokines. This tissue-mediated cell delivery strategy holds promise for controlled release of various cells and therapeutics with long-term activity and augmented function.

Lymph node-biomimetic scaffold boosts CAR-T therapy against solid tumor.

The limited infiltration and persistence of chimeric antigen receptor (CAR)-T cells is primarily responsible for their treatment deficits in solid tumors. Here, we present a three-dimensional scaffold, inspired by the physiological process of T-cell proliferation in lymph nodes. This scaffold gathers the function of loading, delivery, activation and expansion for CAR-T cells to enhance their therapeutic effects on solid tumors. This porous device is made from poly(lactic-co-glycolic acid) by a microfluidic technique with the modification of T-cell stimulatory signals, including anti-CD3, anti-CD28 antibodies, as well as cytokines. This scaffold fosters a 50-fold CAR-T cell expansion in vitro and a 15-fold cell expansion in vivo. Particularly, it maintains long-lasting expansion of CAR-T cells for up to 30 days in a cervical tumor model and significantly inhibits the tumor growth. This biomimetic delivery strategy provides a versatile platform of cell delivery and activation for CAR-T cells in treating solid tumors.

Rare NUP98::PRRX1 fusion transcript in a therapy-related acute myeloid leukemia associated with del(7q) following chemotherapy for diffuse large B-cell lymphoma.

BACKGROUND: Therapy-related acute myeloid leukemia (t-AML) is increasingly recognized as a treatment complication in patients receiving chemotherapy, radiotherapy, or immunosuppressive agents for primary neoplasms. NUP98::PRRX1 fusion gene, caused by t(1;11)(q23;p15), is a rare recurrent cytogenetic alteration in leukemia, and only seven cases with NUP98::PRRX1 were reported so far. METHODS: A 53-year-old female patient was diagnosed with t-AML after 20 months of complete remission (CR) from diffuse large B-cell lymphoma (DLBCL). Conventional karyotype, fluorescence in situ hybridization (FISH), and DNA/RNA next-generation sequence (NGS) were used to detect genetic abnormalities. RESULTS: Abnormal karyotype of 46, XX, t(1;11)(q25;p15), del(7)(q22) was revealed. NUP98 gene rearrangement and del(7)(q22) were verified by FISH. Further, RNA NGS detected NUP98::PRRX1 fusion transcript, and DNA NGS detected KRAS gene mutation. The patient achieved CR after a combined chemotherapy regimen containing BCL-2 inhibitor and underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), but she died of leukemia recurrence 14 months later. CONCLUSIONS: Novel targeted drugs may provide opportunities for patients with NUP98::PRRX1 to undergo allo-HSCT. However, since the cases of carrying the NUP98::PRRX1 are limited, more patients with this genetic change need to be investigated to elucidate the prognostic significance.

Transcriptome-Wide Identification and Integrated Analysis of a UGT Gene Involved in Ginsenoside Ro Biosynthesis in Panax ginseng.

Panax ginseng as a traditional medicinal plant with a long history of medicinal use. Ginsenoside Ro is the only oleanane-type ginsenoside in ginseng, and has various pharmacological activities, including anti-inflammatory, detoxification, and antithrombotic activities. UDP-dependent glycosyltransferase (UGT) plays a key role in the synthesis of ginsenoside, and the excavation of UGT genes involved in the biosynthesis of ginsenoside Ro has great significance in enriching ginsenoside genetic resources and further revealing the synthesis mechanism of ginsenoside. In this work, ginsenoside-Ro-synthesis-related genes were mined using the P. ginseng reference-free transcriptome database. Fourteen hub transcripts were identified by differential expression analysis and weighted gene co-expression network analysis. Phylogenetic and synteny block analyses of PgUGAT252645, a UGT transcript among the hub transcripts, showed that PgUGAT252645 belonged to the UGT73 subfamily and was relatively conserved in ginseng plants. Functional analysis showed that PgUGAT252645 encodes a glucuronosyltransferase that catalyzes the glucuronide modification of the C3 position of oleanolic acid using uridine diphosphate glucuronide as the substrate. Furthermore, the mutation at 622 bp of its open reading frame resulted in amino acid substitutions that may significantly affect the catalytic activity of the enzyme, and, as a consequence, affect the biosynthesis of ginsenoside Ro. Results of the in vitro enzyme activity assay of the heterologous expression product in E. coli of PgUGAT252645 verified the above analyses. The function of PgUGAT252645 was further verified by the result that its overexpression in ginseng adventitious roots significantly increased the content of ginsenoside Ro. The present work identified a new UGT gene involved in the biosynthesis of ginsenoside Ro, which not only enriches the functional genes in the ginsenoside synthesis pathway, but also provides the technical basis and theoretical basis for the in-depth excavation of ginsenoside-synthesis-related genes.

Identification of (4-chlorophenyl)(5-hydroxynaphtho[1,2-b]furan-3-yl)methanone as novel COX-2 inhibitor with analgesic profile.

Chronic pain is a serious problem that affects billions of people worldwide, but current analgesic drugs limit their use in chronic pain management due to their respective side effects. As a first-line clinical drug for chronic pain, COX-2 selective inhibitors can relieve mild to moderate pain, but they also have some problems. The most prominent one is that their analgesic intensity is not enough, and they cannot well meet the treatment needs of chronic pain. Therefore, there is an urgent need to develop COX-2 inhibitors with stronger analgesic intensity. In this article, we used virtual screening method to screen out the structurally novel COX-2 inhibitor for chronic pain management, and conducted a preliminary study on its mechanism of action using molecular dynamics simulation.

Discovery of a novel series of pyridone amides as NaV1.8 inhibitors.

The NaV1.8 channel, mainly found in the peripheral nervous system, is recognized as one of the key factors in chronic pain. The molecule VX-150 was initially promising in targeting this channel, but the phase II trials of VX-150 did not show expected pain relief results. By analyzing the interaction mode of VX-150 and NaV1.8, we developed two series with a total of 19 molecules and examined their binding affinity to NaV1.8 in vitro and analgesic effect in vivo. One compound, named 2j, stood out with notable activity against the NaV1.8 channel and showed effective pain relief in models of chronic inflammatory pain and neuropathic pain. Our research points to 2j as a strong contender for developing safer pain-relief treatments.

A seven-sex species recognizes self and non-self mating-type via a novel protein complex.

Although most species have two sexes, multisexual (or multi-mating type) species are also widespread. However, it is unclear how mating-type recognition is achieved at the molecular level in multisexual species. The unicellular ciliate Tetrahymena thermophila has seven mating types, which are determined by the MTA and MTB proteins. In this study, we found that both proteins are essential for cells to send or receive complete mating-type information, and transmission of the mating-type signal requires both proteins to be expressed in the same cell. We found that MTA and MTB form a mating-type recognition complex that localizes to the plasma membrane, but not to the cilia. Stimulation experiments showed that the mating-type-specific regions of MTA and MTB mediate both self- and non-self-recognition, indicating that T. thermophila uses a dual approach to achieve mating-type recognition. Our results suggest that MTA and MTB form an elaborate multifunctional protein complex that can identify cells of both self and non-self mating types in order to inhibit or activate mating, respectively.

A multiomics analysis-assisted deep learning model identifies a macrophage-oriented module as a potential therapeutic target in colorectal cancer.

Colorectal cancer (CRC) is a common malignancy involving multiple cellular components. The CRC tumor microenvironment (TME) has been characterized well at single-cell resolution. However, a spatial interaction map of the CRC TME is still elusive. Here, we integrate multiomics analyses and establish a spatial interaction map to improve the prognosis, prediction, and therapeutic development for CRC. We construct a CRC immune module (CCIM) that comprises FOLR2+ macrophages, exhausted CD8+ T cells, tolerant CD8+ T cells, exhausted CD4+ T cells, and regulatory T cells. Multiplex immunohistochemistry is performed to depict the CCIM. Based on this, we utilize advanced deep learning technology to establish a spatial interaction map and predict chemotherapy response. CCIM-Net is constructed, which demonstrates good predictive performance for chemotherapy response in both the training and testing cohorts. Lastly, targeting FOLR2+ macrophage therapeutics is used to disrupt the immunosuppressive CCIM and enhance the chemotherapy response in vivo.

Coping target checklist for home-based older adults living with disabilities and their spousal caregivers.

BACKGROUND: The substantial rise in the population of older adults living with disabilities is a prominent concern, presenting a profound challenge for healthcare and social welfare systems. Community-based home care is seen as an effective approach to meet the care needs of older adults living with disabilities. OBJECTIVE: To construct a coping target checklist for home-based older adults living with disabilities and their spousal caregivers. METHODS: The initial draft was developed based on a comprehensive literature review, followed by two rounds of Delphi correspondence final version. RESULTS: A comprehensive literature review resulted in the development of 7 modules, 20 topics. After round 1, 3 items were removed, 3 sections, 1 topic and 1 objective were new additions, 16 items were modified, split or combined. Four sections, 3 sections (Individual coping target for spousal caregivers, Individual coping target for older adults living with disabilities, and Shared coping target), 7 modules, 18 topics and 49 objectives were finally identified in round 2. The content of the list tool is derived from three perspectives: self-management strategies for older adults living with disabilities, caregiving strategies for spousal caregivers, and combined. CONCLUSIONS: The coping target checklist was intended to be evidence-based and reflective of a practical direction for home-based older adults living with disabilities and their spousal caregivers living at home.