Significant spatiotemporal pattern of nitrous oxide emission and its influencing factors from a shallow eutropic lake in Inner Mongolia, China.

Eutrophic shallow lakes are generally considered as a contributor to the emission of nitrous oxide (N2O), while regional and global estimates have remained imprecise. This due to a lack of data and insufficient understanding of the multiple contributing factors. This study characterized the spatiotemporal variability in N2O concentrations and N2O diffusive fluxes and the contributing factors in Lake Wuliangsuhai, a typical shallow eutrophic and seasonally frozen lake in Inner Mongolia with cold and arid climate. Dissolved N2O concentrations of the lake exhibited a range of 4.5 to 101.2 nmol/L, displaying significant spatiotemporal variations. The lowest and highest concentrations were measured in summer and winter, respectively. The spatial distribution of N2O flux was consistent with that of N2O concentrations. Additionally, the hotspots of N2O emissions were detected within close to the main inflow of lake. The wide spatial and temporal variation in N2O emissions indicate the complexity and its relative importance of factors influencing emissions. N2O emissions in different lake zones and seasons were regulated by diverse factors. Factors influencing the spatial and temporal distribution of N2O concentrations and fluxes were identified as WT, WD, DO, Chl-a, SD and COD. Interestingly, the same factor demonstrated opposing effects on N2O emission in various seasons or zones. This research improves our understanding of N2O emissions in shallow eutrophic lakes in cold and arid areas.

Bridging length scales in hard materials with ultra-small angle X-ray scattering - a critical review.

Owing to their exceptional properties, hard materials such as advanced ceramics, metals and composites have enormous economic and societal value, with applications across numerous industries. Understanding their microstructural characteristics is crucial for enhancing their performance, materials development and unleashing their potential for future innovative applications. However, their microstructures are unambiguously hierarchical and typically span several length scales, from sub-ångstrom to micrometres, posing demanding challenges for their characterization, especially for in situ characterization which is critical to understanding the kinetic processes controlling microstructure formation. This review provides a comprehensive description of the rapidly developing technique of ultra-small angle X-ray scattering (USAXS), a nondestructive method for probing the nano-to-micrometre scale features of hard materials. USAXS and its complementary techniques, when developed for and applied to hard materials, offer valuable insights into their porosity, grain size, phase composition and inhomogeneities. We discuss the fundamental principles, instrumentation, advantages, challenges and global status of USAXS for hard materials. Using selected examples, we demonstrate the potential of this technique for unveiling the microstructural characteristics of hard materials and its relevance to advanced materials development and manufacturing process optimization. We also provide our perspective on the opportunities and challenges for the continued development of USAXS, including multimodal characterization, coherent scattering, time-resolved studies, machine learning and autonomous experiments. Our goal is to stimulate further implementation and exploration of USAXS techniques and inspire their broader adoption across various domains of hard materials science, thereby driving the field toward discoveries and further developments.

Probing the Topological Effects on Stability Enhancement and Therapeutic Performance of Protein Bioconjugates: Tadpole, Macrocycle versus Figure-of-Eight.

Chemical topology provides a unique dimension for making therapeutic protein bioconjugates with native structure and intact function, yet the effects of topology remain elusive. Herein, the design, synthesis, and characterization of therapeutic protein bioconjugates in three topologies (i.e., tadpole, macrocycle, and figure-of-eight), are reported. The interferon α2b (IFN) and albumin binding domain (ABD) are selected as the model proteins for bioconjugation and proof-of-concept. The biosynthesis of these topological isoforms is accomplished via direct expression in cells using SpyTag-SpyCatcher chemistry and/or split-intein-mediated ligation for topology diversification. The corresponding topologies are proven with combined techniques of LC-MS, SDS-PAGE, and controlled proteolytic digestion. While the properties of these topological isoforms are similar in most cases, the figure-of-eight-shaped bioconjugate, f8-IFN-ABD, exhibits the best thermal stability and anti-aggregation properties along with prolonged half-life and enhanced tumor retention relative to the tadpole-shaped control, tadp-IFN-ABD, and the macrocyclic control, c-IFN-ABD, showcasing considerable topological effects. The work expands the topological diversity of proteins and demonstrates the potential advantages of leveraging chemical topology for functional benefits beyond multi-function integration in protein therapeutics.

17ß-estradiol promotes the progression of temporomandibular joint osteoarthritis by regulating the FTO/IGF2BP1/m6A-NLRC5 axis.

BACKGROUND: Temporomandibular joint osteoarthritis (TMJOA) is a degenerative cartilage disease. 17ß-estradiol (E2) aggravates the pathological process of TMJOA; however, the mechanisms of its action have not been elucidated. Thus, we investigate the influence of E2 on the cellular biological behaviors of synoviocytes and the molecular mechanisms. METHODS: Primary fibroblast-like synoviocytes (FLSs) isolated from rats were treated with TNF-α to establish cell model, and phenotypes were evaluated using cell counting kit-8, EdU, Tanswell, enzyme-linked immunosorbent assay, and quantitative real-time PCR (qPCR). The underlying mechanism of E2, FTO-mediated NLRC5 m6A methylation, was assessed using microarray, methylated RNA immunoprecipitation, qPCR, and western blot. Moreover, TMJOA-like rat model was established by intra-articular injection of monosodium iodoacetate (MIA), and bone morphology and pathology were assessed using micro-CT and H&E staining. RESULTS: The results illustrated that E2 facilitated the proliferation, migration, invasion, and inflammation of TNF-α-treated FLSs. FTO expression was downregulated in TMJOA and was reduced by E2 in FLSs. Knockdown of FTO promoted m6A methylation of NLRC5 and enhanced NLRC5 stability by IGF2BP1 recognition. Moreover, E2 promoted TMJ pathology and condyle remodeling, and increased bone mineral density and trabecular bone volume fraction, which was rescued by NLRC5 knockdown. CONCLUSION: E2 promoted the progression of TMJOA.

An ultra-long-acting L-asparaginase synergizes with an immune checkpoint inhibitor in starvation-immunotherapy of metastatic solid tumors.

Metastasis stands as the primary contributor to mortality associated with tumors. Chemotherapy and immunotherapy are frequently utilized in the management of metastatic solid tumors. Nevertheless, these therapeutic modalities are linked to serious adverse effects and limited effectiveness in preventing metastasis. Here, we report a novel therapeutic strategy named starvation-immunotherapy, wherein an immune checkpoint inhibitor is combined with an ultra-long-acting L-asparaginase that is a fusion protein comprising L-asparaginase (ASNase) and an elastin-like polypeptide (ELP), termed ASNase-ELP. ASNase-ELP's thermosensitivity enables it to generate an in-situ depot following an intratumoral injection, yielding increased dose tolerance, improved pharmacokinetics, sustained release, optimized biodistribution, and augmented tumor retention compared to free ASNase. As a result, in murine models of oral cancer, melanoma, and cervical cancer, the antitumor efficacy of ASNase-ELP by selectively and sustainably depleting L-asparagine essential for tumor cell survival was substantially superior to that of ASNase or Cisplatin, a first-line anti-solid tumor medicine, without any observable adverse effects. Furthermore, the combination of ASNase-ELP and an immune checkpoint inhibitor was more effective than either therapy alone in impeding melanoma metastasis. Overall, the synergistic strategy of starvation-immunotherapy holds excellent promise in reshaping the therapeutic landscape of refractory metastatic tumors and offering a new alternative for next-generation oncology treatments.

Transdermal characteristic study of bovine sialoglycoproteins with anti-skin aging and accelerating skin wound healing.

BACKGROUND: Sialoglycoproteins play important roles in various biological processes, including cell adhesion, immune response, and cell signaling. Our previous studies indicated that the bovine sialoglycoproteins could be developed as a reagent against skin aging and as a new candidate for accelerating skin wound healing as well as inhibiting scar formation. However, transdermal characteristic of the bovine sialoglycoproteins is still unknown. AIMS: This study investigated the transdermal permeation of the bovine sialoglycoproteins through porcine skin using the Franz diffusion cell method. RESULTS: Our study showed that the bovine sialoglycoproteins could penetrate through the porcine skin with a linear permeation pattern described by the regression equation N% = 11.49 t-3.858, with a high coefficient of determination (R2 = 0.9903). The histochemical results demonstrated the widespread distribution of the bovine sialoglycoproteins between the epidermal and dermal layers, which suggesting parts of the bovine sialoglycoproteins had ability to traverse the epidermal barrier. The results of the lectin microarrays indicated highly enriched glycopatterns on the bovine sialoglycoproteins, which also appeared in permeated porcine skin. The LC-MS/MS analysis further showed that the bovine sialoglycoproteins were composed of approximately 100 proteins with molecular weight ranging from 748.4 kDa to 10 kDa, and there were 23 specific bovine sialoglycoproteins with molecular weight ranging from 69.2 kDa to 10 kDa to be characterized in permeated porcine skin. CONCLUSIONS: Parts of the bovine sialoglycoproteins with molecular weight less than 69.2 kDa had ability to traverse the epidermal barrier. Understanding the permeation characteristics of the bovine sialoglycoproteins for developing innovative formulations with therapeutic benefits, contributing to advancements in cosmetic and dermatological fields.

Revealing the dual impact of VOCs on recycled rubber workers: Health risk and odor perception.

Volatile organic compounds (VOCs) pose potential hazards to human health and contribute significantly to odor pollution. This study examined VOC emissions from a representative recycled rubber industry, evaluating the occupational health risks for frontline workers in various workshops. Variables such as gender and workshop-specific concentration variations were considered using Monte Carlo simulation methods. Employees in the five production workshops and office areas face noncarcinogenic health risks with hazard indices (HIs) greater than 1, with the rubber compounding phase presenting the highest risk. Acetaldehyde is identified as the primary noncarcinogenic health risk substance, with hazard quotient (HQ) values exceeding 1 in all workshops. Carcinogenic health risks vary by area, with the highest risks found in compounding and refining workshops. Formaldehyde poses the greatest risk in rubber grinding workshops and offices, with cumulative weights exceeding unacceptable levels of M80.58 % and W77.56 % in grinding and M94.98 % and W92.24 % in the office. Male workers face 4-7 % greater noncarcinogenic VOC health risks than females and 5-14 % greater carcinogenic risks from individual VOCs, increasing their susceptibility to health risks caused by VOCs. Additionally, our analysis of odor identification and intensity classification revealed that 53 VOCs are capable of causing odor pollution, with several substances reaching odor levels of 2 or higher. The predominant perceived odors, as reflected in the odor wheel, include categories such as "solvent/aromatic" and "sweet/fruit," with aldehydes being the primary odor-causing substances. In summary, emissions of VOCs from rubber industrial processes not only pose substantial health risks to workers but also contribute significantly to odor pollution. Consequently, enterprises must prioritize optimizing workplace conditions to ensure the occupational health and well-being of their employees.

Bromodomain-containing protein 4 knockdown promotes neuronal ferroptosis in a mouse model of subarachnoid hemorrhage.

Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage. Neuronal ferroptosis in particular plays an important role in early brain injury. Bromodomain-containing protein 4, a member of the bromo and extraterminal domain family of proteins, participated in multiple cell death pathways, but the mechanisms by which it regulates ferroptosis remain unclear. The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro. Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons, and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo. In addition, ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage. Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis. Using cleavage under targets and tagmentation analysis, we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro. Furthermore, treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074, a Raf-1 inhibitor, exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway. Moreover, targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage. Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage, and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.

Associations between social isolation, perceived ageism and subjective well-being among rural Chinese older adults: A cross-sectional study.

OBJECTIVE: This study aimed to investigate the relationship between social isolation, perceived ageism and subjective well-being among rural Chinese older adults and its mechanisms of action. METHODS: A total of 403 rural resident older adults were surveyed from March to April 2024. Data were collected using the General Information Questionnaire, the General Alienation Scale (GAS), the Perceived Ageism Questionnaire (PAQ), and the Memorial University of Newfoundland Scale of Happiness (MUNSH). SPSS 27.0 and PROCESS macro were used to analyze the data. RESULTS: Pearson correlation analysis revealed a significant negative correlation (p<0.01) between subjective well-being and social isolation (r = -0.720) and perceived ageism (r = -0.661) among rural older adults. Perceived ageism partially mediated the effect between social isolation and subjective well-being in rural older adults, and the mediating effect accounted for 29.9 % of the total effect (p<0.001). CONCLUSION: Social isolation can reduce the subjective well-being of rural older adults through perceived ageism.

Autonomic Nervous System and Sarcopenia in Elderly Patients: Insights from Long-Term Heart Rate Variability Monitoring in a Hospital Setting.

Background: Emerging evidence suggests a link between muscle health and the autonomic nervous system, but research is scarce. This study examines the connection between long-term heart rate variability (HRV) measured autonomic function and sarcopenia in the elderly, focusing on muscle mass and strength. Patients and Methods: This retrospective cross-sectional study comprised 132 elderly hospitalized patients. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People (EWGSOP2) criteria, involving reduced muscle mass and strength. HRV was assessed using standard deviation of NN intervals (SDNN), with values below 100 milliseconds indicating reduced HRV. Multivariate logistic regression and Pearson's correlation analyses were conducted to explore the associations between sarcopenia, muscle metrics, and HRV parameters. Results: Among elderly hospitalized patients, 45.45% had reduced HRV, with sarcopenia patients showing a fivefold higher risk (OR: 5.042; p = 0.034). Grip strength and SARC-CalF scores were independent factors associated with reduced HRV. Moderate correlations were noted between grip strength and HRV indices, particularly with SDNN (r = 0.393, p = 0.001) and the triangular index (r = 0.385, p < 0.001), while a weaker correlation was found with very low frequency power (VLF) (r = 0.283, p = 0.006). No significant correlations were identified between HRV and muscle mass. Regression analyses revealed significant independent associations between HRV parameters and the decline in muscle strength and the onset of sarcopenia. Conclusion: Reduced HRV is closely linked to sarcopenia and diminished muscle strength in the elderly, with the triangular index and SDNN as key indicators, highlighting HRV's potential in muscle health assessment.

Evaluation of the effect of GSK-3ß on liver cancer based on the PI3K/AKT pathway.

The PI3K/AKT/GSK-3ß signaling pathway plays a pivotal role in numerous physiological and pathological processes, including cell proliferation, apoptosis, differentiation, and metabolic regulation. Aberrant activation of the PI3K/AKT pathway is intricately linked to development of tumor. GSK-3ß, belonging to the serine/threonine protein kinase family, is crucial in the pathogenesis of liver cancer. As a key rate-limiting enzyme in the glucose metabolism pathway, GSK-3ß significantly impacts the growth, proliferation, metastasis, and apoptosis of liver cancer cells. It is also implicated in chemotherapy resistance. Elevated expression of GSK-3ß diminishes the sensitivity of liver cancer cells to chemotherapeutic agents, thereby playing a substantial role in the development of drug resistance. Consequently, targeting of GSK-3ß, particularly within the PI3K/AKT signaling pathway, is regarded as a promising therapeutic strategy for liver cancer. The precise identification and subsequent modulation of this pathway represent a substantial potential for innovative clinical interventions in the management of liver cancer.

Establishment, Prediction, and Validation of a Nomogram for Cognitive Impairment in Elderly Patients With Diabetes.

Objective: The purpose of this study is to establish a predictive model of cognitive impairment in elderly people with diabetes. Methods: We analyzed a total of 878 elderly patients with diabetes who were part of the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014. The data were randomly divided into training and validation cohorts at a ratio of 6:4. The least absolute shrinkage and selection operator (LASSO) logistic regression analysis to identify independent risk factors and construct a prediction nomogram for cognitive impairment. The performance of the nomogram was assessed using receiver operating characteristic (ROC) curve and calibration curve. Decision curve analysis (DCA) was performed to evaluate the clinical utility of the nomogram. Results: LASSO logistic regression was used to screen eight variables, age, race, education, poverty income ratio (PIR), aspartate aminotransferase (AST), blood urea nitrogen (BUN), serum uric acid (SUA), and heart failure (HF). A nomogram model was built based on these predictors. The ROC analysis of our training set yielded an area under the curve (AUC) of 0.786, while the validation set showed an AUC of 0.777. The calibration curve demonstrated a good fit between the two groups. Furthermore, the DCA indicated that the model has a favorable net benefit when the risk threshold exceeds 0.2. Conclusion: The newly developed nomogram has proved to be an important tool for accurately predicting cognitive impairment in elderly patients with diabetes, providing important information for targeted prevention and intervention measures.

Spin-Coupled Electron Densities of Iron-Sulfur Cluster Imaged by In Situ Serial Laue Diffraction.

Iron-sulfur clusters are inorganic cofactors found in many proteins involved in fundamental biological processes. The prokaryotic DNA repair photolyase PhrB carries a four-iron-four-sulfur cluster ([4Fe4S]) in addition to the catalytic flavin adenine dinucleotide (FAD) and a second cofactor ribolumazine. Our recent study suggested that the [4Fe4S] cluster functions as an electron cache to coordinate two interdependent photoreactions of the FAD and ribolumazine. Here we report the crystallography observations of light-induced responses in PhrB using the cryo-trapping method and in situ serial Laue diffraction at room temperature. We capture strong signals that depict electron density changes arising from quantized electronic movements in the [4Fe4S] cluster. Our data reveal the mixed valence layers of the [4Fe4S] cluster due to spin coupling and their dynamic responses to light-induced redox changes. The quantum effects imaged by decomposition of electron density changes have shed light on the emerging roles of metal clusters in proteins.

Retinol dehydrogenase 10 promotes epithelial-mesenchymal transition in spinal cord gliomas via PI3K/AKT pathway.

Background: Spinal cord glioma (SCG), a rare subset of central nervous system (CNS) glioma, represents a complex challenge in neuro-oncology. There has been research showing that Retinol Dehydrogenase 10 (RDH10) may be a tumor promoting factor in brain glioma, but the biological effects of RDH10 remain undefined in SCG. Methods: We performed gene set enrichment analysis (GSEA) and unsupervised clustering analysis to investigate the roles of EMT (epithelial-mesenchymal transition) in glioma. DEG (differently expressed gene) screening and correlation analysis were conducted to filter the candidate genes which were closely associated with EMT process in SCG. Enrichment analysis and GSVA (Gene Set Variation Analysis) were conducted to investigate the potential mechanism of RDH10 for SCG. Trans-well and healing assay were performed to explore the role of RDH10 in the invasion of SCG. Western blotting was performed to evaluate the levels of markers in PI3K-AKT and EMT pathway. In vivo tests were conducted to verify the role of RDH10 in EMT process. Results: Bioinformatic analysis demonstrated the EMT pathway was associated with dismal prognosis of glioma. Further analysis demonstrated that RDH10 showed the strongest correlation with the EMT process. Retinol Dehydrogenase 10 expression was significantly increased in SCG tissues, correlating with advanced tumor grade and unfavorable prognosis. Functional analysis indicated that decreasing RDH10 levels impeded the invasive and migratory abilities of SCG cells, whereas increasing RDH10 levels augmented them. Enrichment analysis and western blot revealed that RDH10 regulated EMT process of SCG by PI3K-AKT pathway. We observed that the enhanced invasion ability and increased EMT-related protein induced by RDH10 overexpression can be suppressed by PI3K-AKT pathway inhibitor (LY294002). Conclusion: Our research found that RDH10 was an effective biomarker associated with tumor grade and prognosis of SCG. RDH10 could regulate EMT process of SCG through PI3K-AKT pathway.

Deep multimodal saliency parcellation of cerebellar pathways: Linking microstructure and individual function through explainable multitask learning.

Parcellation of human cerebellar pathways is essential for advancing our understanding of the human brain. Existing diffusion magnetic resonance imaging tractography parcellation methods have been successful in defining major cerebellar fibre tracts, while relying solely on fibre tract structure. However, each fibre tract may relay information related to multiple cognitive and motor functions of the cerebellum. Hence, it may be beneficial for parcellation to consider the potential importance of the fibre tracts for individual motor and cognitive functional performance measures. In this work, we propose a multimodal data-driven method for cerebellar pathway parcellation, which incorporates both measures of microstructure and connectivity, and measures of individual functional performance. Our method involves first training a multitask deep network to predict various cognitive and motor measures from a set of fibre tract structural features. The importance of each structural feature for predicting each functional measure is then computed, resulting in a set of structure-function saliency values that are clustered to parcellate cerebellar pathways. We refer to our method as Deep Multimodal Saliency Parcellation (DeepMSP), as it computes the saliency of structural measures for predicting cognitive and motor functional performance, with these saliencies being applied to the task of parcellation. Applying DeepMSP to a large-scale dataset from the Human Connectome Project Young Adult study (n = 1065), we found that it was feasible to identify multiple cerebellar pathway parcels with unique structure-function saliency patterns that were stable across training folds. We thoroughly experimented with all stages of the DeepMSP pipeline, including network selection, structure-function saliency representation, clustering algorithm, and cluster count. We found that a 1D convolutional neural network architecture and a transformer network architecture both performed comparably for the multitask prediction of endurance, strength, reading decoding, and vocabulary comprehension, with both architectures outperforming a fully connected network architecture. Quantitative experiments demonstrated that a proposed low-dimensional saliency representation with an explicit measure of motor versus cognitive category bias achieved the best parcellation results, while a parcel count of four was most successful according to standard cluster quality metrics. Our results suggested that motor and cognitive saliencies are distributed across the cerebellar white matter pathways. Inspection of the final k = 4 parcellation revealed that the highest-saliency parcel was most salient for the prediction of both motor and cognitive performance scores and included parts of the middle and superior cerebellar peduncles. Our proposed saliency-based parcellation framework, DeepMSP, enables multimodal, data-driven tractography parcellation. Through utilising both structural features and functional performance measures, this parcellation strategy may have the potential to enhance the study of structure-function relationships of the cerebellar pathways.

Efficacy and safety of laminoplasty combined with C3 laminectomy for patients with multilevel degenerative cervical myelopathy: a systematic review and meta-analysis.

PURPOSE: Laminoplasty (LP) combined with C3 laminectomy (LN) can effectively achieve spinal cord decompression while maintaining the integrity of the posterior ligament-muscle complex, thereby minimizing cervical muscle damage. However, its necessity and safety remain controversial. This study aimed to compare the safety and efficacy of LP and LP combined with C3 LN in the treatment of patients with multilevel degenerative cervical spondylotic myelopathy (DCM). METHODS: A systematic review and meta-analysis of the literature was performed. A search of PubMed, Web of Science, Embase, and the Cochrane Library databases was conducted from inception through December 2023 and updated in February 2024. Search terms included laminoplasty, laminectomy, C3 and degenerative cervical spondylosis. The literature search yielded 14 studies that met our inclusion criteria. Outcomes included radiographic results, neck pain, neurologic function, surgical parameters, and postoperative complications. We also assessed methodologic quality, publication bias, and quality of evidence. RESULTS: Fourteen studies were identified, including 590 patients who underwent LP combined with C3 LN (modified group, MG) compared to 669 patients who underwent LP (traditional group, TG). The results of the study indicated a statistically significant improvement in cervical range of motion (WMD = 3.62, 95% CI: 0.39 to 6.85) and cervical sagittal angle (WMD = 2.07, 95% CI: 0.40 to 3.74) in the MG compared to the TG at the last follow-up (very low-level evidence). The TG had a higher number of patients with complications, especially C2-3 bone fusion. There was no significant difference found in improvement of neck pain, JOA, NDI, cSVA, T1 slope at latest follow-up. CONCLUSION: LP combined with C3 LN is an effective and necessary surgical method for multilevel DCM patients to maintain cervical sagittal balance. However, due to the low quality of evidence in existing studies, more and higher quality research on the technology is needed in the future.

BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance.

PARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame. BRCA1 splice isoforms △11 and △11q can contribute to PARPi resistance by splicing out the mutation-containing exon, producing truncated, partially functional proteins. However, the clinical impacts and underlying drivers of BRCA1 exon skipping are not fully understood.We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs) that drive exon skipping, confirmed using qRT-PCR, RNA sequencing, immunoblotting and minigene modelling. CRISPR/Cas9-mediated disruption of splicing functionally validated exon skipping as a mechanism of PARPi resistance. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials.Few PARPi resistance mechanisms have been confirmed in the clinical setting. While secondary/reversion mutations typically restore a gene's reading frame, we have identified secondary mutations in patient cohorts that hijack splice sites to enhance mutation-containing exon skipping, resulting in the overexpression of BRCA1 hypomorphs, which in turn promote PARPi resistance. Thus, BRCA1 SSMs can and should be clinically monitored, along with frame-restoring secondary mutations.

Application of targeted nursing intervention in patients undergoing synchronous carotid endarterectomy and coronary artery bypass grafting.

OBJECTIVES: To investigate the effect of targeted nursing intervention on the short-term prognosis of patients with coronary heart disease and carotid artery stenosis undergoing synchronous coronary artery bypass grafting (CABG) and carotid endarterectomy (CEA). METHODS: A total of 58 patients who received OPCABG + CEA from February 2018 to May 2021 at the Beijing Anzhen Hospital were selected as the study subjects. They were randomly divided into two groups, with 29 patients in each group. The control group received routine postoperative nursing care, while the observation group received targeted nursing intervention in addition to the routine care. The incidence of postoperative stroke and the length of postoperative stay were observed. RESULTS: There were no statistically significant differences in baseline data between the two groups. Postoperative acute stroke occurred in 2 cases (6.9%) in the control group and 0 cases in the observation group, although this difference was not statistically significant. The median postoperative hospital stay was 13 days in the control group, with the earliest discharge at 10 days. In the observation group, the median postoperative hospital stay was 10 days, with the earliest discharge on the 8th day. This difference was statistically significant. CONCLUSIONS: Targeted nursing intervention can improve the short-term prognosis of patients with coronary heart disease and carotid artery stenosis undergoing OPCABG + CEA, and it can also shorten the length of postoperative hospital stay.