Construction and preclinical evaluation of a 124I-labelled bispecific antibody targeting PD-L1 and PD-L2.

PURPOSE: NB12 is a bispecific antibody that consists of two anti-programmed cell death-ligand 1 (PD-L1) nanobodies and two anti-programmed cell death-ligand 2 (PD-L2) nanobodies. The aim of this study was to design a novel tracer, [124I]I-NB12, targeting PD-L1/2 and perform preclinical evaluations to dynamically monitor PD-L1/2 expression for determining cancer patient responsiveness to ICI therapy. METHODS: NB12 was labelled with the radionuclide 124I at room temperature (RT). An in vitro binding assay was performed to assess the affinity of [124I]I-NB12 for PD-L1 and PD-L2. Cellular uptake, pharmacokinetic, and biodistribution experiments were performed to evaluate the biological properties. Micro-PET/CT imaging with [124I]I-NB12 was conducted at different time points. Immunohistochemical and haematoxylin and eosin (HE) staining experiments were carried out using tumour tissues. Routine blood, biochemical indices and major organ pathology were used to evaluate the biosafety of the tracers. RESULTS: The radiochemical yield of [124I]I-NB12 was 84.62 ± 3.90%, and the radiochemical purity (RCP) was greater than 99%. [124I]I-NB12 had a high affinity for the PD-L1 (Kd = 19.82 nM) and PD-L2 (Kd = 2.93 nM). Cellular uptake experiments confirmed that the uptake of [124I]I-NB12 by A549-PDL1/2 cells was greater than that by A549 cells. The half-lives of the distribution phase and elimination phase were 0.26 h and 4.08 h, respectively. Micro-PET/CT showed significant [124I]I-NB12 uptake in the tumour region of A549-PDL1/2 tumour-bearing mice compared with A549 tumour-bearing mice 24 h postinjection. Immunohistochemical and HE staining experiments confirmed that tumour-bearing mice was successfully constructed. CONCLUSION: We constructed a bispecific antibody that targets PD-L1 and PD-L2, namely, [124I]I-NB12. Biological evaluation revealed its specificity and affinity for PD-L1/2, and micro-PET/CT confirmed the feasibility of visualizing tumour PD-L1/2 in vivo. Using [124I]I-NB12 may be a promising strategy for identifying cancer patients that can potentially benefit from ICI therapy.

The effect of Chinese herbal medicine on male factor infertility: study protocol for a randomized controlled trial.

Background: The global prevalence of infertility is 9%, with male factors potentially accounting for 40% to 60% of cases. Conventional treatments can be ineffective, invasive, costly, and linked to adverse effects and high risks. Previous studies have shown that, Chinese herbal medicine (CHM) can regulate the hypothalamus-pituitary-testis axis, improve sperm abnormalities and quality, mitigate oxidative stress, and decrease DNA fragmentation index (DFI). Yet, the evidence backing the use of Chinese herbal medicine (CHM) for treating male factor infertility lacks conviction due to study design limitations, and there remains a scarcity of studies on the live birth rate following CHM treatment for male factor infertility. Here, we describe the rationale and design of a randomized waitlist-controlled trial to evaluate the effect of CHM on the live birth rate among males with infertility. Methods: This study is a single-center, randomized, waitlist-controlled study. A total of 250 couples diagnosed with male factor infertility will be enrolled in this study and then randomly allocated into two groups in a 1:1 ratio. Male participants in CHM group (treatment group) will receive CHM once a day for 3 months. Male participants in the waitlist group (control group) will not receive any treatment for 3 months. After 3 months, participants in both groups need to be followed up for another 12 months. The primary outcome will be the live birth rate; secondary outcomes include semen quality parameters, DFI and pregnancy related outcomes. Safety will also be assessed. Discussion: The purpose of this trial is to explore the effects and safety of CHM on the live birth rate among couples dealing with male factor infertility. The outcome of this trial may provide a viable treatment option for male factor infertility. Trial registration: Chinese Clinical Trial Registry: ChiCTR2200064416. Registered on 7 October 2022, https://www.chictr.org.cn.

Research of injury mapping relationship of lumbar spine in reclined occupants between anthropomorphic test devices and human body model.

PURPOSE: To judge the injury mode and injury severity of the real human body through the measured values of anthropomorphic test devices (ATD) injury indices, the mapping relationship of lumbar injury between ATD and human body model (HBM) was explored. METHODS: Through the ATD model and HBM simulation, the mapping relationship of lumbar injury between the 2 subjects was explored. The sled environment consisted of a semi-rigid seat with an adjustable seatback angle and a 3-point seat belt system with a seatback-mounted D-ring. Three seatback recline states of 25°, 45°, and 65° were designed, and the seat pan angle was maintained at 15°. A 23 g, 47 km/h pulse was used. The validity of the finite element model of the sled was verified by the comparison of ATD simulation and test results. ATD model was the test device for human occupant restraint for autonomous vehicles (THOR-AV) dummy model and HBM was the total human model for safety (THUMS) v6.1. The posture of the 2 models was adjusted to adapt to the 3 seat states. The lumbar response of THOR-AV and the mechanical and biomechanical data on L1-L5 vertebrae of THUMS were output, and the response relationship between THOR-AV and THUMS was descriptive statistically analyzed. RESULTS: Both THOR-AV and THUMS were submarined in the 65° seatback angle case. With the change of seatback angle, the lumbar spine axial compression force (Fz) of THOR-AV and THUMS changed in the similar trend. The maximum Fz ratio of THOR-AV to THUMS at 25° and 45° seatback angle cases were 1.6 and 1.7. The flexion moment (My) and the time when the maximum My occurred in the 2 subjects were very different. In particular, the form of moment experienced by the L1 - L5 vertebrae of THUMS also changed. The changing trend of My measured by THOR-AV over time can reflect the changing trend of maximum stress of L1 and L2 of THUMS. CONCLUSION: The Fz of ATD and HBM presents a certain proportional relationship, and there is a mapping relationship between the 2 subjects on Fz. The mapping function can be further clarified by applying more pulses and adopting more seatback angles. It is difficult to map My directly because they are very different in ATD and HBM. The My of ATD and stress of HBM lumbar showed a similar change trend over time, and there may be a hidden mapping relationship.

UV-B Radiation Exhibited Tissue-Specific Regulation of Isoflavone Biosynthesis in Soybean Cell Suspension Cultures.

Isoflavones, a class of substances with high biological activity, are abundant in soybeans. This study investigated isoflavone biosynthesis in soybean cell suspension cultures under UV-B radiation. UV-B radiation enhanced the transcription level and activity of key enzymes involved in isoflavone synthesis in cell suspension cultures. As a result, the isoflavone contents significantly increased by 19.80% and 91.21% in hypocotyl and cotyledon suspension cultures compared with the control, respectively. Meanwhile, a significant difference was observed in the composition of isoflavones between soybean hypocotyl and cotyledon suspension cultures. Genistin was only detected in hypocotyl suspension cultures, whereas glycitin, daidzein, and genistein accumulated in cotyledon suspension cultures. Therefore, UV-B radiation exhibited tissue-specific regulation of isoflavone biosynthesis in soybean cell suspension cultures. The combination of suspension cultures and abiotic stress provides a novel technological approach to isoflavone accumulation.

Can items derived from international literature be used in national quality of life instruments? A qualitative study conceptualising the EQ-HWB in China.

INTRODUCTION: The EQ Health and Wellbeing (EQ-HWB) is a new questionnaire for measuring quality of life (QoL) from a broad perspective. The items of the EQ-HWB were derived based on a 'qualitative review' of literature, which reported primarily on Western studies. It can be argued that the QoL is a cultural-related concept and therefore people from China have a different understanding of the QoL. This study aimed to explore whether Chinese citizens could understand the EQ-HWB's candidate items and what they thought of those items. In doing so, we wanted to examine the face validity of the candidate items and explore if further cultural adaptation is necessary. METHODS: This research was part of the E-QALY project, in which 36 candidate items were selected for the EQ-HWB from a 97-item pool. In China, three interviewers investigated the face validity of these EQ-HWB candidate items in semi-structured qualitative face-to-face interviews. Respondents were invited to report 'problems' with regard to the interpretation of the items and these problems were grouped into themes. We explored to what extent those themes related to specific cultural aspects in China. We also classified the rates of reported problems for each item into three groups: 1) less than 20%, 2) from 20-50%, and 3) over 50%. RESULTS: For 17 items the rate of reported problems was less than 20%, 15 items fell into the second group (with 20 - 50%) and for 4 items the rate of problems reported was more than 50%. The thematic analysis revealed eight themes: ambiguous problems in the interpretation of 16 items; difficult to understand (11); contained a complex negative expression (10); examples used seemed inappropriate (7); misleading connotation in Chinese (2); long and complex (2); complex response options (1); and use of non-colloquial language (1). DISCUSSION: Our research shows that EQ-HWB candidate items require careful examination to make them more comprehensible. Most of the reported problem themes were generic problems related to the items, and only a few face validity issues appeared to relate to specific cultural aspects in China, even though most of the items were based on Western studies. Our findings are reassuring for the instrument's international application, especially in China.

Gasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS-STING activation.

Immune checkpoint inhibitor (ICI)-induced myocarditis involves intensive immune/inflammation activation; however, its molecular basis is unclear. Here, we show that gasdermin-E (GSDME), a gasdermin family member, drives ICI-induced myocarditis. Pyroptosis mediated by GSDME, but not the canonical GSDMD, is activated in myocardial tissue of mice and cancer patients with ICI-induced myocarditis. Deficiency of GSDME in male mice alleviates ICI-induced cardiac infiltration of T cells, macrophages, and monocytes, as well as mitochondrial damage and inflammation. Restoration of GSDME expression specifically in cardiomyocytes, rather than myeloid cells, in GSDME-deficient mice reproduces ICI-induced myocarditis. Mechanistically, quantitative proteomics reveal that GSDME-dependent pyroptosis promotes cell death and mitochondrial DNA release, which in turn activates cGAS-STING signaling, triggering a robust interferon response and myocardial immune/inflammation activation. Pharmacological blockade of GSDME attenuates ICI-induced myocarditis and improves long-term survival in mice. Our findings may advance the understanding of ICI-induced myocarditis and suggest that targeting the GSDME-cGAS-STING-interferon axis may help prevent and manage ICI-associated myocarditis.

Advances in hybridized nanoarchitectures for improved oro-dental health.

On a global note, oral health plays a critical role in improving the overall human health. In this vein, dental-related issues with dentin exposure often facilitate the risk of developing various oral-related diseases in gums and teeth. Several oral-based ailments include gums-associated (gingivitis or periodontitis), tooth-based (dental caries, root infection, enamel erosion, and edentulous or total tooth loss), as well as miscellaneous diseases in the buccal or oral cavity (bad breath, mouth sores, and oral cancer). Although established conventional treatment modalities have been available to improve oral health, these therapeutic options suffer from several limitations, such as fail to eradicate bacterial biofilms, deprived regeneration of dental pulp cells, and poor remineralization of teeth, resulting in dental emergencies. To this end, the advent of nanotechnology has resulted in the development of various innovative nanoarchitectured composites from diverse sources. This review presents a comprehensive overview of different nanoarchitectured composites for improving overall oral health. Initially, we emphasize various oral-related diseases, providing detailed pathological circumstances and their effects on human health along with deficiencies of the conventional therapeutic modalities. Further, the importance of various nanostructured components is emphasized, highlighting their predominant actions in solving crucial dental issues, such as anti-bacterial, remineralization, and tissue regeneration abilities. In addition to an emphasis on the synthesis of different nanostructures, various nano-therapeutic solutions from diverse sources are discussed, including natural (plant, animal, and marine)-based components and other synthetic (organic- and inorganic-) architectures, as well as their composites for improving oral health. Finally, we summarize the article with an interesting outlook on overcoming the challenges of translating these innovative platforms to clinics.

Clinical efficacy and immune response of neoadjuvant camrelizumab plus chemotherapy in resectable locally advanced oesophageal squamous cell carcinoma: a phase 2 trial.

BACKGROUND: Neoadjuvant immunotherapy is under intensive investigation for esophageal squamous cell carcinoma (ESCC). This study assesses the efficacy and immune response of neoadjuvant immunochemotherapy (nICT) in ESCC. METHODS: In this phase II trial (ChiCTR2100045722), locally advanced ESCC patients receiving nICT were enrolled. The primary endpoint was the pathological complete response (pCR) rate. Multiplexed immunofluorescence, RNA-seq and TCR-seq were conducted to explore the immune response underlying nICT. RESULTS: Totally 42 patients were enrolled, achieving a 27.0% pCR rate. The 1-year, 2-year DFS and OS rates were 89.2%, 64.4% and 97.3%, 89.2%, respectively. RNA-seq analysis highlighted T-cell activation as the most significantly enriched pathway. The tumour immune microenvironment (TIME) was characterised by high CD4, CD8, Foxp3, and PD-L1 levels, associating with better pathological regression (TRS0/1). TIME was categorised into immune-infiltrating, immune-tolerant, and immune-desert types. Notably, the immune-infiltrating type and tertiary lymphoid structures correlated with improved outcomes. In the context of nICT, TIM-3 negatively influenced treatment efficacy, while elevated TIGIT/PD-1 expression post-nICT correlated positively with CD8+ T cell levels. TCR-seq identified three TCR rearrangements, underscoring the specificity of T-cell responses. CONCLUSIONS: Neoadjuvant camrelizumab plus chemotherapy is effective for locally advanced, resectable ESCC, eliciting profound immune response that closely associated with clinical outcomes.

Luteolin-7-diglucuronide, a novel PTP1B inhibitor, ameliorates hepatic stellate cell activation and liver fibrosis in mice.

Liver fibrosis, one of the leading causes of morbidity and mortality worldwide, lacks effective therapy. The activation of hepatic stellate cells (HSCs) is the dominant event in hepatic fibrogenesis. Luteolin-7-diglucuronide (L7DG) is the major flavonoid extracted from Perilla frutescens and Verbena officinalis. Their beneficial effects in the treatment of liver diseases were well documented. In this study we investigated the anti-fibrotic activities of L7DG and the potential mechanisms. We established TGF-ß1-activated mouse primary hepatic stellate cells (pHSCs) and human HSC line LX-2 as in vitro liver fibrosis models. Co-treatment with L7DG (5, 20, 50 µM) dose-dependently decreased TGF-ß1-induced expression of fibrotic markers collagen 1, α-SMA and fibronectin. In liver fibrosis mouse models induced by CCl4 challenge alone or in combination with HFHC diet, administration of L7DG (40, 150 mg·kg-1·d-1, i.g., for 4 or 8 weeks) dose-dependently attenuated hepatic histopathological injury and collagen accumulation, decreased expression of fibrogenic genes. By conducting target prediction, molecular docking and enzyme activity detection, we identified L7DG as a potent inhibitor of protein tyrosine phosphatase 1B (PTP1B) with an IC50 value of 2.10 µM. Further studies revealed that L7DG inhibited PTP1B activity, up-regulated AMPK phosphorylation and subsequently inhibited HSC activation. This study demonstrates that the phytochemical L7DG may be a potential therapeutic candidate for the treatment of liver fibrosis.

Regulating the Scaling Relations in Ammonia Synthesis through a Light-driven Bendable Seesaw Effect on Tailored Iron Catalyst.

Advancing the energy-intensive Haber-Bosch process faces significant challenges due to the intrinsic constraints of scaling relations in heterogeneous catalysis. Herein, we reported an approach of bending the "seesaw effect" to regulate the scaling relations over a tailored α-Fe metallic material (α-Fe-110s), realizing highly efficient light-driven thermal catalytic ammonia synthesis rate of 1260 µmol gcatalyst-1 h-1 without additional heating. Specifically, the thermal catalytic activity of α-Fe-110s was significantly enhanced by the novel stepped {110} surface, exhibiting a 3.8-fold increase compared to the commercial fused-iron catalyst with promoters at 350 °C. The photo-induced hot electron transfer further accelerates the dinitrogen dissociation and hydrogenation simultaneously, effectively overcoming the limitation of scaling relation over identical sites. Consequently, the ammonia production rate of α-Fe-110s was further enhanced by 30 times at the same temperature with irradiation. This work designs an efficient and sustainable system for ammonia synthesis and provides a novel approach for regulating the scaling relations in heterogeneous catalysis.

Multiomics2Targets identifies targets from cancer cohorts profiled with transcriptomics, proteomics, and phosphoproteomics.

The availability of data from profiling of cancer patients with multiomics is rapidly increasing. However, integrative analysis of such data for personalized target identification is not trivial. Multiomics2Targets is a platform that enables users to upload transcriptomics, proteomics, and phosphoproteomics data matrices collected from the same cohort of cancer patients. After uploading the data, Multiomics2Targets produces a report that resembles a research publication. The uploaded matrices are processed, analyzed, and visualized using the tools Enrichr, KEA3, ChEA3, Expression2Kinases, and TargetRanger to identify and prioritize proteins, genes, and transcripts as potential targets. Figures and tables, as well as descriptions of the methods and results, are automatically generated. Reports include an abstract, introduction, methods, results, discussion, conclusions, and references and are exportable as citable PDFs and Jupyter Notebooks. Multiomics2Targets is applied to analyze version 3 of the Clinical Proteomic Tumor Analysis Consortium (CPTAC3) pan-cancer cohort, identifying potential targets for each CPTAC3 cancer subtype. Multiomics2Targets is available from https://multiomics2targets.maayanlab.cloud/.

Endothelial TRPV4 channel mediates the vasodilation induced by Tanshinone IIA.

Tanshinone IIA (TSA), the main lipo-soluble component from the dried rhizome of Salvia miltiorrhiza, has been shown to induce vasodilation. However, the underlying mechanisms remains unclear. This study aimed to investigate the effect of TSA on the vasodilation of small resistant arteries ex vivo. Vascular myography revealed that endothelial denudation reduced significantly the vasodilatory effect of TSA. Blocking transient receptor potential vanilloid 4 (TRPV4) channels prevented TSA-induced vasodilation. Whole-cell patch-clamp analysis revealed that the current passing through TRPV4 channels increased after TSA treatment in endothelial cells (ECs). This was attributed to reduced TRPV4 protein degradation along with its increased expression. The TRPV4 inhibitor HC-067047 lowed nitric oxide (NO) production and TSA-induced expression of endothelial nitric oxide synthase (eNOS). Moreover, it increased the production of cyclic guanosine monophosphate (cGMP) and protein kinase G (PKG). The present results indicate that TSA induces endothelium-dependent vasodilation, which is mediated by the TRPV4-NO-PKG signaling pathway. These findings highlight the potential of TSA, a compound known in traditional Chinese medicine as Danshen (Salvia miltiorrhiza), for future cardiovascular therapeutic strategies.

Oxycodone attenuates lipopolysaccharide-induced myocardial injury by inhibiting inflammation, oxidation and pyroptosis via Nrf2/HO-1 signalling pathway.

Myocardial injury and cardiovascular dysfunction are the most common complications of sepsis, and effective therapeutic candidate is still lacking. This study aims to investigate the protective effect of oxycodone in myocardial injury of lipopolysaccharide-induced sepsis and its related signalling pathways. Wild-type and nuclear factor erythroid 2-related factor 2 (Nrf2)-knockout mice, as well as H9c2 cardiomyocytes cultures treated with lipopolysaccharide (LPS) were used as models of septic myocardial injury. H9c2 cardiomyocytes culture showed that oxycodone protected cells from pyroptosis induced by LPS. Mice model confirmed that oxycodone pretreatment significantly attenuated myocardial pathological damage and improved cardiac function demonstrated by increased ejection fraction (EF) and fractional shortening (FS), as well as decreased cardiac troponin I (cTnI) and creatine kinase isoenzymes MB (CK-MB). Oxycodone also reduced the levels of inflammatory factors and oxidative stress damage induced by LPS, which involves pyroptosis-related proteins including: Nod-like receptor protein 3 (NLRP3), Caspase 1, Apoptosis-associated speck-like protein contain a CARD (ASC), and Gasdermin D (GSDMD). These changes were mediated by Nrf2 and heme oxygenase-1 (HO-1) because Nrf2-knockout mice or Nrf2 knockdown in H9c2 cells significantly reversed the beneficial effect of oxycodone on oxidative stress, inflammatory responses and NLRP3-mediated pyroptosis. Our findings yielded that oxycodone therapy reduces LPS-induced myocardial injury by suppressing NLRP3-mediated pyroptosis via the Nrf2/HO-1 signalling pathway in vivo and in vitro.

The processed Euphorbia lathyris L. alleviates the inflammatory injury via regulating LXRα/ABCA1 expression and TLR4 positioning to lipid rafts.

Euphorbia lathyris L. (EL) is a traditional poisonous herbal medicine used to treat dropsy, ascites, amenorrhea, anuria and constipation. Processing to reduce toxicity of EL is essential for its safe and effective application. However, there is little known regarding the molecular mechanism of reducing toxicity after EL processing. This research aimed to screen the differential markers for EL and PEL, explore the differential mechanisms of inflammatory injury induced by EL and processed EL (PEL) to expound the mechanism of alleviating toxicity after EL processing. The results showed that 15 potential biomarkers, mainly belonging to diterpenoids, were screened to distinguish EL from PEL. EL promoted the expressions of TLR4, NLRP3, NF-κB p65, IL-1ß and TNF-α, increased lipid rafts abundance and promoted TLR4 positioning to lipid rafts. Meanwhile, EL decreased LXRα and ABCA1 expression, and reduced cholesterol efflux. In contrast to EL, the effects of PEL on these indicators were markedly weakened. In addition, Euphorbia factors L1, L2, and L3 affected LXRα, ABCA1, TLR4, NLRP3, NF-κB p65, TNF-α and IL-1ß expression, influenced cholesterol efflux and lipid rafts abundance, and interfered with the colocalization of TLR4 and lipid rafts. The inflammatory injury caused by processed EL was significantly weaker than that caused by crude EL, and reduction of Euphorbia factors L1, L2, and L3 as well as attenuation of inflammatory injury participated in processing-based detoxification of EL. Our results provide valuable insights into the attenuated mechanism of EL processing and will guide future research on the processing mechanism of toxic traditional Chinese medicine.

Dissecting the vascular-cognitive nexus: energetic vs. conventional hemodynamic parameters.

Blood pressure or flow measurements have been associated with vascular health and cognitive function. We proposed that energetic hemodynamic parameters may provide a more nuanced understanding and stronger correlation with cognitive function, in comparisons with conventional aortic and carotid pressure and flow parameters. The study comprised 1858 participants, in whom we assessed cognitive function via MoCA method, and measured central aortic and carotid pressure and flow waveforms. In addition to various pressure and flow parameters, we calculated energetic hemodynamic parameters through integration of pressure multiplying flow with respect to time. Energetic hemodynamic parameters, particularly aortic and carotid mean and pulsatile energy and pulsatility index (PI), were significantly associated with MoCA score more than any aortic and carotid pressure and flow parameters, after adjusting for age, sex, education, depression score, heart rate, BMI, HDL-cholesterol, and glucose levels. MoCA exhibited a strong positive relationship with carotid mean energy (standardized beta = 0.053, P = 0.0253) and a negative relationship with carotid energy PI (standardized beta = -0.093, P = 0.0002), exceeding the association with all traditional pressure- or flow-based parameters. Aortic pressure reflection coefficient at the aorto-carotid junction was positively correlated with mean carotid energy and negatively correlated with PI. Aortic characteristic impedance positively correlated with carotid energy PI but not mean energy. Our research indicates that energetic hemodynamic parameters, particularly carotid mean energy and carotid energy PI, have a stronger association with MoCA scores than traditional pressure- or flow-based metrics. This correlation with cognitive function is notably influenced by the properties of the aorto-carotid interface.

3D Printing Elastocaloric TiNiCu Thermoelectric Shape Memory Alloys.

The development of new thermoelectric conversion and cooling materials is an important means of addressing global climate and heat emissions in the future. While heavy and toxic elements like tellurium and lead are traditionally used to make thermoelectric materials with poor mechanical properties, recent decades have seen a gradual push towards greener and more sustainable alternatives. One such potential alternative material for thermoelectric and thermal management applications would be the Nitinol (TiNi) shape memory alloy, due to their superior mechanical properties. In this study, we have investigated the use of 3D melt printing techniques that can be used to achieve thermoelectric performance and efficiency of elastic memory alloys below 500 °C.　The electrical and thermal properties of TiNiCu materials and their relation to morphology were investigated. All the alloys show similar effect sizes, their fatigue behavior is however different. By adjusting the composition of Ti and Ni elements and we have obtained memory alloys with high thermoelectric properties, with a 50% increase in power factor and a 100% increase in ZT values.

The associations between interparental conflict and adolescent adjustment: a cross-lagged panel network analysis.

Extensively studied in interparental relationship literature suggests interparental conflict is a risk factor for adolescent adjustment, but the specific, dimension level relationships between interparental conflict and adolescent adjustment remain unclear. This study explored the interactions between the various dimensions of interparental conflict and adolescent adjustment in Chinese adolescents. A total of 1870 Chinese adolescents (42.27% males; Mage = 16.18, SD = 0.43, range = 15-18) completed a survey at two time points spaced three months apart. Data was analyzed using both cross-sectional and longitudinal network analysis. The cross-sectional network analysis found that resolution has the greatest connections with the dimensions of adolescent adjustment, suggesting that adolescents reporting high resolution are more prone to experience concurrent poor adjustment and therefore should be a primary focus of attention. The longitudinal network analysis revealed that, in general, previous hyperactivity-inattention is a significant and strong predictor of future interparental conflict, underscoring a child-driven effect. Meanwhile, prosocial behavior contributes to decreases in both interparental conflict and adjustment problems over time. These findings highlight the importance of addressing hyperactivity-inattention and cultivating prosocial behavior in adolescents as key intervention points-these can help resolve conflicts between parents and reduce adjustment problems for adolescents.

Dual-Barb Microneedle with JAK/STAT Inhibitor-Loaded Nanovesicles Encapsulation for Tendinopathy.

Tendon stem/progenitor cells (TSPCs) are crucial for tendon repair, regeneration, and homeostasis. Dysfunction of TSPCs, due to aberrant activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, contributes to tendinopathy. Unfortunately, the effectiveness of conventional subcutaneous injection targeting at suppressing JAK/STAT signaling pathway is limited due to the passive diffusion of drugs away from the injury site. Herein, a novel poly-gamma-glutamic acid (γ-PGA) dual-barb microneedle (MN) path loaded with TSPCs-derived nanovesicles (NVs) containing JAK/STAT inhibitor WP1066 (MN-WP1066-NVs) for tendinopathy treatment is designed. The dual-barb design of the MN ensures firm adhesion to the skin, allowing for sustained and prolonged release of WP1066-NVs, facilitating enhanced TSPCs self-renewal, migration, and stemness in tendinopathy. In vitro and in vivo experiments demonstrate that the degradation of γ-PGA patch tips facilitates the gradual release of WP1066-NVs at the lesion site. This release alleviates inflammation, suppresses extracellular matrix degradation, and restores normal tendon histological structure by inhibiting the JAK/STAT pathway. These findings suggest that the multifunctional dual-barb MN patch offers a novel and effective therapeutic strategy for tendinopathy treatment.

The methane-oxidizing microbial communities of three maar lakes in tropical monsoon Asia.

Methane-oxidizing bacteria (MOB) is a group of planktonic microorganisms that use methane as their primary source of cellular energy. For tropical lakes in monsoon Asia, there is currently a knowledge gap on MOB community diversity and the factors influencing their abundance. Herewith, we present a preliminary assessment of the MOB communities in three maar lakes in tropical monsoon Asia using Catalyzed Reporter Deposition, Fluorescence In-Situ Hybridization (CARD-FISH), 16S rRNA amplicon sequencing, and pmoA gene sequencing. Correlation analysis between MOB abundances and lakes' physicochemical parameters following seasonal monsoon events were performed to explain observed spatial and temporal patterns in MOB diversity. The CARD-FISH analyses detected the three MOB types (I, II, and NC10) which aligned with the results from 16S rRNA amplicons and pmoA gene sequencing. Among community members based on 16S rRNA genes, Proteobacterial Type I MOB (e.g., Methylococcaceae and Methylomonadaceae), Proteobacterial Type II (Methylocystaceae), Verrucomicrobial (Methylacidiphilaceae), Methylomirabilota/NC10 (Methylomirabilaceae), and archaeal ANME-1a were found to be the dominant methane-oxidizers in three maar lakes. Analysis of microbial diversity and distribution revealed that the community compositions in Lake Yambo vary with the seasons and are more distinct during the stratified period. Temperature, DO, and pH were significantly and inversely linked with type I MOB and Methylomirabilota during stratification. Only MOB type I was influenced by monsoon changes. This research sought to establish a baseline for the diversity and ecology of planktonic MOB in tropical monsoon Asia to better comprehend their contribution to the CH4 cycle in tropical freshwater ecosystems.