Isolation and Diverse Reactivity of an Unsymmetrical 1,2-Bis(silylene)-Stabilized Pentacarbonyl Chromium(0) Species.

The construction of the unsymmetrical 1,2-bis(silylene) pentacarbonyl chromium(0) complex 1 was achieved through the reaction of chlorosilylene with half an equivalent of K2Cr(CO)5. X-ray diffraction analysis of 1 confirms the formation of the Si-Si bond and the coordination of one of the silicon atoms to the Cr center. Density functional theory (DFT) calculations disclose that highest occupied molecular orbital (HOMO) mainly corresponds to the lone pair of electrons on the silicon atom and the σ-bonding interaction between two Si atoms. Based on its unique electronic structure, its diverse reactivity toward the transition metal compounds and small molecules was investigated in detail. The reactions of 1 with Fe2(CO)9 or CuCl yielded the 1,2-bis(silylene)-stabilized heterobimetallic complex 2 or oxidized product 3, respectively. Additionally, treatments of 1 with selenium, CO2, or Me3SiN3 led to the formation of the corresponding selenium-, oxo-, and nitrogen-bridged complexes 4-7. All compounds were characterized by multinuclear NMR spectroscopy and X-ray crystallography.

Establishment of LC-MS/MS Methodology for the Determination of Rapamycin Concentration in Rat Whole Blood.

BACKGROUND: The establishment and validation of methods for testing biological samples are crucial steps in pharmacokinetic studies. Currently, several methodological reports have been published on the detection of rapamycin plasma concentrations. OBJECTIVE: The objective of this study was to explore an effective method for detecting rapamycin in rat whole blood biological samples. METHOD: In this study, we designed a rapid, sensitive, and specific liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS) methodology for detecting rapamycin in rat whole blood biological samples. We comprehensively validated the specificity, linear range, lower limit of quantification (LLOQ), precision, accuracy, recovery, and stability of this method. RESULTS: The findings of this study confirmed the successful implementation of LC-MS/MS for the detection of rapamycin, demonstrating its sensitivity, specificity, and reliability in quantitative analysis. This method ensures the accuracy and reliability of subsequent study data through our validated LC-MS/MS approach. CONCLUSION: The results demonstrated the successful implementation of an LC-MS/MS method for sensitive, specific, and reliable quantitative analysis of rapamycin in rat whole blood samples. This method ensures the accuracy and reliability of subsequent study data. SIGNIFICANCE: The importance of this study lies in the successful establishment of a rapid, sensitive, and specific LC-MS/MS method for detecting rapamycin concentration in rat whole blood, ensuring the accuracy and reliability of subsequent research data. This provides a crucial tool and foundation for further understanding the metabolism and pharmacological effects of rapamycin in vivo, aiding in the advancement of drug research and clinical applications in related fields.

Role of extracellular vesicle-associated proteins in the progression, diagnosis, and treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, characterized by difficulties in early diagnosis, prone to distant metastasis, and high recurrence rates following surgery. Extracellular vesicles (EVs) are a class of cell-derived particles, including exosomes, characterized by a phospholipid bilayer. They serve as effective carriers for intercellular communication cargo, including proteins and nucleic acids, and are widely involved in tumor progression. They are being explored as potential tumor biomarkers and novel therapeutic avenues. We provide a brief overview of the biogenesis and characteristics of EVs to better understand their classification standards. The focus of this review is on the research progress of EV-associated proteins in the field of HCC. EV-associated proteins are involved in tumor growth and regulation in HCC, participate in intercellular communication within the tumor microenvironment (TME), and are implicated in events including angiogenesis and epithelial-mesenchymal transition (EMT) during tumor metastasis. In addition, EV-associated proteins show promising diagnostic efficacy for HCC. For the treatment of HCC, they also demonstrate significant potential including enhancing the efficacy of tumor vaccines, and as targeting cargo anchors. Facing current challenges, we propose the future directions of research in this field. Above all, research on EV-associated proteins offers the potential to enhance our comprehension of HCC and offer novel insights for developing new treatment strategies.

All-natural aerogel of nanoclay/cellulose nanofibers with hierarchical porous structure for rapid hemostasis.

Developing an effective and user-friendly hemostatic agent is highly desired in the treatment of hemorrhage. Inspired by the natural nanostructure and abundant hydroxyl groups of cellulose and clay minerals, we designed an aerogel (HNTs/TOCNs) composed of halloysite nanotubes (HNTs) and TEMPO-oxidized cellulose nanofibers (TOCNs) with a hierarchical porous structure for the treatment of bleeding, using a simple and environmentally friendly self-assembly method. TOCNs formed a three-dimensional porous scaffold with excellent water-holding capacity. The incorporation of HNTs enhanced the hemostatic efficiency and mechanical properties of the 3D framework. The large interlayer spaces and wide channels within the HNTs/TOCNs aerogel provided rapid passage for blood, facilitating blood concentration and offering ample room for interactions between the HNTs/TOCNs aerogel and platelets, erythrocytes, and coagulation factors, thereby promoting hemostasis. Benefiting from the natural hemostatic properties and well-designed structure, the HNTs/TOCNs aerogel displayed excellent hemostatic performance both in vitro and in vivo. Notably, the hemostatic time of HNTs/TOCNs-2 was only 74 ± 8 s, which is approximately 50 % shorter than the blank control (151 ± 20 s) in liver femoral artery injury model. This design of an HNTs/TOCNs aerogel presents a unique opportunity to enhance hemostatic efficacy by synergizing the advantages of natural materials.

Dosage sensitivity shapes balanced expression and gene longevity of homoeologs after whole-genome duplications in angiosperms.

Following whole-genome duplication (WGD), duplicate gene pairs (homoeologs) can evolve varying degrees of expression divergence. However, the determinants influencing these relative expression level differences (RFPKM) between homoeologs remain elusive. Here, we analyzed the RFPKM between homoeologs in three angiosperms, Nymphaea colorata, Nelumbo nucifera, and Acorus tatarinowii, all having undergone a single WGD since the origin of angiosperms. Our results show significant positive correlations in RFPKM of homoeologs among tissues within the same species, and among orthologs across these three species, indicating convergent expression balance/bias between homoeologous gene copies following independent WGDs. We linked RFPKM between homoeologs to gene attributes associated with dosage balance constraints, such as protein-protein interactions, lethal-phenotype scores in Arabidopsis (Arabidopsis thaliana) orthologs, domain numbers, and expression breadth. Notably, homoeologs with lower RFPKM often had more interactions and higher lethal-phenotype scores, indicating selective pressures favoring balanced expression. Also, homoeologs with lower RFPKM were more likely to be retained after WGDs in angiosperms. Within Nelumbo, greater RFPKM between homoeologs correlated with increased cis- and trans-regulatory differentiation between species, highlighting the ongoing escalation of gene expression divergence. We further found that expression degeneration in one copy of homoeologs is inclined towards nonfunctionalization. Our research highlights the importance of balanced expression, shaped by dosage balance constraints, in the evolutionary retention of homoeologs in plants.

Altered memory CCR6+ Th17-polarised T-cell function and biology in people with HIV under successful antiretroviral therapy and HIV elite controllers.

BACKGROUND: Despite successful antiretroviral therapy (ART), frequencies and immunological functions of memory CCR6+ Th17-polarised CD4+ T-cells are not fully restored in people with HIV (PWH). Moreover, long-lived Th17 cells contribute to HIV persistence under ART. However, the molecular mechanisms underlying these observations remain understudied. METHODS: mRNA-sequencing was performed using Illumina technology on freshly FACS-sorted memory CCR6+CD4+ T-cells from successfully ART-treated (ST), elite controllers (EC), and uninfected donors (HD). Gene expression validation was performed by RT-PCR, flow cytometry, and in vitro functional assays. FINDINGS: Decreased Th17 cell frequencies in STs and ECs versus HDs coincided with reduced Th17-lineage cytokine production in vitro. Accordingly, the RORγt/RORC2 repressor NR1D1 was upregulated, while the RORγt/RORC2 inducer Semaphorin 4D was decreased in memory CCR6+ T-cells of STs and ECs versus HDs. The presence of HIV-DNA in memory CCR6+ T-cells of ST and EC corresponded with the downregulation of HIV restriction factors (SERINC3, KLF3, and RNF125) and HIV inhibitors (tetraspanins), along with increased expression of the HIV-dependency factor MRE11, indicative of higher susceptibility/permissiveness to HIV-1 infection. Furthermore, markers of DNA damage/modification were elevated in memory CCR6+ T-cells of STs and ECs versus HDs, in line with their increased activation (CD38/HLA-DR), senescence/exhaustion phenotype (CTLA-4/PD-1/CD57) and their decreased expression of proliferation marker Ki-67. INTERPRETATION: These results reveal new molecular mechanisms of Th17 cell deficit in ST and EC PWH despite a successful control of HIV-1 replication. This knowledge points to potential therapeutic interventions to limit HIV-1 infection and restore frequencies, effector functions, and senescence/exhaustion in Th17 cells. FUNDING: This study was funded by the Canadian Institutes of Health Research (CIHR, operating grant MOP 142294, and the Canadian HIV Cure Enterprise [CanCURE 2.0] Team Grant HB2 164064), and in part, by the Réseau SIDA et maladies infectieuses du Fonds de recherche du Québec-Santé (FRQ-S).

Immunotherapies targeting the oncogenic fusion gene CLDN18-ARHGAP in gastric cancer.

The CLDN18-ARHGAP fusion gene is an oncogenic driver newly discovered in gastric cancer. It was detected in 9% (8/87) of gastric cancer patients in our center. An immunogenic peptide specifically targeting CLDN18-ARHGAP fusion gene was generated to induce neoantigen-reactive T cells, which was proved to have specific and robust anti-tumor capacity both in in vitro coculture models and in vivo xenograft gastric cancer models. Apart from the immunogenic potential, CLDN18-ARHGAP fusion gene was also found to contribute to immune suppression by inducing a regulatory T (Treg) cell-enriched microenvironment. Mechanistically, gastric cancer cells with CLDN18-ARHGAP fusion activate PI3K/AKT-mTOR-FAS signaling, which enhances free fatty acid production of gastric cancer cells to favor the survival of Treg cells. Furthermore, PI3K inhibition could effectively reverse Treg cells upregulation to enhance anti-tumor cytotoxicity of neoantigen-reactive T cells in vitro and reduce tumor growth in the xenograft gastric cancer model. Our study identified the CLDN18-ARHGAP fusion gene as a critical source of immunogenic neoepitopes, a key regulator of the tumor immune microenvironment, and immunotherapeutic applications specific to this oncogenic fusion.

Comparison and use of explainable machine learning-based survival models for heart failure patients.

Objective: Explainable machine learning (XAI) was introduced in this study to improve the interpretability, explainability and transparency of the modelling results. The survex package in R was used to interpret and compare two survival models - the Cox proportional hazards regression (coxph) model and the random survival forest (rfsrc) model - and to estimate overall survival (OS) and its determinants in heart failure (HF) patients using these models. Methods: We selected 1159 HF patients hospitalised at the First Affiliated Hospital of Kunming Medical University. First, the performance of the two models was investigated using the C-index, the integrated C/D AUC, and the integrated Brier score. Second, a global explanation of the whole cohort was carried out using the time-dependent variable importance and the partial dependence survival profile. Finally, the SurvSHAP(t) and SurvLIME plots and the ceteris paribus survival profile were used to obtain a local explanation for each patient. Results: By comparing the C-index, the C/D AUC, and the Brier score, this study showed that the model performance of rfsrc was better than coxph. The global explanation of the whole cohort suggests that the C-reactive protein, lg BNP (brain natriuretic peptide), estimated glomerular filtration rate, albumin, age and blood chloride were significant unfavourable predictors of OS in HF patients in both the cxoph and the rfsrc models. By including individual patients in the model, we can provide a local explanation for each patient, which guides the clinician in individualising the patient's treatment. Conclusion: By comparison, we conclude that the model performance of rfsrc is better than that of coxph. These two predictive models, which address not only the whole population but also selected patients, can help clinicians personalise the treatment of each HF patient according to his or her specific situation.

The role of amino acid metabolism alterations in acute ischemic stroke: From mechanism to application.

Acute ischemic stroke (AIS) is the most prevalent type of stroke, and due to its high incidence, disability rate, and mortality rate, it imposes a significant burden on the health care system. Amino acids constitute one of the most crucial metabolic products within the human body, and alterations in their metabolic pathways have been identified in the microenvironment of AIS, thereby influencing the pathogenesis, severity, and prognosis of AIS. The amino acid metabolism characteristics in AIS are complex. On one hand, the dynamic progression of AIS continuously reshapes the amino acid metabolism pattern. Conversely, changes in the amino acid metabolism pattern also exert a double-edged effect on AIS. This interaction is bidirectional, dynamic, heterogeneous, and dose-specific. Therefore, the distinctive metabolic reprogramming features surrounding amino acids during the AIS process are systematically summarized in this paper, aiming to provide potential investigative strategies for the early diagnosis, treatment approaches, and prognostic enhancement of AIS.

Relationship between low molecular weight heparin calcium therapy and prognosis in severe acute kidney injury in sepsis: Mendelian randomized analysis and retrospective study.

Background: Sepsis-associated acute kidney injury (SA-AKI) poses an independent risk for mortality due to the absence of highly sensitive biomarkers and a specific treatment plan. Objective: Investigate the association between low molecular weight heparin (LMWH) calcium therapy and prognosis in critically ill SA-AKI patients, and assess the causal relationship through Mendelian randomization (MR) analysis. Methods: A single-center, retrospective, cross-sectional study included 90 SA-AKI patients and 30 septic patients without acute kidney injury (AKI) from the intensive care unit (ICU) of the First Hospital of Lanzhou University. SA-AKI patients were categorized into control or LMWH groups based on LMWH calcium usage. Primary outcome was renal function recovery, with secondary outcomes including 28-day mortality, ICU stay length, number of renal replacement therapy (RRT) recipients, and 90-day survival. MR and related sensitivity analyses explored causal effects. Results: The combination of heparin-binding protein (HBP), heparanase (HPA), and neutrophil gelatinase-associated lipocalin (NGAL) demonstrated high diagnostic value for SA-AKI. MR analysis suggested a potential causal link between gene-predicted HBP and AKI (OR: 1.369, 95%CI: 1.040-1.801, p = 0.024). In the retrospective study, LMWH-treated patients exhibited improved renal function, reduced levels of HPA, HBP, Syndecan-1, and inflammation, along with enhanced immune function compared to controls. However, LMWH did not impact 28-day mortality, 90-day survival, or ICU stay length. Conclusion: LMWH could enhance renal function in SA-AKI patients. MR analysis supports this causal link, underscoring the need for further validation in randomized controlled trials.

Fe doping enhanced Cr(VI) adsorption efficiency of cerium-based adsorbents: Adsorption behaviors and inner removal mechanisms.

Cerium-based adsorbents possessed unique advantages of valence variability and abundant oxygen vacancies in hexavalent chromium (Cr(VI)) adsorption, but high cost and unstable properties restricted their application in Cr(VI) contained wastewater treatment. Herein, a series of bimetallic adsorbents with different cerium/iron ratios (CeFe@C) were prepared by adding inexpensive Fe into Ce-based adsorbents (Ce@C), and the effect of Fe doping on adsorption properties of Ce@C for Cr(VI) was investigated thoroughly. Compared with pristine Ce@C, CeFe@C exhibited excellent removal performance for Cr(VI), and the improved maximum adsorption capacity reached 75.11 mg/g at 25℃. Benefiting from Fe doping, CeFe@C had good regeneration property, with only 25 % decrease after five adsorption-desorption cycles. Contents of trivalent cerium (Ce(III)) and oxygen vacancies (Ov) in bimetallic adsorbents were positively correlated with divalent iron (Fe(II)) doping, indicating that the formation of Ce(III) and surface defects on Ce@C could be effectively regulated by Fe doping. Density functional theory (DFT) calculation results further proved that the doped Fe enhanced the electron transfer effectively and lowered the energy barriers of Cr(VI) adsorption onto Ce@C surface, strengthening the reduction and complexation to Cr(VI). This study provides new insights for improving the Cr(VI) removal performance by modified Ce-based adsorbents, and further promotes the utilization potentiality of low-cost and low-toxicity Ce-based adsorbents in Cr(VI)-containing wastewater treatment.

Glycoengineering-based anti-PD-1-iRGD peptide conjugate boosts antitumor efficacy through T cell engagement.

Despite the important breakthroughs of immune checkpoint inhibitors in recent years, the objective response rates remain limited. Here, we synthesize programmed cell death protein-1 (PD-1) antibody-iRGD cyclic peptide conjugate (αPD-1-(iRGD)2) through glycoengineering methods. In addition to enhancing tissue penetration, αPD-1-(iRGD)2 simultaneously engages tumor cells and PD-1+ T cells via dual targeting, thus mediating tumor-specific T cell activation and proliferation with mild effects on non-specific T cells. In multiple syngeneic mouse models, αPD-1-(iRGD)2 effectively reduces tumor growth with satisfactory biosafety. Moreover, results of flow cytometry and single-cell RNA-seq reveal that αPD-1-(iRGD)2 remodels the tumor microenvironment and expands a population of "better effector" CD8+ tumor infiltrating T cells expressing stem- and memory-associated genes, including Tcf7, Il7r, Lef1, and Bach2. Conclusively, αPD-1-(iRGD)2 is a promising antibody conjugate therapeutic beyond antibody-drug conjugate for cancer immunotherapy.

A data-driven method for estimating sewer inflow and infiltration based on temperature and conductivity monitoring.

Quantitation of sewer inflow and infiltration (I/I) is important for maintaining efficient wastewater transport and treatment. I/I flows can be quantified based on flow rate and water quality measurements. Flow rate-based methods require continuous monitoring of flow rates using flow meters that are costly and prone to fouling. In comparison, conductivity and temperature, as simple water quality parameters, are more easily measurable with more cost-effective and reliable sensors. In this study, a data-driven methodology is developed for estimating I/I flows based on online conductivity and temperature measurements. A Prophet-model-based analytic algorithm is first developed to reconstruct the temperature and conductivity profiles of the base wastewater flow (BWF) from the measured temperature and conductivity time series. The algorithm is shown to be able to reconstruct the BWF temperature and conductivity profiles in two monitored catchments. The reconstructed BWF data are then incorporated into mass/energy balance equations for estimating I/I flows from the measured temperature and conductivity data. The overall I/I quantification method is finally demonstrated using simulation studies of a real-life sewer network and validated against the known I/I flows. This work provides a reliable method for I/I quantification based on simple measurements.

CTRP9 Promotes Brown Adipose Tissue Lipolysis in Mice Fed a High-Fat Diet.

BACKGROUND: This study aimed to elucidate the molecular mechanism through which C1q/tumor necrosis factor (TNF)-related protein 9 (CTRP9) acts in the formation and differentiation of brown adipose tissue (BAT). METHODS: Adenovirus particles encoding CTRP9 and green fluorescent protein were inoculated into the scapula of C57BL/6J mice and fed a high-fat diet for 8 weeks; the body weight, lipid droplet morphology, glucose tolerance, insulin tolerance, and protein expression levels were analyzed. In addition, CTRP9 adenovirus was transfected into brown preadipocytes, and differentiation was induced to identify the effect of CTRP9 overexpression on adipocyte differentiation. RESULTS: CTRP9 overexpression significantly increased the weight gain of mice. Additionally, the CTRP9 overexpression group exhibited significantly increased adipose tissue weight and glucose clearance rates and decreased insulin sensitivity and serum triglyceride levels compared to the control group. Furthermore, CTRP9 overexpression significantly upregulated the adipose triglyceride lipase (ATGL) and perilipin 1 protein expression levels in BAT. The cell experiment results confirmed that CTRP9 overexpression significantly inhibited the adipogenesis of brown adipocytes as evidenced by the downregulation of uncoupling protein 1, beta-3 adrenergic receptor, ATGL, and hormone-sensitive lipase mRNA levels and the significant suppression of uncoupling protein 1, ATGL, and perilipin 1 protein levels in brown adipocytes. CONCLUSIONS: The finding of this study demonstrated that CTRP9 promotes lipolysis by upregulating ATGL expression in vivo and inhibits the differentiation of brown preadipocytes in vitro.

Predictive value of bone turnover markers and thyroid indicators for bone metabolism in GD patients after treatment.

Purpose: To investigate the relationship between bone turnover markers (BTMs) and thyroid indicators in Graves' disease (GD) and to further assess predictive value of changes in early stage retrospectively. Methods: We studied 435 patients with GD and 113 healthy physical examiners retrospectively and followed up these two groups of patients after 6 months. We investigated the correlations between BTMs and other 15 observed factors, and analyzed the predictive value of FT3 and FT4 before and after treatment (FT3-P/FT3-A, FT4-P/FT4-A) on whether BTMs recovered. Results: The levels of thyroid hormones and BTMs in GD group were significantly higher than those in control group (P < 0.05) and decreased after 6 months of treatment. FT3, W, Ca and ALP were independent factors in predicting the elevation of OST. Duration of disease, FT3, TSH and ALP were independent factors in predicting the elevation of P1NP. Age, duration of disease, TRAb and ALP were independent factors in predicting the elevation of CTX-1. The AUC of FT3-P/FT3-A and FT4-P/FT4-A for predicting OST recovery were 0.748 and 0.705 (P < 0.05), respectively, and the cut-off values were 0.51 and 0.595. There was no predictive value for P1NP and CTX-1 recovery (P > 0.05). Conclusion: BTMs were abnormally elevated in GD and were significantly correlated with serum levels of FT3, FT4, TRAb, Ca, and ALP. FT3 decreased more than 51% and FT4 dropped more than 59.5% after 6 months of treatment were independent predictors for the recovery of BTMs in GD.

Spatially resolved transcriptomic profiling of placental development in dairy cow.

The placenta plays a crucial role in successful mammalian reproduction. Ruminant animals possess a semi-invasive placenta characterized by a highly vascularized structure formed by maternal endometrial caruncles and fetal placental cotyledons, essential for full-term fetal development. The cow placenta harbors at least two trophoblast cell populations: uninucleate (UNC) and binucleate (BNC) cells. However, the limited capacity to elucidate the transcriptomic dynamics of the placental natural environment has resulted in a poor understanding of both the molecular and cellular interactions between trophoblast cells and niches, and the molecular mechanisms governing trophoblast differentiation and functionalization. To fill this knowledge gap, we employed Stereo-seq to map spatial gene expression patterns at near single-cell resolution in the cow placenta at 90 and 130 days of gestation, attaining high-resolution, spatially resolved gene expression profiles. Based on clustering and cell marker gene expression analyses, key transcription factors, including YBX1 and NPAS2, were shown to regulate the heterogeneity of trophoblast cell subpopulations. Cell communication and trajectory analysis provided a framework for understanding cell-cell interactions and the differentiation of trophoblasts into BNCs in the placental microenvironment. Differential analysis of cell trajectories identified a set of genes involved in regulation of trophoblast differentiation. Additionally, spatial modules and co-variant genes that help shape specific tissue structures were identified. Together, these findings provide foundational insights into important biological pathways critical to the placental development and function in cows.

Highly Stable Polyaniline-Based Cathode Material Enabled by Phosphorene for Zinc-Ion Batteries with Superior Specific Capacity and Cycle Life.

Aqueous zinc-ion batteries (ZIBs) are regarded as a type of promising energy-storage device because of their high safety and low cost, and polyaniline (PANI) is normally employed as a cathode material for ZIBs owing to its unique electrochemical properties and high environmental stability. However, a low specific capacity and a short cycle life limit the development and applications of PANI-based electrodes. Herein, we have developed a novel type of highly stable PANI-based cathode material enabled by phosphene (PR) for aqueous Zn-PANI batteries through in situ chemical oxidative polymerization. The introduction of PR nanoflakes not only inhibits the degradation of PANI and generates more active sites for Zn2+ storage but also enables a synergistic effect of the Zn2+ insertion/extraction and P-Zn alloying reaction. This promotes a high reversible specific capacity of 240.2 mAh g-1 at 0.2 A g-1 and excellent rate performance for the PR/PANI nanocomposite cathode material. Compared to the pristine PANI cathode material, the PR/PANI nanocomposite cathode material is more suitable for the Zn-PANI battery, thanks to its higher specific capacity and better cycle stability. This study provides an innovative approach for developing the next generation of reliable PR-based electrode materials for aqueous energy-storage devices.

Effects of anti-osteoporosis treatment in elderly patients with osteoporosis and lumbar discectomy and fusion.

BACKGROUND: The effect of anti-osteoporosis treatment in elderly patients with osteoporosis and lumbar discectomy and fusion (LIF) for lumbar degenerative diseases is not well known. OBJECTIVE: This study aimed to evaluate the effect of perioperative anti-osteoporosis treatment in the patients with osteoporosis and LIF. METHODS: From January to December 2022, patients were divided into three groups according to the inclusive criteria: the normal group (Group A), the osteopenia group (Group B) and the osteoporosis group (Group C). Quantitative computed tomography (QCT), height of the intervertebral space (HIS), segmental sagittal angle (SSA), visual analogue scale (VAS) score and Oswestry Disability Index (ODI) were compared between the groups at the follow-up time. The serum Ca2 + , osteocalcin (OC), propeptide of type I procollagen (PINP) C-terminal cross-linking telopeptide of type I collagen (ß-CTX) and 25-OH vitamin D (25-OH VD) levels were compared between the groups at the time of follow-up. Interbody fusion was graded on the X-ray and CT images at the follow-up time. RESULTS: There were 165 patients in this study. There were significant differences in the mean age, mean score, HIS and SSA between the groups at the different follow-up times. There were significant differences in the concentrations of serum Ca2 + , OC, ß-CTX, 25-OH VD and PINP at the sixth month after surgery between the groups. There were significant differences in the concentrations of serum Ca2 + , ß-CTX and 25-OH VD between the pre-surgery and at six months after surgery in Group B and ß-CTX and 25-OH VD in Group C. There was a significant difference in the degree of fusion between Group B and C (χ2= 5.6243, P< 0.05). CONCLUSION: In elderly patients with LIF and osteoporosis, anti-osteoporosis therapy could reduce bone resorption and thus facilitate fusion. Anti-osteoporosis medication tends to enhance radiological, functional, and fusion short-term outcomes.

BLM helicase unwinds lagging strand substrates to assemble the ALT telomere damage response.

The Bloom syndrome (BLM) helicase is critical for alternative lengthening of telomeres (ALT), a homology-directed repair (HDR)-mediated telomere maintenance mechanism that is prevalent in cancers of mesenchymal origin. The DNA substrates that BLM engages to direct telomere recombination during ALT remain unknown. Here, we determine that BLM helicase acts on lagging strand telomere intermediates that occur specifically in ALT-positive cells to assemble a replication-associated DNA damage response. Loss of ATRX was permissive for BLM localization to ALT telomeres in S and G2, commensurate with the appearance of telomere C-strand-specific single-stranded DNA (ssDNA). DNA2 nuclease deficiency increased 5'-flap formation in a BLM-dependent manner, while telomere C-strand, but not G-strand, nicks promoted ALT. These findings define the seminal events in the ALT DNA damage response, linking aberrant telomeric lagging strand DNA replication with a BLM-directed HDR mechanism that sustains telomere length in a subset of human cancers.