α-Ketoglutarate plays an inflammatory inhibitory role by regulating scavenger receptor class a expression through N6-methyladenine methylation during sepsis.

Sepsis arises from an uncontrolled inflammatory response triggered by infection or stress, accompanied by alteration in cellular energy metabolism, and a strong correlation exists between these factors. Alpha-ketoglutarate (α-KG), an intermediate product of the TCA cycle, has the potential to modulate the inflammatory response and is considered a crucial link between energy metabolism and inflammation. The scavenger receptor (SR-A5), a significant pattern recognition receptor, assumes a vital function in anti-inflammatory reactions. In the current investigation, we have successfully illustrated the ability of α-KG to mitigate inflammatory factors in the serum of septic mice and ameliorate tissue damage. Additionally, α-KG has been shown to modulate metabolic reprogramming and macrophage polarization. Moreover, our findings indicate that the regulatory influence of α-KG on sepsis is mediated through SR-A5. We also elucidated the mechanism by which α-KG regulates SR-A5 expression and found that α-KG reduced the N6-methyladenosine level of macrophages by up-regulating the m6A demethylase ALKBH5. α-KG plays a crucial role in inhibiting inflammation by regulating SR-A5 expression through m6A demethylation during sepsis. The outcomes of this research provide valuable insights into the relationship between energy metabolism and inflammation regulation, as well as the underlying molecular regulatory mechanism.

The association between declining lung function and stroke risk: insights from an observational study and Mendelian randomization.

Background: Stroke, prevalent globally, particularly impacts low- and middle-income countries. Decreased lung function is one of the risk factors for stroke, and there is a lack of sufficient research on the association between the two, especially based on evidence from representative large samples. We aimed to explore the association between lung function and stroke incidence. Methods: We collected data from 13,371 participants from the 2007-2012 U.S. national cross-sectional study and 11,192 participants from the Chinese national cohort study during the 2011-2018 follow-up period. Multivariate logistic regression and Cox proportional hazards regression were used to assess cross-sectional and longitudinal associations of peak expiratory flow with stroke risks. Additionally, we used publicly available GWAS data from a European population to conduct Mendelian randomization analysis, further exploring the potential causal relationship. Results: The results of the cross-sectional study suggest that a decline in peak expiratory flow may be associated with an increased risk of stroke. The cohort study revealed that, compared to the first tertile group, the risk of stroke incidence in the second and third tertile groups of PEF decreased by 19% (hazard ratio (HR) = 0.810, 95%CI = 0.684-0.960) and 21.4% (HR = 0.786, 95%CI = 0.647-0.956), respectively. Mendelian randomization analysis clarified that higher PEF levels are significantly associated with a reduced risk of stroke (OR = 0.852, 95%CI = 0.727-0.997). Conclusion: Decreased lung function is a risk factor for stroke. As a simple and accurate indicator of lung function, PEF can be used to monitor lung function in community populations and patients for primary stroke prevention.

Petaloid Metal-Organic Frameworks for Resiquimod Delivery To Potentiate Antitumor Immunity.

The morphological features of materials significantly influence their interactions with cells, consequently affecting the cellular uptake of these materials. In this study, we examine the cellular uptake behavior of spherical metal-organic frameworks (MOFs) and petaloid MOFs, both possessing similar sizes and compositions. In comparison to spherical MOFs, dendritic cells (DCs) and macrophages exhibit superior phagocytic uptake of petaloid MOFs. Next, the results demonstrate that R848@petaloid MOFs more effectively promote the repolarization of tumor-associated macrophages (TAMs) from the M2 to M1 phenotype and the maturation of DCs. More importantly, the R848-loaded petaloid MOFs are found to significantly enhance the therapeutic effects of radiotherapy (RT) by eliciting antitumor responses. Furthermore, R848@petaloid MOFs combined with RT and αPD-L1 elicit a potent abscopal effect, effectively suppressing tumor metastasis. Therefore, this work proposes a new strategy to enhance the uptake of immunomodulators by immune cells through modulating the morphology of drug delivery carriers.

Polyphenols as Potential Antioxidants for the Treatment of Intervertebral Disc Degeneration.

Intervertebral disc degeneration (IDD) is a common musculoskeletal system disease, which is one of the most important causes of low back pain. Despite the high prevalence of IDD, current treatments are limited to relieving symptoms, and there are no effective therapeutic agents that can block or reverse the progression of IDD. Oxidative stress, the result of an imbalance between the production of reactive oxygen species (ROS) and clearance by the antioxidant defense system, plays an important role in the progression of IDD. Polyphenols are antioxidant compounds that can inhibit ROS production, which can scavenge free radicals, reduce hydrogen peroxide production, and inhibit lipid oxidation in nucleus pulposus (NP) cells and IDD animal models. In this review, we discussed the antioxidant effects of polyphenols and their regulatory role in different molecular pathways associated with the pathogenesis of IDD, as well as the limitations and future prospects of polyphenols as a potential treatment of IDD.

Equivalent analytical model for liquid sloshing in a 2-D rectangular container with multiple vertical baffles by subdomain partition approach.

An equivalent analytical model of sloshing in a two-dimensional (2-D) rigid rectangular container equipped with multiple vertical baffles is presented. Firstly, according to the subdomain partition approach, the total liquid domain is partitioned into subdomains with the pure interface and boundary conditions. The separation of variables is utilized to achieve the velocity potential for subdomains. Then, sloshing characteristics are solved according to continuity and free surface conditions. According to the mode orthogonality of sloshing, the governing motion equation for sloshing under horizontal excitation is given by introducing generalized time coordinates. Besides, by producing the same hydrodynamic shear and overturning moment as those from the original container-liquid-baffle system, a mass-spring analytical model of the continuous liquid sloshing is established. The equivalent masses and corresponding locations are presented in the model. The feasibility of the present approach is verified by conducting comparative investigations. Finally, by utilizing normalized equivalent model parameters, the sloshing behaviors of the baffled container are investigated regarding baffle positions and heights as well as the liquid height, respectively.

Lower ratio of IMPDH1 to IMPDH2 sensitizes gliomas to chemotherapy.

Gliomas are the most common primary tumors of the central nervous system, with approximately half of patients presenting with the most aggressive form of glioblastoma. Although several molecular markers for glioma have been identified, they are not sufficient to predict the prognosis due to the extensive genetic heterogeneity within glioma. Our study reveals that the ratio of IMPDH1 to IMPDH2 expression levels serves as a molecular indicator for glioma treatment prognosis. Patients with a higher IMPDH1/IMPDH2 ratio exhibit a worse prognosis, while those with a lower ratio display a more favorable prognosis. We further demonstrate that IMPDH1 plays a crucial role in maintaining cellular GTP/GDP levels following DNA damage compared to IMPDH2. In the absence of IMPDH1, cells experience an imbalance in the GTP/GDP ratio, impairing DNA damage repair capabilities and rendering them more sensitive to TMZ. This study not only introduces a novel prognostic indicator for glioma clinical diagnosis but also offers innovative insights for precise and stratified glioma treatment.

The ARK2N-CK2 complex initiates transcription-coupled repair through enhancing the interaction of CSB with lesion-stalled RNAPII.

Transcription is extremely important for cellular processes but can be hindered by RNA polymerase II (RNAPII) pausing and stalling. Cockayne syndrome protein B (CSB) promotes the progression of paused RNAPII or initiates transcription-coupled nucleotide excision repair (TC-NER) to remove stalled RNAPII. However, the specific mechanism by which CSB initiates TC-NER upon damage remains unclear. In this study, we identified the indispensable role of the ARK2N-CK2 complex in the CSB-mediated initiation of TC-NER. The ARK2N-CK2 complex is recruited to damage sites through CSB and then phosphorylates CSB. Phosphorylation of CSB enhances its binding to stalled RNAPII, prolonging the association of CSB with chromatin and promoting CSA-mediated ubiquitination of stalled RNAPII. Consistent with this finding, Ark2n-/- mice exhibit a phenotype resembling Cockayne syndrome. These findings shed light on the pivotal role of the ARK2N-CK2 complex in governing the fate of RNAPII through CSB, bridging a critical gap necessary for initiating TC-NER.

Independent and joint associations of monocyte to high-density lipoprotein-cholesterol ratio and body mass index with cardiorenal syndrome: insights from NHANES 2003-2020.

BACKGROUND: With the development of pathophysiology, cardiorenal syndrome (CRS), a complex and severe disease, has received increasing attention. Monocyte to high-density lipoprotein-cholesterol ratio (MHR) and body mass index (BMI) are independent risk factors for cardiovascular diseases, but their association with CRS remains unexplored. This study aims to explore the independent and joint effects of MHR and BMI on CRS. METHODS: We included 42,178 NHANES participants. The determination of CRS referred to the simultaneous presence of cardiovascular disease (identified through self-report) and chronic kidney disease (eGFR < 60 mL/min per 1.73 m²). We employed multivariate weighted logistic regression to evaluate the odds ratio (OR) and 95% confidence interval (CI) for the independent and joint associations of MHR and BMI with CRS. We also conducted restricted cubic spines to explore nonlinear associations. RESULTS: The prevalence of CRS was 3.45% among all participants. An increase in both MHR and BMI is associated with a higher risk of CRS (MHR: OR = 1.799, 95% CI = 1.520-2.129, P < 0.001, P-trend < 0.001; BMI: OR = 1.037, 95% CI = 1.023-1.051, P < 0.001). Individuals who simultaneously fall into the highest quartile of MHR and have a BMI of 30 or more face the highest risk of CRS compared to those in the lowest MHR quartile with a BMI of less than 25 (OR = 3.45, 95% CI = 2.40-4.98, P < 0.001). However, there is no interactive association between MHR and BMI with CRS. CONCLUSIONS: Higher MHR and BMI are associated with higher odds of CRS. MHR and BMI can serve as tools for early prevention and intervention of CRS, respectively.

Synergistic Development of Natural Rubber/Butyl Rubber Composites for Improved Interfacial Bonding and Enhanced Shock-Absorbing Capabilities.

Shock-absorbing materials play a vital role in various industrial sectors, including construction and transportation. Among these materials, natural rubber (NR) stands out due to its exceptional elastic and mechanical properties, coupled with its robust crack resistance. Nevertheless, with the rising demand for enhanced damping capacities, there is a need to further optimize the damping performance of NR. One direct approach is to blend it with high-damping rubber. Butyl rubber (IIR) is a prominent member of the high-damping rubber category. Integrating IIR effectively with the NR, however, presents challenges. These challenges arise from IIR's inherent characteristics, such as its low unsaturation, slower vulcanization rate, and restricted compatibility with NR. Addressing these challenges, our study employed isoprene and isobutene to synthesize a variant of butyl rubber with a higher degree of unsaturation-achieving an unsaturation level between 4 and 6 mol %. Notably, this heightened unsaturation significantly expedited the curing time of IIR and facilitated the concurrent vulcanization of both IIR and NR. Utilizing atomic force microscopy, we observed that the introduction of unsaturated double bonds ameliorated the compatibility between NR and IIR, leading to an interfacial region extending up to 1000 nm. Our tests using a dynamic mechanical analyzer and rubber processing analyzer demonstrated the material's damping temperature range. Furthermore, there was a noticeable rise in the loss factor (tan δ) at ambient temperature, which remains over 0.1 across both a frequency window of 0.2 to 5 Hz and a strain spectrum of 10 to 200%. This tan δ enhancement ensured the potential of these rubber composites for shock-absorbing applications.

Computer gaming alters resting-state brain networks, enhancing cognitive and fluid intelligence in players: evidence from brain imaging-derived phenotypes-wide Mendelian randomization.

The debate on whether computer gaming enhances players' cognitive function is an ongoing and contentious issue. Aiming to delve into the potential impacts of computer gaming on the players' cognitive function, we embarked on a brain imaging-derived phenotypes (IDPs)-wide Mendelian randomization (MR) study, utilizing publicly available data from a European population. Our findings indicate that computer gaming has a positive impact on fluid intelligence (odds ratio [OR] = 6.264, P = 4.361 × 10-10, 95% confidence interval [CI] 3.520-11.147) and cognitive function (OR = 3.322, P = 0.002, 95% CI 1.563-7.062). Out of the 3062 brain IDPs analyzed, only one phenotype, IDP NET100 0378, was significantly influenced by computer gaming (OR = 4.697, P = 1.10 × 10-5, 95% CI 2.357-9.361). Further MR analysis suggested that alterations in the IDP NET100 0378 caused by computer gaming may be a potential factor affecting fluid intelligence (OR = 1.076, P = 0.041, 95% CI 1.003-1.153). Our MR study lends support to the notion that computer gaming can facilitate the development of players' fluid intelligence by enhancing the connectivity between the motor cortex in the resting-state brain and key regions such as the left dorsolateral prefrontal cortex and the language center.

The structure of anthocyanins and the copigmentation by common micromolecular copigments: A review.

Under natural physiological conditions, anthocyanins can keep bright and stable color for a long time due to the relatively stable acid-base environment of plant vacuoles and the copigmentation from various copigment substances, such as polyphenols, nucleotides, metallic ions and other substances. Therefore, the copigmentation caused by copigments is considered an effective way to stabilize anthocyanins against adverse environmental conditions. This is attributed to the covalent and noncovalent interactions between colored forms of anthocyanins (flavylium ions and quinoidal bases) and colorless or pale yellow organic molecules (copigments). These interactions are usually manifested in both hyperchromic effect and bathochromic shifts. In addition to making anthocyanins more stable, the copigmentation also could make an important contribution to the diversification of their tone. Based on the molecular structure of anthocyanins, this review focuses on the interaction mode of auxochrome groups or copigments with anthocyanins and their effects on the chemical and color stability of anthocyanins.

Organoboron flank-substituted donor-acceptor polymer anode with ultra-long cycling stability for lithium ion batteries.

The tunable structure and other properties of organic materials suggest that they can potentially solve the shortcomings of traditional anodes such as graphite. We successfully introduced an organoboron unit into the thiophene-based polymer PBT-2 to construct a donor-acceptor polymer anode. The charge delocalization and LUMO energy level resulting from the unique structure of this material enabled good redox activity and a very stable electrochemical performance in electrochemical tests, with a reversible capacity of 262 mA h g-1 at 0.5 A g-1 and >10 000 cycles at 1 A g-1 with a decay of 0.056‰ per cycle. Accordingly, targeted structural design to overcome the shortcomings of active units such as thiophene can effectively regulate their electrochemical performance, providing a solution for the development of high-performance anode materials for use in lithium ion batteries.

PP2A inhibition causes synthetic lethality in BRCA2-mutated prostate cancer models via spindle assembly checkpoint reactivation.

Mutations in the BRCA2 tumor suppressor gene have been associated with an increased risk of developing prostate cancer. One of the paradoxes concerning BRCA2 is the fact that its inactivation affects genetic stability and is deleterious for cellular and organismal survival, while BRCA2-mutated cancer cells adapt to this detriment and malignantly proliferate. Therapeutic strategies for tumors arising from BRCA2 mutations may be discovered by understanding these adaptive mechanisms. In this study, we conducted forward genetic synthetic viability screenings in Caenorhabditis elegans brc-2 (Cebrc-2) mutants and found that Ceubxn-2 inactivation rescued the viability of Cebrc-2 mutants. Moreover, loss of NSFL1C, the mammalian ortholog of CeUBXN-2, suppressed the spindle assembly checkpoint (SAC) activation and promoted the survival of BRCA2-deficient cells. Mechanistically, NSFL1C recruited USP9X to inhibit the polyubiquitination of AURKB and reduce the removal of AURKB from the centromeres by VCP, which is essential for SAC activation. SAC inactivation is common in BRCA2-deficient prostate cancer patients, but PP2A inhibitors could reactivate the SAC and achieve BRCA2-deficient prostate tumor synthetic lethality. Our research reveals the survival adaptation mechanism of BRCA2-deficient prostate tumor cells and provides different angles for exploring synthetic lethal inhibitors in addition to targeting DNA damage repair pathways.

MBD1 protects replication fork stability by recruiting PARP1 and controlling transcription-replication conflicts.

The replication-stress response is essential to ensure the faithful transmission of genetic information to daughter cells. Although several stress-resolution pathways have been identified to deal with replication stress, the precise regulatory mechanisms for replication fork stability are not fully understood. Our study identified Methyl-CpG Binding Domain 1 (MBD1) as essential for the maintaining genomic stability and protecting stalled replication forks in mammalian cells. Depletion of MBD1 increases DNA lesions and sensitivity to replication stress. Mechanistically, we found that loss of MBD1 leads to the dissociation of Poly(ADP-ribose) polymerase 1 (PARP1) from the replication fork, potentially accelerating fork progression and resulting in higher levels of transcription-replication conflicts (T-R conflicts). Using a proximity ligation assay combined with 5-ethynyl-2'-deoxyuridine, we revealed that the MBD1 and PARP1 proteins were recruited to stalled forks under hydroxyurea (HU) treatment. In addition, our study showed that the level of R-loops also increased in MBD1-delated cells. Without MBD1, stalled replication forks resulting from T-R conflicts were primarily degraded by the DNA2 nuclease. Our findings shed light on a new aspect of MBD1 in maintaining genome stability and providing insights into the mechanisms underlying replication stress response.

Metabolic regulation of homologous recombination repair by MRE11 lactylation.

Lactylation is a lactate-induced post-translational modification best known for its roles in epigenetic regulation. Herein, we demonstrate that MRE11, a crucial homologous recombination (HR) protein, is lactylated at K673 by the CBP acetyltransferase in response to DNA damage and dependent on ATM phosphorylation of the latter. MRE11 lactylation promotes its binding to DNA, facilitating DNA end resection and HR. Inhibition of CBP or LDH downregulated MRE11 lactylation, impaired HR, and enhanced chemosensitivity of tumor cells in patient-derived xenograft and organoid models. A cell-penetrating peptide that specifically blocks MRE11 lactylation inhibited HR and sensitized cancer cells to cisplatin and PARPi. These findings unveil lactylation as a key regulator of HR, providing fresh insights into the ways in which cellular metabolism is linked to DSB repair. They also imply that the Warburg effect can confer chemoresistance through enhancing HR and suggest a potential therapeutic strategy of targeting MRE11 lactylation to mitigate the effects.

Reconstitution of the antagonistic effect between C1orf112/FIRRM-FIGNL1 and BRCA2 on RAD51 filament stabilization.

C1orf112/FIRRM is a recently identified DNA damage repair factor that regulates RAD51 in homologous recombination through interacting with the anti-recombinase FIGNL1. Here, we describe steps for purifying C1orf112/FIRRM, FIGNL1, miBRCA2, and RAD51 proteins from Escherichia coli or Saccharomyces cerevisiae cells. We then detail procedures for reconstituting the disassembly of RAD51 filament by C1orf112/FIRRM-FIGNL1 in vitro and the antagonistic effect between C1orf112/FIRRM-FIGNL1 and miBRCA2 on RAD51 filament stabilization. For complete details on the use and execution of this protocol, please refer to Zhou et al. (2023).1.

Energetic benefits in coordinated circular swimming motion of two swimmers.

The coordinated movement of multiple swimmers is a crucial component of fish schools. Fish swimming in different formations, such as tandem, side-by-side, diamond, and phalanx, can achieve significant energetic advantages. However, the energetic benefits of nonstraight swimming behaviors, such as the collective motion of a milling pattern, are not well understood. To fill in this gap, we consider two swimmers in circular tracks, controlled by a PID approach to reach stable configurations. Our study finds that the optimal phase is affected by circumferential effects, and that substantial energy savings can result from both propulsion and turning. We also explore the radial effect in terms of energetic benefits. In a milling pattern, the inner swimmers can easily gain a certain energetic benefit (-8%), while their peers on the outside must be close enough to the inner swimmer with a proper phase to gain the energetic benefit (-14%). When the radial spacing becomes larger or is in an unmatched phase, the swimming of the outer swimmers becomes more laborious (+16%). Our results indicate that swimmers who maintain a matched phase and minimum radial effect obtain the highest energetic benefits (-26%). These findings highlight the energetic benefits of swimmers, even in a milling pattern, where the position difference dominates the extent of benefit.

[Clinical research progress of spinal epidural lipomatosis].

Objective: To review the clinical research progress of spinal epidural lipomatosis (SEL). Methods: The clinical studies on SEL at home and abroad in recent years were extensively reviewed, and the pathogenesis, clinical and imaging manifestations, and treatment status of SEL were summarized and analyzed. Results: SEL is a disease characterized by compression of the spinal cord and nerve roots due to abnormal accumulation of epidural adipose tissue in the spinal canal. Its prevalence and diagnosis rate are low and the pathogenesis is not fully understood. MRI is the most sensitive and specific diagnostic test for SEL. Surgical decompression and removal of excess adipose tissue are the only options for patients with acute SEL or those who have failed conservative management, and conservative management should be considered for other patients. Conclusion: SEL is a rare disease and related research still needs to be improved. In the future, high-quality, multi-center and large-sample studies will be of great significance for evaluating the choice of treatment methods and effectiveness of SEL patients.

Quantification Characterization of Hierarchical Structure of Polyurethane by Advanced AFM and X-ray Techniques.

Polyurethane (PU) with microphase separation has garnered significant attention due to its highly designable molecular structure and a wide range of adjustable properties. However, there is currently a lack of systematic approaches for quantifying PU's microphase separation. To address this research gap, we utilized an atomic force microscopy (AFM) nanomechanical mapping technique along with Gaussian fitting to recolor and quantitatively analyze the evolution of PU's microphase separation. By varying the ratios of the chain extender to cross-linking agent, we observed the changes in the hydrogen bonding between the soft and hard segments. As the ratio of the chain extender to cross-linking agent decreases, the strength of the hydrogen bonding weakens, resulting in a reduction in the quantity and phase percentage of hard segment (HS) domains. Consequently, the degree of microphase separation between the soft and hard segments decreases, leading to specific alterations in the material's mechanical properties and dynamic viscoelasticity. To further investigate the hierarchical structure of PU, we employed various techniques, such as X-ray analysis, transmission electron microscopy (TEM), and AFM-based infrared spectroscopy (AFM-IR). Our findings reveal a spherulite pattern composed of lamellae within the HS domains, with the cross-linking density gradually increasing from the center to the periphery. Overall, our comprehensive characterization of PU provides valuable insights into its hierarchical structure and establishes a quantitative framework to explore the intricate relationship between the structure and properties.

Tert-butyl hydroperoxide induces ferroptosis of bone mesenchymal stem cells by repressing the prominin2/BACH1/ROS axis.

Ferroptosis has been proven critical for survival following bone marrow mesenchymal stem cells (BMSCs) explantation. Suppression of ferroptosis in BMSCs will be a valid tactic to elevate the therapeutic potential of engrafted BMSCs. Prominin2 is a pentaspanin protein involved in mediating iron efflux and thus modulates resistance to ferroptosis, but its role in tert-butyl hydroperoxide (TBHP)-induced BMSCs ferroptosis remains elusive. We examined the biological effect of prominin2 in vitro and in vivo by using cell proliferation assay, iron assay, reactive oxygen species (ROS) examination, malondialdehyde assay, glutathione (GSH) examination, Western blot, quantitative reverse transcription-PCR, immunofluorescence staining assay, gene expression inhibition and activation, co-immunoprecipitation (CO-IP) assay, radiographic analysis, and histopathological analysis. Our study demonstrated that prominin2 activity was impaired in TBHP-induced BMSCs ferroptosis. We found that PROM2 (encoding the protein prominin2) activation delayed the onset of ferroptosis and PROM2 knockdown deteriorated the course of ferroptosis. CO-IP, Western blot, and immunofluorescence demonstrated that prominin2 exerts antiferroptosis effects by inhibiting BTB and CNC homology 1 (BACH1) that promotes ROS generation, and thus exerts potent antioxidant effects in oxidative stress (OS)-induced BMSCs ferroptosis, including elevating BMSCs' survival rate and enhancing GSH contents. BMSCs with PROM2 overexpression also partially delayed the progression of intervertebral disk degeneration in vivo, as illustrated by less loss of disk height and lower histological scores. Our findings revealed a mechanism that the prominin2/BACH1/ROS axis participates in BMSCs ferroptosis and the strengthening of this axis is promising to maintain BMSCs' survival after explantation.NEW & NOTEWORTHY We found that prominin2 might be a potential biomarker and is expected to be utilized to augment engrafted bone marrow mesenchymal stem cells (BMSCs) survival rate. The prominin2/BTB and CNC homology 1 (BACH1)/reactive oxygen species (ROS) axis, which participates in the regulation of BMSCs ferroptosis induced by tert-butyl hydroperoxide (TBHP), is uncovered in our study. The therapeutic targeting of the prominin2/BACH1/ROS axis components is promising to elevate the survival of transplanted BMSCs in clinical practice.