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The primary and secondary somatosensory cortices (S1 and S2) play crucial roles in processing sensory inputs from various body regions, encompassing tactile, pressure, thermal, and nociceptive stimuli. These cortices are anatomically distinct, with S1 primarily involved in mechanical and cold stimulus discrimination and S2 in the interpretation of mechanical and thermal inputs, particularly in pain perception. However, the upstream innervation patterns of the somatosensory system remain less explored. In this study, we employed a modified rabies virus (RV)-mediated transsynaptic retrograde tracing system to map and compare the whole-brain input patterns of S1 and S2 in mice. Our results revealed that both S1 and S2 receive inputs from diverse brain regions, including the cortical plate, thalamus, cortical subplate, striatum, and pallidum. Notably, the cortical plate emerged as the primary source of input neurons for both S1 and S2, while the thalamus demonstrated preferential projections to S1. Through quantitative analysis, we identified distinct input distribution patterns across 64 brain subregions, revealing that S1 and S2 exhibit complex internal circuitry, including abundant local projections. Furthermore, we observed notable variations in the proportional contributions of inputs from diverse subregions to S1 and S2. This comprehensive anatomical framework provides new insights into the neural circuits underlying somatosensory perception and modulation, with potential implications for the development of targeted therapeutic strategies for pain and other somatosensory disorders.

Polycystic ovary syndrome (PCOS) is a major health concern for women of reproductive age and a leading cause of infertility and metabolic dysfunction. Current treatments mainly involve lifestyle modification and pharmacological therapies, such as oral contraceptives and metformin, and may also include laparoscopic ovarian drilling (LOD), acupuncture, and probiotic interventions. Although these approaches can be effective, they often produce adverse effects and show a high relapse rate after discontinuation. This review summarizes recent advances in exosome-based therapies as emerging strategies for PCOS. Exosomes derived from adipose-derived mesenchymal stem cells, menstrual blood-derived stem cells, bone marrow mesenchymal stem cells, brown adipocytes, and human umbilical cord-derived mesenchymal stem cells have demonstrated therapeutic potential. As nanosized extracellular vesicles carrying bioactive molecules, exosomes exhibit strong targeting capacity and low immunogenicity. We discuss the mechanisms by which exosomes may ameliorate PCOS, including suppression of chronic low-grade inflammation, enhancement of mitochondrial function, inhibition of apoptosis, modulation of angiogenesis, and improvement of metabolic disturbances. However, translating these promising findings into clinical practice faces significant challenges. The main obstacles include lack of standardization, high production costs, and limited clinical data to confirm safety and efficacy. Addressing these issues could pave the way for mechanism-based, personalized exosome treatments and offer new approaches for managing PCOS.

The orbitofrontal cortex (ORB) exhibits a complex structure and diverse functional roles, including emotion regulation, decision-making, and reward processing. Structurally, it comprises three distinct regions: the medial part (ORBm), the ventrolateral part (ORBvl), and the lateral part (ORBl), each with unique functional attributes, such as ORBm’s involvement in reward processing, ORBvl’s regulation of depression-like behavior, and ORBl’s response to aversive stimuli. Dysregulation of the ORB has been implicated in various psychiatric disorders. However, the neurocircuitry underlying the functions and dysfunctions of the ORB remains poorly understood. This study employed recombinant adeno-associated viruses (rAAV) and rabies viruses with glycoprotein deletion (RV-ΔG) to retrogradely trace monosynaptic inputs to three ORB subregions in male C57BL/6J mice. Inputs were quantified across the whole brain using fluorescence imaging and statistical analysis. Results revealed distinct input patterns for each ORB subregion, with significant contributions from the isocortex and thalamus. The ORBm received prominent inputs from the prelimbic area, agranular insular area, and hippocampal field CA1, while the ORBvl received substantial intra-ORB inputs. The ORBl exhibited strong inputs from the somatomotor and somatosensory areas. Thalamic inputs, particularly from the mediodorsal nucleus and submedial nucleus of the thalamus, were widespread across all ORB subregions. These findings provide novel insights into the functional connectivity of ORB subregions and their roles in neural circuit mechanisms underlying behavior and psychiatric disorders.

Arthritis treatment has been challenging because of low drug exposure to the articular cavity. This study was intended to develop hyaluronic acid (HA)-functionalized bilosomes for targeted delivery of tripterine (Tri), an antiphlogistic phytomedicine, to the inflamed joint via ligand-receptor interaction. Tri-loaded bilosomes (Tri-BLs) with cationic lipid (DOTAP) were prepared by a thin film hydration method followed by HA coating to form HA@Tri-BLs. HA@Tri-BLs were then characterized by particle size (PS), entrapment efficiency (EE), and structural morphology. The in vitro drug release, hemocompatibility test and cellular uptake were performed to examine the formulation performances of HA@Tri-BLs. The in vivo pharmacokinetics and antiarthritic efficacy were evaluated in arthritic models, respectively. The obtained HA@Tri-BLs possessed a PS of 118.5 nm around with an EE of 99.56%. HA@Tri-BLs exhibited excellent cellular uptake and targeted delivery efficiency for Tri, which resulted in elongation of circulatory residence time and enhancement of intra-arthritic bioavailability (799.9% relative to Tri solution). The in vivo antiarthritic efficacy of HA@Tri-BLs was also significantly superior to uncoated Tri-BLs that gave rise to obvious inflammation resolution. Our findings suggest that HA-functionalized bilosomes are a promising vehicle for articular delivery of antiphlogistic drugs to potentiate their efficacy.

Cyclin-dependent kinases (CDKs) control the progression of the cell cycle. D-type cyclin (CYCD) is generally believed to form a complex with CDK and control the G1/S transition. In plants, CYCD and CDK gene families can be divided into 6 (D1–D7) and 7 (CDKA–CDKG) subclasses, respectively. Different subclasses in the CYCD and CDK families have different numbers, structures and functions. In some heterologous woody plants, the functions of these subclass family members remain unclear. In this study, 43 CYCD and 27 CDK gene family members were identified in the allodiploid Populus tomentosa Carr . Phylogenetic analysis suggested that these CYCDs and CDKs were divided into 6 and 7 subclasses, respectively, which were the same as other species. The analysis of protein properties, gene structure, motifs, domains, cis-acting elements and tissue-specific expression of all members of these CYCDs and CDKs showed that the differences between members of different subclasses varied widely, but members of the same subclass especially in the CDK gene family were very similar. These findings also demonstrated a strong correlation between CYCD and CDK gene family members in response to hormones and specific expression. The collinear analysis of P. tomentosa , Populus trichocarpa and Arabidopsis thaliana showed that the expansion patterns of CYCD and CDK gene families were predominantly whole genome duplications (WGD). The protein interaction prediction results of different subclasses of CYCD and CDKs showed that the interaction between different subclasses of CYCD and CDKs was significantly different. Our previous study found that transgenic PtoCYCD2;1 and PtoCYCD3;3 poplars exhibited opposite phenotypes. Y2H and BIFC results showed that the interaction between PtoCYCD2;1 and PtoCYCD3;3 was significantly different with CDKs. This finding might suggest that the functional differences of different CYCD subclasses in plant growth and development were closely related to the different interactions between CYCD and CDK. Our results provide a good idea and direction for the functional study of CYCD and CDK proteins in woody plants.

Background Financial Toxicity (FT) is prevalent among lung cancer patients. Identifying high-risk groups and implementing comprehensive, targeted interventions can alleviate FT and improve patients’ quality of life. Hence, the objective of this study was to analyze the status and potential profiles of FT in lung cancer patients and explore the related factors of FT levels in different categories of lung cancer patients. Methods A cross-sectional design was used in this study. A total of 421 patients with lung cancer hospitalized in the oncology department of a Grade A general hospital and a provincial oncology hospital in Shandong Province from October to December 2023 were selected by convenience sampling. General data questionnaires, FT scale for reported outcomes of cancer patients, Chinese version of the Quality of Life Scale for lung cancer patients, Social Support Rating Scale and simplified version of the Mental Resilience Scale were used. Potential profile analysis of FT levels in lung cancer patients was performed, and multiple logistic regression was used to analyze the related factors of FT levels in different categories. Results Among 421 lung cancer patients, the median FT (FT) score was 16 (IQR: 9–24). Latent profile analysis identified four distinct FT patterns: mild (19.5%), moderate resource-deficient (7.8%), moderate balanced (35.6%), and severe (37.1%). Multivariate analysis revealed significant associations between FT severity and hospitalization frequency, lifestyle modifications, employment status, insurance coverage, education level, social support, emotional distress, family resilience, problem-solving capacity, and social resource utilization. Conclusion FT demonstrates high prevalence and substantial heterogeneity in lung cancer patients, with over 70% experiencing moderate-to-severe levels. Clinical interventions should prioritize early screening and stratified management through psychological support, financial navigation programs, cost-containment strategies, and enhanced health literacy to alleviate economic burdens and optimize treatment outcomes.

Background Chronic obstructive pulmonary disease (COPD) is underdiagnosed with the current gold standard measure pulmonary function test (PFT). A more sensitive and simple option for early detection and severity evaluation of COPD could benefit practitioners and patients. Methods In this multicenter retrospective study, frontal chest X-ray (CXR) images and related clinical information of 1055 participants were collected and processed. Different deep learning algorithms and transfer learning models were trained to classify COPD based on clinical data and CXR images from 666 subjects, and validated in internal test set based on 284 participants. External test including 105 participants was also performed to verify the generalization ability of the learning algorithms in diagnosing COPD. Meanwhile, the model was further used to evaluate disease severity of COPD by predicting different grads. Results The Ensemble model showed an AUC of 0.969 in distinguishing COPD by simultaneously extracting fusion features of clinical parameters and CXR images in internal test, better than models that used clinical parameters (AUC = 0.963) or images (AUC = 0.946) only. For the external test set, the AUC slightly declined to 0.934 in predicting COPD based on clinical parameters and CXR images. When applying the Ensemble model to determine disease severity of COPD, the AUC reached 0.894 for three-classification and 0.852 for five-classification respectively. Conclusion The present study used DL algorithms to screen COPD and predict disease severity based on CXR imaging and clinical parameters. The models showed good performance and the approach might be an effective case-finding tool with low radiation dose for COPD diagnosis and staging.

Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) have had an increasing role in the treatment of ovarian and breast cancers. PARP inhibitors are selectively active in cells with homologous recombination DNA repair deficiency caused by mutations in BRCA1/2 and other DNA repair pathway genes. Cancers with homologous recombination DNA repair proficiency respond poorly to PARP inhibitors. Cancers that initially respond to PARP inhibitors eventually develop drug resistance. We have identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 and ARN3261, which decreased DNA double-strand break (DSB) repair functions and produced synthetic lethality with multiple PARP inhibitors in both homologous recombination DNA repair deficiency and proficiency cancer cells. SIK2 is required for centrosome splitting and PI3K activation and regulates cancer cell proliferation, metastasis, and sensitivity to chemotherapy. Here, we showed that SIK2 inhibitors sensitized ovarian and triple-negative breast cancer (TNBC) cells and xenografts to PARP inhibitors. SIK2 inhibitors decreased PARP enzyme activity and phosphorylation of class-IIa histone deacetylases (HDAC4/5/7). Furthermore, SIK2 inhibitors abolished class-IIa HDAC4/5/7-associated transcriptional activity of myocyte enhancer factor-2D (MEF2D), decreasing MEF2D binding to regulatory regions with high chromatin accessibility in FANCD2, EXO1, and XRCC4 genes, resulting in repression of their functions in the DNA DSB repair pathway. The combination of PARP inhibitors and SIK2 inhibitors provides a therapeutic strategy to enhance PARP inhibitor sensitivity for ovarian cancer and TNBC.

BackgroundAngiogenin is a multifunctional secreted ribonuclease that is upregulated in human cancers and downregulated or mutationally inactivated in neurodegenerative diseases. A role for angiogenin in glioblastoma was inferred from the inverse correlation of angiogenin expression with patient survival but had not been experimentally investigated.MethodsAngiogenin knockout mice were generated and the effect of angiogenin deficiency on glioblastoma progression was examined. Angiogenin and plexin-B2 genes were knocked down in glioblastoma cells and the changes in cell proliferation, invasion and vascular association were examined. Monoclonal antibodies of angiogenin and small molecules were used to assess the therapeutic activity of the angiogenin-plexin-B2 pathway in both genetic and xenograft animal models.ResultsDeletion of Ang1 gene prolonged survival of PDGF-induced glioblastoma in mice in the Ink4a/Arf−/−:Pten−/− background, accompanied by decreased invasion, vascular association and proliferation. Angiogenin upregulated MMP9 and CD24 leading to enhanced invasion and vascular association. Inhibition of angiogenin or plexin-B2, either by shRNA, monoclonal antibody or small molecule inhibitor, decreases sphere formation of patient-derived glioma stem cells, reduces glioblastoma proliferation and invasion and inhibits glioblastoma growth in both genetic and xenograft animal models.ConclusionsAngiogenin and its receptor, plexin-B2, are a pair of novel regulators that mediate invasion, vascular association and proliferation of glioblastoma cells. Inhibitors of the angiogenin-plexin-B2 axis have therapeutic potential against glioblastoma.

Ferroptosis, a distinct form of programmed cell death characterized by iron-dependent lipid peroxidation, has emerged as a critical factor in the pathogenesis of various diseases. Given the increasing prevalence of osteoporosis worldwide and the increasing incidence of osteoporosis, understanding the molecular mechanisms underlying bone loss is imperative for developing targeted therapies. Recent evidence suggests that ferroptosis plays a pivotal role in osteoporosis by influencing the balance between osteoblast and osteoclast activity. This review examines the mechanistic basis of ferroptosis and its pathological implications in osteoporosis. By delineating the interplay between ferroptosis and skeletal remodeling, we highlight potential therapeutic strategies aimed at modulating ferroptosis to mitigate osteoporosis progression.