Rhodium-Promoted C-H Activation/Annulation between DNA-Linked Terminal Alkyne and Aromatic Acid: A Finding from the Selection Outcomes.

Inspired by previous selection outcomes, we investigated and developed a rhodium-promoted C-H activation/annulation reaction of DNA-linked terminal alkynes and aromatic acids. This reaction exhibits excellent efficiency with high conversions and a broad substrate scope. Most importantly, the unique DEL-compatible conditions provide a better scenario for yielding an isocoumarin scaffold compared to conventional organic reaction conditions, and this newly developed on-DNA method has confirmed its feasibility in preparing DNA-encoded libraries.

The roles of nuclear orphan receptor NR2F6 in anti-viral innate immunity.

Proper transcription regulation by key transcription factors, such as IRF3, is critical for anti-viral defense. Dynamics of enhancer activity play important roles in many biological processes, and epigenomic analysis is used to determine the involved enhancers and transcription factors. To determine new transcription factors in anti-DNA-virus response, we have performed H3K27ac ChIP-Seq and identified three transcription factors, NR2F6, MEF2D and MAFF, in promoting HSV-1 replication. NR2F6 promotes HSV-1 replication and gene expression in vitro and in vivo, but not dependent on cGAS/STING pathway. NR2F6 binds to the promoter of MAP3K5 and activates AP-1/c-Jun pathway, which is critical for DNA virus replication. On the other hand, NR2F6 is transcriptionally repressed by c-Jun and forms a negative feedback loop. Meanwhile, cGAS/STING innate immunity signaling represses NR2F6 through STAT3. Taken together, we have identified new transcription factors and revealed the underlying mechanisms involved in the network between DNA viruses and host cells.

A wearable flexible triboelectric nanogenerator for bio-mechanical energy harvesting and badminton monitoring.

Recently, textile materials used for wearable flexible sensors have received much attention. Wearable textile based triboelectric nanogenerator (TENG) not only has unique advantages in mechanical energy harvesting, but also has application value in the direction of motion sensing. Here, we proposed a non-woven fabric triboelectric nanogenerator (NW-TENG) for mechanical energy harvesting and badminton monitoring. The non-woven fabric play the role of positive triboelectric, and the fluffy fiber structure endows NW-TENG with a sensitive response to pressure. The pressure sensing sensitivity of NW-TENG sensor can reach 1.22 V N-1 (Pressure range: 0-7 N) and 0.18 V N-1 (Pressure range: 8 N-55 N). Furthermore, the NW-TENG can be installed on the body joints of badminton players for analyzing joint movements, thereby achieving data-driven badminton training and facilitating the evaluation of training effectiveness. This research provide a new path to promote TENG to the badminton monitoring field.

PLA2G12A protects against diet-induced obesity and insulin resistance by enhancing energy expenditure and clearance of circulating triglycerides.

Secreted phospholipase A2s are involved in the development of obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease, which have become serious and growing health concerns worldwide. Integration of genome-wide association study and gene co-expression networks analysis showed that the secreted phospholipase A2 group XIIA (PLA2G12A) may participate in hepatic lipids metabolism. Nevertheless, the role of PLA2G12A in lipid metabolism and its potential mechanism remain elusive. Here, we used AAV9 vector carrying human PLA2G12A gene to exogenously express hPLA2G12A in the liver of mice. We demonstrated that the overexpression of hPLA2G12A resulted in a significant decrease in serum lipid levels in wild-type mice fed with chow diet or high-fat diet (HFD). Moreover, hPLA2G12A treatment protected against diet-induced obesity and insulin resistance in mice fed a HFD. Notably, we found that hPLA2G12A treatment confers protection against obesity and hyperlipidemia independent of its enzymatic activity, but rather by increasing physical activity and energy expenditure. Furthermore, we demonstrated that hPLA2G12A treatment induced upregulation of ApoC2 and Cd36 and downregulation of Angptl8, which contributed to the increase in clearance of circulating triglycerides and hepatic uptake of fatty acids without affecting hepatic de novo lipogenesis, very low-density lipoprotein secretion, or intestinal lipid absorption. Our study highlights the potential of PLA2G12A gene therapy as a promising approach for treating obesity, insulin resistance and T2DM.

The dyadic associations among self-efficacy, dyadic coping, and health-related quality of life between high-risk pregnant women and spouses: a cross-sectional study.

AIM: Health-related quality of life(HRQoL) is essential for high-risk pregnant women and their spouses. This study aimed to explore the dyadic associations (including actor and partner effects) among self-efficacy, dyadic coping, and HRQoL of high-risk pregnant women and their spouses and examine the mediating effect of dyadic coping. METHODS: This cross-sectional study recruited participants from two Grade A tertiary hospitals in China from October 2022 to September 2023. A questionnaire including the Chinese version of the General Self-Efficacy Scale, Dyadic Coping Inventory, and 12 Short Form Health Survey Scales was used for the survey. The actor-partner interdependence mediation model was constructed to test dyadic associations and mediating effects. RESULTS: In the actor effects, self-efficacy was positively associated with dyadic coping and HRQoL (P < 0.05). Regarding partner effects, pregnant women's self-efficacy was positively associated with spouses' dyadic coping and physical health (P < 0.05). Dyadic coping partially mediated the relationship between self-efficacy and HRQoL for both groups(P < 0.05). CONCLUSION: The HRQoL of high-risk pregnant women and their spouses requires urgent attention. Enhancing self-efficacy and dyadic coping in these couples is related to their improved physical and mental health. Healthcare professionals should consider interactions between couples and include them together in perinatal care. Intervention programs for couples or families based on existing positive psychology and dyadic interventions may work together to improve the HRQoL of couples.

Cancer cell membrane-camouflaged biomimetic nanoparticles for enhancing chemo-radiation therapy efficacy in glioma.

Glioblastoma multiforme (GBM) presents significant challenges in treatment, with current standard-of-care approaches offering limited efficacy and survival benefits. This necessitates the development of innovative therapeutic strategies to enhance treatment outcomes. Nanotechnology has emerged as a promising avenue in cancer therapy, offering targeted drug delivery and enhanced therapeutic efficacy. Polymeric nanoparticles, particularly those based on Poly (lactic-co-glycolic acid) (PLGA), have gained traction as drug carriers due to their biocompatibility and controlled release properties. However, their interception by macrophages poses challenges to effective drug delivery. Superparamagnetic iron oxide (SPIO) nanoparticles have shown promise as radiosensitizers, enhancing the efficacy of radiotherapy through the generation of reactive oxygen species (ROS). Moreover, cell membrane biomimetic drug delivery systems have garnered attention for their ability to improve biocompatibility and targeting capabilities. Leveraging these concepts, our study introduces a novel multifunctional platform, GM@P (T/S), comprising polymeric nanoparticles coated with cancer cell membrane. By encapsulating temozolomide (TMZ) and SPIO nanoparticles within GM@P (T/S), we aim to synergistically enhance the cytotoxic effects of chemotherapy and radiotherapy against GBM while overcoming limitations associated with conventional treatments. This innovative approach holds promise for addressing the unmet clinical needs in GBM therapy and advancing towards more effective and personalized treatment strategies.

CFTR dysfunction leads to defective bacterial eradication on cystic fibrosis airways.

Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel by genetic mutations causes the inherited disease cystic fibrosis (CF). CF lung disease that involves multiple disorders of epithelial function likely results from loss of CFTR function as an anion channel conducting chloride and bicarbonate ions and its function as a cellular regulator modulating the activity of membrane and cytosol proteins. In the absence of CFTR activity, abundant mucus accumulation, bacterial infection and inflammation characterize CF airways, in which inflammation-associated tissue remodeling and damage gradually destroys the lung. Deciphering the link between CFTR dysfunction and bacterial infection in CF airways may reveal the pathogenesis of CF lung disease and guide the development of new treatments. Research efforts towards this goal, including high salt, low volume, airway surface liquid acidosis and abnormal mucus hypotheses are critically reviewed.

Candida parapsilosis bone marrow infection in an immunocompetent patient.

Background: We discuss a case of an immunocompetent patient who presented with fever and tachypnoea, found to have Candida parapsilosis bone marrow infection, cultured on bone marrow aspirate sample. Candida parapsilosis is an opportunistic yeast pathogen that typically affects immunocompromised individuals, or occurs in patients with apparent introduced source; neither of these factors were present for this case. Bone marrow aspirates and trephines are not regular investigations for fever; however they can be useful diagnostic aids as evidenced in this case. Case report: An 83-year-old woman presenting with fevers and tachypnoea was being treated for a systemic bacterial infection, however was unresponsive to empirical antibiotic therapy. To exclude an occult malignancy, an 18-fluorodeoxyglucose positron emission tomography scan was conducted. Significant bone marrow uptake was noted, prompting a bone marrow aspirate and trephine to investigate for a hematological malignancy. While the trephine biopsy was benign, a culture of the aspirate grew Candida parapsilosis. Intravenous antifungal therapy was initiated; however, the patient did not improve despite targeted therapy likely due to delays in diagnosis, and was palliated. Conclusion: Our case seeks to demonstrate a novel case whereby a bone marrow aspirate culture provided a conclusive diagnosis of invasive Candida parapsilosis bone marrow infection, and guided treatment in an immunocompetent patient. It is important for clinicians to consider invasive fungal infections in febrile patients regardless of immune status. Additionally, when performing a bone marrow aspirate and trephine on a febrile patient, we recommend including aspirate fungal cultures to investigate for an invasive fungal infection.

Integrated proteomic profiling identifies amino acids selectively cytotoxic to pancreatic cancer cells.

Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers, characterized by extremely limited therapeutic options and a poor prognosis, as it is often diagnosed during late disease stages. Innovative and selective treatments are urgently needed, since current therapies have limited efficacy and significant side effects. Through proteomics analysis of extracellular vesicles, we discovered an imbalanced distribution of amino acids secreted by PDAC tumor cells. Our findings revealed that PDAC cells preferentially excrete proteins with certain preferential amino acids, including isoleucine and histidine, via extracellular vesicles. These amino acids are associated with disease progression and can be targeted to elicit selective toxicity to PDAC tumor cells. Both in vitro and in vivo experiments demonstrated that supplementation with these specific amino acids effectively eradicated PDAC cells. Mechanistically, we also identified XRN1 as a potential target for these amino acids. The high selectivity of this treatment method allows for specific targeting of tumor metabolism with very low toxicity to normal tissues. Furthermore, we found this treatment approach is easy-to-administer and with sustained tumor-killing effects. Together, our findings reveal that exocytosed amino acids may serve as therapeutic targets for designing treatments of intractable PDAC and potentially offer alternative treatments for other types of cancers.

Dyadic coping and associated factors in women with high-risk pregnancy and their spouses: Do they interact?

OBJECTIVE: The objective of this study was to examine the present situation of dyadic coping in pregnant women with high-risk pregnancy and their spouses, as well as the relevant factors and the interactions between partners. METHODS: From October 2022 to September 2023, a cross-sectional survey was undertaken, involving 460 pairs of pregnant women with high-risk pregnancy who were hospitalized for childbirth and their accompanying spouses. These participants completed self-assessments on dyadic coping, marital satisfaction, perceived stress, and self-efficacy through the completion of paper questionnaires. The collected data was then subjected to analysis utilizing correlation analysis and multiple linear regression. The actor-partner interdependence model (APIM) was then developed using the structural equation modeling(SEM) to test the binary association. FINDINGS: Pregnant women preferred to utilize stressful communication, whereas their spouses employed supportive and delegated coping. Both external (such as education level, employment status, and medical insurance) and internal (such as marital satisfaction, perceived stress, and self-efficacy) factors were associated with pregnant women's dyadic coping. Education level and internal factors were also associated with the spouses' dyadic coping. In contrast to spouses, who can only have a partner effect on pregnant women through marriage satisfaction, all pregnant women's internal elements played the partner effect on the spouses' dyadic coping. IMPLICATIONS: The study's findings help identify populations with inadequate coping ability. Promoting marital satisfaction, self-efficacy, and reducing perceived stress are associated with enhancing the dyadic coping ability of pregnant women with high-risk pregnancy and their spouses. It also suggests that antenatal care should intervene with pregnant women with high-risk pregnancy and their spouses as a whole, and emphasize collaborative coping and effective mutual support between couples rather than spousal support alone.

Low caveolin-1 levels and symptomatic intracranial haemorrhage risk in large-vessel occlusive stroke patients after endovascular thrombectomy.

BACKGROUND AND PURPOSE: Caveolin-1 (Cav-1) is reported to mediate blood-brain barrier integrity after ischaemic stroke. Our purpose was to assess the role of circulating Cav-1 levels in predicting symptomatic intracranial haemorrhage (sICH) amongst ischaemic stroke patients after endovascular thrombectomy (EVT). METHODS: Patients with large-vessel occlusive stroke after EVT from two stroke centres were prospectively included. Serum Cav-1 level was tested after admission. sICH was diagnosed according to the Heidelberg Bleeding Classification. RESULTS: Of 325 patients (mean age 68.6 years; 207 men) included, 47 (14.5%) were diagnosed with sICH. Compared with patients without sICH, those with sICH had a lower concentration of Cav-1. After adjusting for potential confounders, multivariate regression analysis demonstrated that the increased Cav-1 level was associated with a lower sICH risk (odds ratio 0.055; 95% confidence interval 0.005-0.669; p = 0.038). Similar results were obtained when Cav-1 levels were analysed as a categorical variable. Using a logistic regression model with restricted cubic splines, a linear and negative association of Cav-1 concentration was found with sICH risk (p = 0.001 for linearity). Furthermore, the performance of the conventional risk factors model in predicting sICH was substantially improved after addition of the Cav-1 levels (integrated discrimination index 2.7%, p = 0.002; net reclassification improvement 39.7%, p = 0.007). CONCLUSIONS: Our data demonstrate that decreased Cav-1 levels are related to sICH after EVT. Incorporation of Cav-1 into clinical decision-making may help to identify patients at a high risk of sICH and warrants further consideration.

Anisotropic Hyperelastic Strain Energy Function for Carbon Fiber Woven Fabrics.

The present paper introduces an innovative strain energy function (SEF) for incompressible anisotropic fiber-reinforced materials. This SEF is specifically designed to understand the mechanical behavior of carbon fiber-woven fabric. The considered model combines polyconvex invariants forming an integrity basisin polynomial form, which is inspired by the application of Noether's theorem. A single solution can be obtained during the identification because of the relationship between the SEF we have constructed and the material parameters, which are linearly dependent. The six material parameters were precisely determined through a comparison between the closed-form solutions from our model and the corresponding tensile experimental data with different stretching ratios, with determination coefficients consistently reaching a remarkable value of 0.99. When considering only uniaxial tensile tests, our model can be simplified from a quadratic polynomial to a linear polynomial, thereby reducing the number of material parameters required from six to four, while the fidelity of the model's predictive accuracy remains unaltered. The comparison between the results of numerical calculations and experiments proves the efficiency and accuracy of the method.

CRF08_BC subtype is more prone to ART failure and new generation NNRTI-resistance under long-term first line ART.

OBJECTIVE: To investigate the characteristics of drug resistance mutations (DRMs) and their contextual influence on drug susceptibility in CRF07_BC and CRF_08BC subtypes. METHODS: Patients with virological failure were genotyped using phylogenetic analysis. DRMs and susceptibility to antiretroviral drugs were analyzed using the Stanford University HIV Drug Resistance Database. RESULTS: Six HIV subtypes were identified among 1296 successfully amplified sequences, with the CRF07_BC subtype prevailing at a rate of 91.7%, followed by CRF08_BC. Overall, the CRF07_BC and CRF08_BC subtypes were similar in the distribution and frequency of DRMs, the most common DRMs were K103N and M184V. However, among patients with ART duration of ≥3 years who developed resistance, CRF08_BC exhibited a higher mutation frequency at sites 184, 138, 221, and 188 (Chi-square test, p<0.05), and compared with CRF07_BC, patients with CRF08_BC had higher prevalence of abacavir, emtricitabine, lamivudine, doravirine, etravirine, and rilpivirine resistance. Moreover, there was an increased prevalence of cross-resistance between efavirenz/nevirapine and new generation NNRTIs in patients with CRF08_BC; doravirine (r=1.0), rilpivirine (r=0.93), and etravirine (r=0.86) resistance highly correlated with efavirenz/nevirapine. CONCLUSIONS: The present study provides valuable insights into the profile of DRMs and resistance patterns in patients with CRF07_BC and CRF08_BC experiencing treatment failure in Butuo. These findings have the potential to contribute to future strategies for HIV control and treatment.

Nonlinear dynamics in phosphoinositide metabolism.

Phosphoinositides broadly impact membrane dynamics, signal transduction and cellular physiology. The orchestration of signaling complexity by this seemingly simple metabolic pathway remains an open question. It is increasingly evident that comprehending the complexity of the phosphoinositides metabolic network requires a systems view based on nonlinear dynamics, where the products of metabolism can either positively or negatively modulate enzymatic function. These feedback and feedforward loops may be paradoxical, leading to counterintuitive effects. In this review, we introduce the framework of nonlinear dynamics, emphasizing distinct dynamical regimes such as the excitable state, oscillations, and mixed-mode oscillations-all of which have been experimentally observed in phosphoinositide metabolisms. We delve into how these dynamical behaviors arise from one or multiple network motifs, including positive and negative feedback loops, coherent and incoherent feedforward loops. We explore the current understanding of the molecular circuits responsible for these behaviors. While mapping these circuits presents both conceptual and experimental challenges, redefining cellular behavior based on dynamical state, lipid fluxes, time delay, and network topology is likely essential for a comprehensive understanding of this fundamental metabolic network.

Consolidation therapy with autologous stem cell transplantation after remission of induction chemotherapy prolongs the survival of patients with peripheral T-cell lymphoma.

Background: There was little evidence of autologous stem cell transplantation (ASCT) as consolidation therapy after remission of induction for patients with Peripheral T-cell lymphoma (PTCL). In this study, we conducted a comparative analysis of real-world survival outcomes between consolidation therapy and observation in patients with PTCL. Methods: A total of 92 patients with peripheral T-cell lymphoma (PTCL) who were admitted to the Department of Hematology, Huadong Hospital Affiliated with Fudan University from January 2013 to April 2019 were divided into two groups based on whether they were treated with high-dose therapy (HDT) followed by autologous hematopoietic stem cell transplantation (ASCT): ASCT as consolidation therapy (n=30) and observation (n=62). Clinical characteristics, treatment patterns, and survival outcomes were analyzed between the two groups. Univariate and Cox multivariate regression analyses were also performed to detect prognostic factors of survival. Results: With a median follow-up time of 41 months, the median overall survival (OS) of peripheral T-cell lymphoma patients treated with ASCT was not reached; the median progression-free survival (PFS) was 77.0 months, which was much higher than that of patients without ASCT (p<0.003 for OS, p=0.015 for PFS). Subgroup analysis found that patients with high risks benefited more from ASCT. Combination with hemophagocytic lymphohistiocytosis (HLH) (p<0.001), clinical stage more than III (p=0.014), IPI score above 3 (p=0.049), and bone marrow involvement (p=0.010) were the independent prognostic factors significantly associated with worse OS and PFS. Additionally, pegylated liposomal doxorubicin (PLD)-containing chemotherapy regimen could bring a higher overall response rate (ORR) and prolong the survival of patients with PTCL who underwent ASCT. Conclusion: ASCT may improve the long-term survival of patients with PTCL as consolidation therapy after achieving complete or partial remission of induction treatment, particularly for those with high risks. The chemotherapy regimen containing pegylated liposomal doxorubicin may induce deeper remission than traditional doxorubicin in PTCL. It is crucial to identify the specific groups most likely to benefit from upfront ASCT.

New camaenid genus and species from Zhejiang, East China (Eupulmonata, Helicoidea).

We report a new land snail species representing a new genus from the mountainous area of Zhejiang, China. The snail has a depressed shell with granules all over the surface. The soft part of the new taxon is characterized by the presence of a mantle lobe whose form is reviewed herein across a wide range of helicoid snails, the presence of a developed epiphallic papilla, and the absence of a penial sheath, a dart sac apparatus and a flagellum. As indicated by a molecular-based phylogeny (16S + ITS2), the new taxon is deeply nested in the eastern Asian camaenid genera and shows a close relationship with the camaenids distributed in Central China.

Innervation of nociceptor neurons in the spleen promotes germinal center responses and humoral immunity.

Peripheral sensory neurons widely innervate various tissues to continuously monitor and respond to environmental stimuli. Whether peripheral sensory neurons innervate the spleen and modulate splenic immune response remains poorly defined. Here, we demonstrate that nociceptive sensory nerve fibers extensively innervate the spleen along blood vessels and reach B cell zones. The spleen-innervating nociceptors predominantly originate from left T8-T13 dorsal root ganglia (DRGs), promoting the splenic germinal center (GC) response and humoral immunity. Nociceptors can be activated by antigen-induced accumulation of splenic prostaglandin E2 (PGE2) and then release calcitonin gene-related peptide (CGRP), which further promotes the splenic GC response at the early stage. Mechanistically, CGRP directly acts on B cells through its receptor CALCRL-RAMP1 via the cyclic AMP (cAMP) signaling pathway. Activating nociceptors by ingesting capsaicin enhances the splenic GC response and anti-influenza immunity. Collectively, our study establishes a specific DRG-spleen sensory neural connection that promotes humoral immunity, suggesting a promising approach for improving host defense by targeting the nociceptive nervous system.

Inhibition of NOTCH4 sensitizes FLT3/ITD acute myeloid leukemia cells to FLT3 tyrosine kinase inhibition.

Internal tandem duplication mutations of FLT3 (FLT3/ITD) confer poor prognosis in AML. FLT3 tyrosine kinase inhibitors (TKIs) alone have limited and transient clinical efficacy thus calling for new targets for more effective combination therapy. In a loss-of-function RNAi screen, we identified NOTCH4 as one such potential target whose inhibition proved cytotoxic to AML cells, and also sensitized them to FLT3 inhibition. Further investigation found increased NOTCH4 expression in FLT3/ITD AML cell lines and primary patient samples. Inhibition of NOTCH4 by shRNA knockdown, CRISPR-Cas9-based knockout or γ-secretase inhibitors synergized with FLT3 TKIs to kill FLT3/ITD AML cells in vitro. NOTCH4 inhibition sensitized TKI-resistant FLT3/ITD cells to FLT3 TKI inhibition. The combination reduced phospho-ERK and phospho-AKT, indicating inhibition of MAPK and PI3K/AKT signaling pathways. It also led to changes in expression of genes involved in regulating cell cycling, DNA repair and transcription. A patient-derived xenograft model showed that the combination reduced both the level of leukemic involvement of primary human FLT3/ITD AML cells and their ability to engraft secondary recipients. In summary, these results demonstrate that NOTCH4 inhibition synergizes with FLT3 TKIs to eliminate FLT3/ITD AML cells, providing a new therapeutic target for AML with FLT3/ITD mutations.

Three-dimensional Ni foam supported Pt/NiFe LDH catalyst with enhanced oxygen activation for room-temperature formaldehyde oxidation.

Room-temperature catalytic oxidation of formaldehyde (HCHO) has been extensively investigated due to its high efficiency, convenience, and environmental friendliness. Herein, nickel-iron layered double hydroxide (NiFe LDH) nanosheets were synthesized in-situ on a nickel foil (NF) using a facile one-step hydrothermal method, followed by the deposition of ultra-low content (0.069 wt%) of Pt nanoparticles through NaBH4 reduction. The resulting three-dimensional (3D) hierarchical Pt/NiFe-NF catalyst exhibited exceptional activity for the complete decomposition of formaldehyde to carbon dioxide (CO2) at room temperature (∼95 % conversion within 1 h), as well as remarkable cycling stability. The 3D porous structure of Pt/NiFe-NF provides fast transport channels for the diffusion of gas molecules, making the active catalyst surfaces more accessible. Moreover, abundant hydroxyl groups in NiFe LDH serve as adsorption centers for HCHO molecules to form dioxymethylene (DOM) and formate intermediates. Furthermore, electronic interactions between NiFe LDH and Pt enhance the adsorption and activation of O2 on Pt surfaces, leading to the complete decomposition of intermediates into non-toxic products. This work presents new insights into the design and preparation of Pt-based 3D hierarchical catalysts with surface-rich hydroxyl groups for the efficient removal of indoor HCHO.