Potential treatment of glutathione in bullfrogs with abnormal hepatic lipid metabolism revealed by hepatic lipid metabolism and serum metabolomics analysis.

Introduction: With the continuous growth of bullfrog supply, it has become an important aquaculture species. Due to the lack of actionable industry standards and regulation, the misuse of anti-disease drugs and abnormal liver lipid metabolism in bullfrogs have become a major obstacle to the development of bullfrog aquaculture industry. Glutathione is a natural tripeptide that can be synthesized intracellularly, and its physiological functions mainly include the treatment of liver diseases, antioxidant, detoxification, anti-tumor, enhancement of immunity, and delaying aging. Methods: In this study, the therapeutic effect of glutathione on bullfrogs with abnormal liver lipid metabolism was revealed from hepatic lipid metabolism and serum metabolomics analysis. The survival rate, liver histomorphology, serum antioxidant enzyme activity, liver lipase activity and serum metabolomics, liver metabolomics were studied and analyzed by feeding the bullfrogs with abnormal lipid metabolism with glutathione for 20 days in the NC, FI and GSH groups. Results: The results of the study showed that glutathione was able to repair the liver and improve the survival rate of bullfrogs with abnormal lipid metabolism; the activity of serum SOD enzymes was significantly increased; the activities of ACP and AKP were significantly decreased; the activities of HDL-C and T-CHO were significantly increased; and the activities of LDL-C, TBA, and TG were significantly decreased in the liver; the contents of metabolites, such as PC, PS, and PE were significantly up-regulated, and the levels of up-regulated Autophagy - other, Necroptosis and ErbB signaling pathway, and down-regulated Sphingolipid metabolism, D-Amino acid metabolism metabolic pathway, to some extent The metabolic pathways of Sphingolipid metabolism and D-Amino acid metabolism were down-regulated to alleviate the disorders of glycerophospholipid and amino acid metabolism to a certain extent, thus alleviating the abnormalities of liver lipid metabolism. Discussion: The results showed that glutathione could effectively treat the liver lipid metabolism disorder of bullfrogs, promote the growth and development of bullfrogs, repair the liver function, reduce the inflammation, and promote the healthy and green development of bullfrog industry.

Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping.

The ability to spatially map multiple layers of the omics information over different time points allows for exploring the mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed and applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) and DBiT CTRP-seq (spatial CUT&Tag-RNA-Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) to map spatial dynamic remodeling in brain development and neuroinflammation. A spatiotemporal tri-omic atlas of the mouse brain was obtained at different stages from postnatal day P0 to P21, and compared to the regions of interest in the human developing brains. Specifically, in the cortical area, we discovered temporal persistence and spatial spreading of chromatin accessibility for the layer-defining transcription factors. In corpus callosum, we observed dynamic chromatin priming of myelin genes across the subregions. Together, it suggests a role for layer specific projection neurons to coordinate axonogenesis and myelination. We further mapped the brain of a lysolecithin (LPC) neuroinflammation mouse model and observed common molecular programs in development and neuroinflammation. Microglia, exhibiting both conserved and distinct programs for inflammation and resolution, are transiently activated not only at the core of the LPC lesion, but also at distal locations presumably through neuronal circuitry. Thus, this work unveiled common and differential mechanisms in brain development and neuroinflammation, resulting in a valuable data resource to investigate brain development, function and disease.

Inhibition of OLR1 reduces SASP of nucleus pulposus cells by targeting autophagy-GATA4 axis.

Targeting cellular senescence and Senescence Associated Secretory Phenotype (SASP) through autophagy has emerged as a promising intervertebral disc (IVD) degeneration (IDD) treatment strategy in recent years. This study aimed to clarify the role and mechanism of autophagy in preventing IVD SASP. Methods involved in vitro experiments with nucleus pulposus (NP) tissues from normal and IDD patients, as well as an in vivo IDD animal model. GATA4's regulatory role in SASP was validated both in vitro and in vivo, while autophagy modulators were employed to assess their impact on GATA4 and SASP. Transcriptomic sequencing identified Oxidized low-density lipoprotein receptor 1 (OLR1) as a key regulator of autophagy and GATA4. A series of experiments manipulated OLR1 expression to investigate associated effects. Results demonstrated significantly increased senescent NP cells (NPCs) and compromised autophagy in IDD patients and animal models, with SASP closely linked to IDD progression. The aged disc milieu impeded autophagic GATA4 degradation, leading to elevated SASP expression in senescent NPCs. Restoring autophagy reversed senescence by degrading GATA4, hence disrupting the SASP cascade. Moreover, OLR1 was identified for its regulation of autophagy and GATA4 in senescent NPCs. Silencing OLR1 enhanced autophagic activity, suppressing GATA4-induced senescence and SASP expression in senescent NPCs. In conclusion, OLR1 was found to control autophagy-GATA4 and SASP, with targeted OLR1 inhibition holding promise in alleviating GATA4-induced senescence and SASP expression while delaying extracellular matrix degradation, offering a novel therapeutic approach for IDD management.

Spatial dynamics of mammalian brain development and neuroinflammation by multimodal tri-omics mapping.

The ability to spatially map multiple layers of the omics information over different time points allows for exploring the mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed and applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) and DBiT CTRP-seq (spatial CUT&Tag-RNA-Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) to map spatial dynamic remodeling in brain development and neuroinflammation. A spatiotemporal tri-omic atlas of the mouse brain was obtained at different stages from postnatal day P0 to P21, and compared to the regions of interest in the human developing brains. Specifically, in the cortical area, we discovered temporal persistence and spatial spreading of chromatin accessibility for the layer-defining transcription factors. In corpus callosum, we observed dynamic chromatin priming of myelin genes across the subregions. Together, it suggests a role for layer specific projection neurons to coordinate axonogenesis and myelination. We further mapped the brain of a lysolecithin (LPC) neuroinflammation mouse model and observed common molecular programs in development and neuroinflammation. Microglia, exhibiting both conserved and distinct programs for inflammation and resolution, are transiently activated not only at the core of the LPC lesion, but also at distal locations presumably through neuronal circuitry. Thus, this work unveiled common and differential mechanisms in brain development and neuroinflammation, resulting in a valuable data resource to investigate brain development, function and disease.

P300 regulates histone crotonylation and preimplantation embryo development.

Histone lysine crotonylation, an evolutionarily conserved modification differing from acetylation, exerts pivotal control over diverse biological processes. Among these are gene transcriptional regulation, spermatogenesis, and cell cycle processes. However, the dynamic changes and functions of histone crotonylation in preimplantation embryonic development in mammals remain unclear. Here, we show that the transcription coactivator P300 functions as a writer of histone crotonylation during embryonic development. Depletion of P300 results in significant developmental defects and dysregulation of the transcriptome of embryos. Importantly, we demonstrate that P300 catalyzes the crotonylation of histone, directly stimulating transcription and regulating gene expression, thereby ensuring successful progression of embryo development up to the blastocyst stage. Moreover, the modification of histone H3 lysine 18 crotonylation (H3K18cr) is primarily localized to active promoter regions. This modification serves as a distinctive epigenetic indicator of crucial transcriptional regulators, facilitating the activation of gene transcription. Together, our results propose a model wherein P300-mediated histone crotonylation plays a crucial role in regulating the fate of embryonic development.

Surface Engineering Enhances Vanadium Carbide MXene-Based Nanoplatform Triggered by NIR-II for Cancer Theranostics.

Despite the advantages of high tissue penetration depth, selectivity, and non-invasiveness of photothermal therapy for cancer treatment, developing NIR-II photothermal agents with desirable photothermal performance and advanced theranostics ability remains a key challenge. Herein, a universal surface modification strategy is proposed to effectively improve the photothermal performance of vanadium carbide MXene nanosheets (L-V2C) with the removal of surface impurity ions and generation of mesopores. Subsequently, MnOx coating capable of T1-weighted magnetic resonance imaging can be in situ formed through surface redox reaction on L-V2C, and then, stable nanoplatforms (LVM-PEG) under physiological conditions can be obtained after further PEGylation. In the tumor microenvironment irradiated by NIR-II laser, multivalent Mn ions released from LVM-PEG, as a reversible electronic station, can consume the overexpression of glutathione and catalyze a Fenton-like reaction to produce ·OH, resulting in synchronous cellular oxidative damage. Efficient synergistic therapy promotes immunogenic cell death, improving tumor-related immune microenvironment and immunomodulation, and thus, LVM-PEG can demonstrate high accuracy and excellent anticancer efficiency guided by multimodal imaging. As a result, this study provides a new approach for the customization of 2D surface strategies and the study of synergistic therapy mechanisms, highlighting the application of MXene-based materials in the biomedical field.

Long-term outcomes and predictive factors of achieving low disease activity status in childhood systemic lupus erythematosus: a Chinese bicentric retrospective registered study.

Background: This study aims to explore the clinical value of low disease activity state (LDAS) in the treat-to-target strategy of pediatric systemic lupus erythematosus (pSLE) and find the risk factors for never reaching LDAS. Methods: A total of 272 children with SLE who were diagnosed and followed up in two tertiary hospitals in China during the period from January 2012 to December 2019 were involved in this study, and the clinical presentation, pathology, and treatment were retrospectively studied. Results: The male-to-female ratio was 1:5.2, the age at diagnosis was 11.1 years (IQR, 9.8-13.1 years), the disease duration was 1.0 month (IQR, 0.5-2.0 months), and follow-up was 36.5 months (IQR, 25.7-50.9 months). During follow-up, 230 children achieved LDAS, and 42 were never been in. Male (P = 0.018), mucosal ulcer (P = 0.048), liver function damage (P = 0.026), cardiac effusion (P = 0.034), anemia (P = 0.048), urine red blood cells (P = 0.017), urinary leukocytes (P = 0.032), and endothelial cell proliferation in renal biopsy (P = 0.004)-these indexes have statistical differences between the two groups in the baseline. At baseline, endothelial cell proliferation (P = 0.02) is an independent risk factor for never achieving LDAS by multivariate logistic analysis. During follow-up, non-compliance was a risk factor for never achieving LDAS by comparing between groups. Children with biologics achieved LDAS at a higher rate than children without biologics (P = 0.038). The proportion of organ damage in patients never been in LDAS was significantly higher than that in patients who achieved LDAS (P < 0.001). Conclusion: Endothelial cell proliferation in renal biopsy and non-compliance during follow-up were independent risk factors for never achieving LDAS. At the end of the follow-up, the organ damage in the remission group was similar to that in the LDAS group, indicating that LDAS can be used as a target for pSLE treatment.

Occurrence, distribution characteristics and exposure assessment of perchlorate in the environment in China.

Recognizing the extent of perchlorate pollution in the environment is critical to preventing and mitigating potential perchlorate harm to human health. The presence and distribution of perchlorate in Chinese environmental matrixes (water, atmosphere, and soil) were systematically investigated and comprehensively analyzed, and cumulative perchlorate exposure at the regional level was assessed using a combined aggregate exposure pathway method. The results showed that perchlorate is ubiquitous in the environment of China with significant regional differences. The total perchlorate exposure levels in each region of China ranked as South China > Southwest China > East China > North China > Northeast China > Northwest China. Although the average exposure dose of 0.588 (95 %CI: 0.142 -1.914) µg/kg bw/day being lower than the reference dose of 0.70 µg/kg bw/day, it was observed that the intake of perchlorate in some regions exceed this reference dose. Oral ingestion was the primary route of perchlorate exposure (89.97-96.57 % of the total intake), followed by dermal contact (3.21-9.16 %) and respiratory inhalation. Food and drinking water were the main sources of total perchlorate intake, contributing 52.54 % and 31.12 % respectively, with the latter contributing significantly more in southern China than in northern China. In addition, perchlorate exposure from dust sources was also noteworthy, as its contribution was as high as 23.18 % in some regions. These findings will improve understanding of the perchlorate risk and serve as a critical reference for policymakers in crafting improved environmental management and risk mitigation strategies in China and other nations.

Monomeric compounds from natural products for the treatment of pulmonary fibrosis: a review.

Pulmonary fibrosis (PF) is the end stage of lung injury and chronic lung diseases that results in diminished lung function, respiratory failure, and ultimately mortality. Despite extensive research, the pathogenesis of this disease remains elusive, and effective therapeutic options are currently limited, posing a significant clinical challenge. In addition, research on traditional Chinese medicine and naturopathic medicine is hampered by several complications due to complex composition and lack of reference compounds. Natural product monomers, possessing diverse biological activities and excellent safety profiles, have emerged as potential candidates for preventing and treating PF. The effective anti-PF ingredients identified can be generally divided into flavonoids, saponins, polysaccharides, and alkaloids. Specifically, these monomeric compounds can attenuate inflammatory response, oxidative stress, and other physiopathological processes of the lung through many signaling pathways. They also improve pulmonary factors. Additionally, they ameliorate epithelial-mesenchymal transition (EMT) and fibroblast-myofibroblast transdifferentiation (FMT) by regulating multiple signal amplifiers in the lungs, thereby mitigating PF. This review highlights the significant role of monomer compounds derived from natural products in reducing inflammation, oxidative stress, and inhibiting EMT process. The article provides comprehensive information and serves as a solid foundation for further exploration of new strategies to harness the potential of botanicals in the treatment of PF.

The potential roles of salivary biomarkers in neurodegenerative diseases.

Current research efforts on neurodegenerative diseases are focused on identifying novel and reliable biomarkers for early diagnosis and insight into disease progression. Salivary analysis is gaining increasing interest as a promising source of biomarkers and matrices for measuring neurodegenerative diseases. Saliva collection offers multiple advantages over the currently detected biofluids as it is easily accessible, non-invasive, and repeatable, allowing early diagnosis and timely treatment of the diseases. Here, we review the existing findings on salivary biomarkers and address the potential value in diagnosing neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Based on the available research, ß-amyloid, tau protein, α-synuclein, DJ-1, Huntington protein in saliva profiles display reliability and validity as the biomarkers of neurodegenerative diseases.

Ecological Risk Assessment of Organochlorine Pesticides and Polychlorinated Biphenyls in Coastal Sediments in China.

Although the ecological risk of emerging contaminants is currently a research hotspot in China and abroad, few studies have investigated the ecological risk of pesticide pollutants in Chinese coastal sediments. In this study, nine pesticide pollutants included in the "List of New Key Pollutants for Control (2023 Edition)" issued by the Chinese government were used as the research objects, and the environmental exposure of pesticide pollutants in China's coastal sediments was analyzed. The baseline sediment quality criteria were deduced using the balanced distribution method, and a multi-level ecological risk assessment of pesticides in sediment was performed. The results showed that the nine pesticide pollutants were widespread in Chinese coastal sediments, with concentrations ranging from 0.01 ng·g-1 to 330 ng·g-1. The risk quotient assessment showed that endosulfan and DDT posed medium environmental risks to the Chinese coastal sediment environment, and PCBs posed medium risks in some bays of the East China Sea. The semi-probabilistic, optimized semi-probability evaluation and joint probability curve (JPC) assessments all show that endosulfan and DDT pose a certain degree of risk to the environment.

Comparison of embryo quality and pregnancy outcomes for patients with low ovarian reserve in natural cycles and mildly stimulated cycles: a cohort study.

BACKGROUND: As women with low ovarian reserve embark on the challenging journey of in-vitro fertilisation (IVF) treatment, the choice between natural and mildly stimulated cycles becomes a pivotal consideration. It is unclear which of these two regimens is superior for women with low ovarian reserve. Our study aims to assess the impact of natural cycles on embryo quality and pregnancy outcomes in women with low ovarian reserve undergoing IVF treatment compared to mildly stimulated cycles. METHODS: This retrospective study enrolled consecutive patients with low ovarian reserve who underwent IVF/intracytoplasmic sperm injection (ICSI) at Guangdong Second Provincial General Hospital between January 2017 and April 2021. The primary outcome for pregnancy rate of 478 natural cycles and 448 mild stimulated cycles was compared. Secondary outcomes included embryo quality and oocyte retrieval time of natural cycles. RESULTS: The pregnancy rate in the natural cycle group was significantly higher than that in the mildly stimulated cycle group (51.8% vs. 40.1%, p = 0.046). Moreover, natural cycles exhibited higher rates of available embryos (84.1% vs. 78.6%, p = 0.040), high-quality embryos (61.8% vs. 53.2%, p = 0.008), and utilisation of oocytes (73% vs. 65%, p = 0.001) compared to mildly stimulated cycles. Oocyte retrievals in natural cycles were predominantly performed between 7:00 and 19:00, with 94.9% occurring during this time frame. In natural cycles with high-quality embryos, 96.4% of oocyte retrievals were also conducted between 7:00 and 19:00. CONCLUSION: Natural cycles with appropriately timed oocyte retrieval may present a valuable option for patients with low ovarian reserve.

In the realm of in-vitro fertilisation (IVF) treatment, women with low ovarian reserve often face the crucial decision of opting for natural or mildly stimulated cycles. This retrospective study, conducted between January 2017 and April 2021 at Guangdong Second Provincial General Hospital, delves into the impact of these cycles on pregnancy outcomes. Examining 478 natural cycles and 448 mildly stimulated cycles, the study reveals a notably higher pregnancy rate in the natural cycle group (51.8% vs. 40.1%). Additionally, natural cycles demonstrated higher rates of available embryos, high-quality embryos, and oocyte utilisation compared to their mildly stimulated counterparts. The findings suggest that natural cycles, with proper oocyte retrieval timing, could be a favourable choice for those with low ovarian reserve seeking IVF treatment.

Bufotalin attenuates pulmonary fibrosis via inhibiting Akt/GSK-3ß/ß-catenin signaling pathway.

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with no cure. Bufotalin (BT), an active component extracted from Venenum Bufonis, has been prescribed as a treatment for chronic inflammatory diseases. However, whether BT has antifibrotic properties has never been investigated. In this study, we report on the potential therapeutic effect and mechanism of BT on IPF. BT was shown to attenuate lung injury, inflammation, and fibrosis as well as preserve pulmonary function in bleomycin (BLM)-induced pulmonary fibrosis model. We next confirmed BT's ability to inhibit TGF-ß1-induced epithelial-mesenchymal transition (EMT) and myofibroblast activation (including differentiation, proliferation, migration, and extracellular matrix production) in vitro. Furthermore, transcriptional profile analysis indicated the Wnt signaling pathway as a potential target of BT. Mechanistically, BT effectively prevented ß-catenin from translocating into the nucleus to activate transcription of profibrotic genes. This was achieved by blunting TGF-ß1-induced increases in phosphorylated Akt Ser437 (p-Akt S437) and phosphorylated glycogen synthase kinase (GSK)-3ß Ser9 (p-GSK-3ß S9), thereby reactivating GSK-3ß. Additionally, the antifibrotic effects of BT were further validated in another in vivo model of radiation-induced pulmonary fibrosis. Collectively, these data demonstrated the potent antifibrotic actions of BT through inhibition of Akt/GSK-3ß/ß-catenin axis downstream of TGF-ß1. Thus, BT could be a potential option to be further explored in IPF treatment.

Research progress in biological control of tomato bacterial wilt.

Bacterial wilt caused by the infection of Ralstonia solanacearum, is one of the most harmful diseases to tomatoes, one of the most important greenhouse vegetables in China. R. solanacearum can survive and remain active in the deep soil for a long time, and the chemical control of tomato bacterial wilt is consequently limited. In this study, we introduced the characteristics of tomato bacterial wilt disease and the types of R. solanacearum, and systematically reviewed the research progresses of biological control methods from the aspects of botanical insecticides, agricultural antibiotics, biocontrol bacteria. We emphatically introduced the principle and current status of these methods, discussed the limitations and the improvement strategies, and prospected a new environmental protection and efficient biological control system based on micro-ecological regulation would be the development direction of biological control of tomato bacterial wilt.

Migrasome: a new functional extracellular vesicle.

Migrasome is a novel cellular organelle produced during cell migration, and its biogenesis depends on the migration process. It is generated in a variety of cells such as immune cells, metastatic tumor cells, other special functional cells like podocytes and cells in developing organisms. It plays important roles in various fields especially in the information exchange between cells. The discovery of migrasome, as an important supplement to the extracellular vesicle system, provides new mechanisms and targets for comprehending various biological or pathological processes. In this article, we will review the discovery, structure, distribution, detection, biogenesis, and removal of migrasomes and mainly focus on summarizing its biological functions in cell-to-cell communication, homeostatic maintenance, embryonic development and multiple diseases. This review also creates prospects for the possible research directions and clinical applications of migrasomes in the future.

Reconstruction of Nasal Tip Using "Seagull-shaped" Cavum Concha Cartilage Composite Scaffold.

BACKGROUND: The nasal tip plays a crucial role both esthetically and functionally. The application of nasal tip grafts is an effective method for improving nasal tip form. Ear cartilage is a common choice for nasal tip grafts, but it still presents several challenges in clinical application that need to be addressed. This study aims to address the issues associated with the use of ear cartilage in clinical rhinoplasty applications through the development of a novel septal extension graft using ear cartilage for nasal tip reconstruction. METHODS: From May 2018 to April 2022, a total of 132 cases of nasal tip reconstruction surgeries were performed using a seagull-shaped nasal septum extension graft, constructed with bilateral cavum concha cartilage. Among these cases, 25 patients had previously undergone rhinoplasty using silicone implant, 7 patients had undergone augmentation rhinoplasty using expanded polytetrafluoroethylene, whereas the rest were primary rhinoplasty cases. All patients were followed up for a period ranging from 3 months to 4 years postoperatively, with photographs taken to assess the nasal tip morphology. RESULTS: In this study, all patients exhibited good healing of the incisions made at the posterior aspect of the auricular concha, with no occurrences of hematoma and inconspicuous scarring. In 116 cases, significant improvement in nasal appearance and a realistic nasal tip form were achieved postoperatively, yielding satisfactory outcomes. Only 16 patients experienced minor issues with nasal tip morphology, which were subsequently improved through further surgical procedures. CONCLUSION: This study reports a surgical technique for nasal tip refinement using bilaterally harvested cavum concha cartilage to construct a seagull-shaped nasal septal extension graft. The procedure has achieved satisfactory outcomes, and its application is worth extending to clinical practice.

Shape-Memory Three-Dimensional Evaporators with High Portability for Efficient Solar-Driven Freshwater Production.

Solar-driven water evaporation can alleviate the severe water scarcity situation in a nonpolluting and sustainable manner. Although the design of integrated three-dimensional (3D) solar evaporators has been proven to be effective in achieving ultrahigh evaporation rates and energy efficiency, their scalable application is still hindered by complex manufacturing processes and poor portability. Herein, we report a highly portable shape-memory 3D solar evaporator by depositing MXene on low-cost lignin-cellulosic sponges for freshwater production. When not in use, the 3D evaporator can be compressed into a thin film with up to 89.3% volume reduction, ensuring minimal space occupation and high portability. When needed, due to the shape-memory effect, the 3D structure can be rapidly restored by swelling the compressed film in water, resulting in an efficient 3D solar evaporator. This 3D evaporator exhibits not only a high evaporation rate of 2.48 kg m-2 h-1 under 1 sun illumination but also excellent long-term stability and recyclability. In addition, the 3D evaporator itself can serve as a water reservoir without requiring a continuous water supply during evaporation, showing remarkable application flexibility. This work opens a new perspective for manufacturing highly portable and efficient 3D solar evaporators and may facilitate their progress from the laboratory to commercial applications.

Behavioural Variant Frontotemporal Dementia due to CCNF Gene Mutation: A Case Report.

BACKGROUND: Frontal, temporal lobe dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative diseases. Studies have found that CCNF mutations have been found in patients with familial and sporadic ALS and FTD. Behavioural variant frontotemporal dementia (bvFTD) is a clinical syndrome characterized by progressive deterioration of personality, social behaviour, and cognitive function, which is most closely related to genetic factors. As the early symptoms of bvFTD are highly heterogeneous, the condition is often misdiagnosed as Alzheimer's disease or psychiatric disorders. In this study, a bvFTD patient had a CCNF gene mutation, which led to ubiquitinated protein accumulation and ultimately caused neurodegenerative disease. Genetic detection should be improved urgently for bvFTD patients and family members to provide a clinical reference for early diagnosis of frontotemporal dementia. CASE PRESENTATION: In this case, the patient was 65 years old with an insidious onset, early-onset memory loss, a significant decline in the episodic memory, an early AD diagnosis, and oral treatment with donepezil hydrochloride for 3 years with poor efficacy, followed by a change to oral memantine hydrochloride tablets, which controlled the condition for several months. His medication was switched to sodium oligomannate capsules, and his condition was gradually controlled, but no significant improvement was observed. After spontaneous drug withdrawal, the patient's condition progressed rapidly; therefore, he visited our hospital and underwent neuropsychological tests for moderate to severe cognitive impairment. AD cerebrospinal fluid markers showed no significant abnormalities, and cranial MRI revealed frontotemporal lobe atrophy and decreased hippocampal volume. Genetic testing for the presence of the CCNF gene revealed a c.1532C > A (p. T511N) heterozygous variant, which might be a diagnostic criterion for bvFTD. Therefore, the patient's symptoms recurred after transient improvement with the combination of donepezil, oral memantine hydrochloride tablets, and sodium oligomannate, but his overall condition was improved compared to that before, and this treatment regimen was continued to observe changes during the follow-up. CONCLUSION: The early clinical manifestations of bvFTD are complex and variable, and the condition is easily misdiagnosed, thus delaying treatment. Therefore, for patients with a high clinical suspicion of FTD, in addition to a detailed understanding of their medical history and family history and improvement of relevant examinations, genetic testing should be performed as early as possible to help confirm the diagnosis. For diseases closely related to genes, genetic testing of other family members should be optimised as much as possible to allow early diagnosis and intervention and guide fertility in the next generation.

ATR-binding lncRNA ScaRNA2 promotes cancer resistance through facilitating efficient DNA end resection during homologous recombination repair.

BACKGROUND: Our previous study first showed that ATR-binding long noncoding RNA (lncRNA) is necessary for ATR function and promotes cancer resistance. However, the specific lncRNAs instrumental in ATR activation remain largely unclear, which limits our comprehensive understanding of this critical biological process. METHODS: RNA immunoprecipitation (RIP) followed by RNA sequencing was employed to identify ATR-binding lncRNAs, which were further validated using RIP-qPCR assays. Immunofluorescence staining and Western blotting were applied to detect the activation of DNA damage repair factors. After the effect of scaRNA2 on cellular sensitivity to DNA-damaging reagents was determined, the effects of scaRNA2 on radiotherapy were investigated in patient-derived organoids and xenograft preclinical models. The clinical relevance of scaRNA2 was also validated in tissues isolated from rectal cancer patients. RESULTS: ScaRNA2 was identified as the most enriched ATR-binding lncRNA and was found to be essential for homologous recombination (HR) mediated DNA damage repair. Furthermore, scaRNA2 knockdown abrogated the recruitment of ATR and its substrates in response to DNA damage. Mechanistically, scaRNA2 was observed to be necessary for Exo1-mediated DNA end resection and bridged the MRN complex to ATR activation. Knockdown of scaRNA2 effectively increased the sensitivity of cancer cells to multiple kinds of DNA damage-related chemoradiotherapy. Preclinically, knockdown of scaRNA2 improved the effects of radiotherapy on patient-derived organoids and xenograft models. Finally, an increase in scaRNA2 colocalized with ATR was also found in clinical patients who were resistant to radiotherapy. CONCLUSIONS: ScaRNA2 was identified as the most abundant lncRNA bound to ATR and was demonstrated to bridge DNA end resection to ATR activation; thus, it could be applied as a potent target for combined cancer treatments with chemoradiotherapy.

SENP5 promotes homologous recombination-mediated DNA damage repair in colorectal cancer cells through H2AZ deSUMOylation.

BACKGROUND: Neoadjuvant radiotherapy has been used as the standard treatment of colorectal cancer (CRC). However, radiotherapy resistance often results in treatment failure. To identify radioresistant genes will provide novel targets for combined treatments and prognostic markers. METHODS: Through high content screening and tissue array from CRC patients who are resistant or sensitive to radiotherapy, we identified a potent resistant gene SUMO specific peptidase 5 (SENP5). Then, the effect of SENP5 on radiosensitivity was investigated by CCK8, clone formation, comet assay, immunofluorescence and flow cytometric analysis of apoptosis and cell cycle to investigate the effect of SENP5 on radiosensitivity. SUMO-proteomic mass spectrometry combined with co-immunoprecipitation assay were used to identify the targets of SENP5. Patient-derived organoids (PDO) and xenograft (PDX) models were used to explore the possibility of clinical application. RESULTS: We identified SENP5 as a potent radioresistant gene through high content screening and CRC patients tissue array analysis. Patients with high SENP5 expression showed increased resistance to radiotherapy. In vitro and in vivo experiments demonstrated that SENP5 knockdown significantly increased radiosensitivity in CRC cells. SENP5 was further demonstrated essential for efficient DNA damage repair in homologous recombination (HR) dependent manner. Through SUMO mass spectrometry analysis, we characterized H2AZ as a deSUMOylation substrate of SENP5, and depicted the SUMOylation balance of H2AZ in HR repair and cancer resistance. By using PDO and PDX models, we found targeting SENP5 significantly increased the therapeutic efficacy of radiotherapy. CONCLUSION: Our findings revealed novel role of SENP5 in HR mediated DNA damage repair and cancer resistance, which could be applied as potent prognostic marker and intervention target for cancer radiotherapy.