Hematopoietic stem cell niche generation and maintenance are distinguishable by an epitranscriptomic program.

The niche is typically considered as a pre-established structure sustaining stem cells. Therefore, the regulation of its formation remains largely unexplored. Whether distinct molecular mechanisms control the establishment versus maintenance of a stem cell niche is unknown. To address this, we compared perinatal and adult bone marrow mesenchymal stromal cells (MSCs), a key component of the hematopoietic stem cell (HSC) niche. MSCs exhibited enrichment in genes mediating m6A mRNA methylation at the perinatal stage and downregulated the expression of Mettl3, the m6A methyltransferase, shortly after birth. Deletion of Mettl3 from developing MSCs but not osteoblasts led to excessive osteogenic differentiation and a severe HSC niche formation defect, which was significantly rescued by deletion of Klf2, an m6A target. In contrast, deletion of Mettl3 from MSCs postnatally did not affect HSC niche. Stem cell niche generation and maintenance thus depend on divergent molecular mechanisms, which may be exploited for regenerative medicine.

m6A RNA modification regulates innate lymphoid cell responses in a lineage-specific manner.

Innate lymphoid cells (ILCs) can quickly switch from a quiescent state to an active state and rapidly produce effector molecules that provide critical early immune protection. How the post-transcriptional machinery processes different stimuli and initiates robust gene expression in ILCs is poorly understood. Here, we show that deletion of the N6-methyladenosine (m6A) writer protein METTL3 has little impact on ILC homeostasis or cytokine-induced ILC1 or ILC3 responses but significantly diminishes ILC2 proliferation, migration and effector cytokine production and results in impaired antihelminth immunity. m6A RNA modification supports an increase in cell size and transcriptional activity in activated ILC2s but not in ILC1s or ILC3s. Among other transcripts, the gene encoding the transcription factor GATA3 is highly m6A methylated in ILC2s. Targeted m6A demethylation destabilizes nascent Gata3 mRNA and abolishes the upregulation of GATA3 and ILC2 activation. Our study suggests a lineage-specific requirement of m6A for ILC2 responses.

Perovskite/silicon tandem solar cells with bilayer interface passivation.

Two-terminal monolithic perovskite/silicon tandem solar cells demonstrate huge advantages in power conversion efficiency compared with their respective single-junction counterparts1,2. However, suppressing interfacial recombination at the wide-bandgap perovskite/electron transport layer interface, without compromising its superior charge transport performance, remains a substantial challenge for perovskite/silicon tandem cells3,4. By exploiting the nanoscale discretely distributed lithium fluoride ultrathin layer followed by an additional deposition of diammonium diiodide molecule, we have devised a bilayer-intertwined passivation strategy that combines efficient electron extraction with further suppression of non-radiative recombination. We constructed perovskite/silicon tandem devices on a double-textured Czochralski-based silicon heterojunction cell, which featured a mildly textured front surface and a heavily textured rear surface, leading to simultaneously enhanced photocurrent and uncompromised rear passivation. The resulting perovskite/silicon tandem achieved an independently certified stabilized power conversion efficiency of 33.89%, accompanied by an impressive fill factor of 83.0% and an open-circuit voltage of nearly 1.97 V. To the best of our knowledge, this represents the first reported certified efficiency of a two-junction tandem solar cell exceeding the single-junction Shockley-Queisser limit of 33.7%.

Mechanism of noncoding RNA-associated N6-methyladenosine recognition by an RNA processing complex during IgH DNA recombination.

Immunoglobulin heavy chain (IgH) locus-associated G-rich long noncoding RNA (SµGLT) is important for physiological and pathological B cell DNA recombination. We demonstrate that the METTL3 enzyme-catalyzed N6-methyladenosine (m6A) RNA modification drives recognition and 3' end processing of SµGLT by the RNA exosome, promoting class switch recombination (CSR) and suppressing chromosomal translocations. The recognition is driven by interaction of the MPP6 adaptor protein with nuclear m6A reader YTHDC1. MPP6 and YTHDC1 promote CSR by recruiting AID and the RNA exosome to actively transcribe SµGLT. Direct suppression of m6A modification of SµGLT or of m6A reader YTHDC1 reduces CSR. Moreover, METTL3, an essential gene for B cell development in the bone marrow and germinal center, suppresses IgH-associated aberrant DNA breaks and prevents genomic instability. Taken together, we propose coordinated and central roles for MPP6, m6A modification, and m6A reader proteins in controlling long noncoding RNA processing, DNA recombination, and development in B cells.

Two chemoattenuated PfSPZ malaria vaccines induce sterile hepatic immunity.

The global decline in malaria has stalled1, emphasizing the need for vaccines that induce durable sterilizing immunity. Here we optimized regimens for chemoprophylaxis vaccination (CVac), for which aseptic, purified, cryopreserved, infectious Plasmodium falciparum sporozoites (PfSPZ) were inoculated under prophylactic cover with pyrimethamine (PYR) (Sanaria PfSPZ-CVac(PYR)) or chloroquine (CQ) (PfSPZ-CVac(CQ))-which kill liver-stage and blood-stage parasites, respectively-and we assessed vaccine efficacy against homologous (that is, the same strain as the vaccine) and heterologous (a different strain) controlled human malaria infection (CHMI) three months after immunization ( https://clinicaltrials.gov/ , NCT02511054 and NCT03083847). We report that a fourfold increase in the dose of PfSPZ-CVac(PYR) from 5.12 × 104 to 2 × 105 PfSPZs transformed a minimal vaccine efficacy (low dose, two out of nine (22.2%) participants protected against homologous CHMI), to a high-level vaccine efficacy with seven out of eight (87.5%) individuals protected against homologous and seven out of nine (77.8%) protected against heterologous CHMI. Increased protection was associated with Vδ2 γδ T cell and antibody responses. At the higher dose, PfSPZ-CVac(CQ) protected six out of six (100%) participants against heterologous CHMI three months after immunization. All homologous (four out of four) and heterologous (eight out of eight) infectivity control participants showed parasitaemia. PfSPZ-CVac(CQ) and PfSPZ-CVac(PYR) induced a durable, sterile vaccine efficacy against a heterologous South American strain of P. falciparum, which has a genome and predicted CD8 T cell immunome that differs more strongly from the African vaccine strain than other analysed African P. falciparum strains.

Hematopoietic Stem Cells Are the Major Source of Multilineage Hematopoiesis in Adult Animals.

Hematopoietic stem cells (HSCs) sustain long-term reconstitution of hematopoiesis in transplantation recipients, yet their role in the endogenous steady-state hematopoiesis remains unclear. In particular, recent studies suggested that HSCs provide a relatively minor contribution to immune cell development in adults. We directed transgene expression in a fraction of HSCs that maintained reconstituting activity during serial transplantations. Inducible genetic labeling showed that transgene-expressing HSCs gave rise to other phenotypic HSCs, confirming their top position in the differentiation hierarchy. The labeled HSCs rapidly contributed to committed progenitors of all lineages and to mature myeloid cells and lymphocytes, but not to B-1a cells or tissue macrophages. Importantly, labeled HSCs gave rise to more than two-thirds of all myeloid cells and platelets in adult mice, and this contribution could be accelerated by an induced interferon response. Thus, classically defined HSCs maintain immune cell development in the steady state and during systemic cytokine responses.

Structural insights into Ras regulation by SIN1.

Over the years it has been established that SIN1, a key component of mTORC2, could interact with Ras family small GTPases through its Ras-binding domain (RBD). The physical association of Ras and SIN1/mTORC2 could potentially affect both mTORC2 and Ras-ERK pathways. To decipher the precise molecular mechanism of this interaction, we determined the high-resolution structures of HRas/KRas-SIN1 RBD complexes, showing the detailed interaction interface. Mutation of critical interface residues abolished Ras-SIN1 interaction and in SIN1 knockout cells we demonstrated that Ras-SIN1 association promotes SGK1 activity but inhibits insulin-induced ERK activation. With structural comparison and competition fluorescence resonance energy transfer (FRET) assays we showed that HRas-SIN1 RBD association is much weaker than HRas-Raf1 RBD but is slightly stronger than HRas-PI3K RBD interaction, providing a possible explanation for the different outcome of insulin or EGF stimulation. We also found that SIN1 isoform lacking the PH domain binds stronger to Ras than other longer isoforms and the PH domain appears to have an inhibitory effect on Ras-SIN1 binding. In addition, we uncovered a Ras dimerization interface that could be critical for Ras oligomerization. Our results advance our understanding of Ras-SIN1 association and crosstalk between growth factor-stimulated pathways.

Probing the Nanonewton Mitotic Cell Deformation Force by Ion-Resonance-Enhanced Photonics Force Microscopy.

Mechanical forces are essential for regulating dynamic changes in cellular activities. A comprehensive understanding of these forces is imperative for unraveling fundamental mechanisms. Here, we develop a microprobe capable of facilitating the measurement of biological forces up to nanonewton levels in living cells. This probe is designed by coating the core of anatase titania particles with amorphous titania and silica shells and an upconversion nanoparticles (UCNPs) layer. Leveraging both antireflection and ion resonance effects from the shells, the optically trapped probe attains a maximum lateral optical trap stiffness of 14.24 pN µm-1 mW-1, surpassing the best reported value by a factor of 3. Employing this advanced probe in a photonic force microscope, we determine the elasticity modulus of mitotic HeLa cells as 1.27 ± 0.3 kPa. Nanonewton probes offer the potential to explore 3D cellular mechanics with unparalleled precision and spatial resolution, fostering a deeper understanding of the underlying biomechanical mechanisms.

Versatile Metal-Organic Framework Incorporating Ag2S for Constructing a Photoelectrochemical Immunosensor for Two Breast Cancer Markers.

Breast cancer poses the significance of early diagnosis and treatment. Here, we developed an innovative photoelectrochemical (PEC) immunosensor characterized by high-level dual photocurrent signals and exceptional sensitivity. The PEC sensor, denoted as MIL&Ag2S, was constructed by incorporating Ag2S into a metal-organic framework of MIL-101(Cr). This composite not only enhanced electron-hole separation and conductivity but also yielded robust and stable dual photocurrent signals. Through the implementation of signal switching, we achieved the combined detection of cancer antigen 15-3 (CA15-3) and carcinoembryonic antigen (CEA) with outstanding stability, reproducibility, and specificity. The results revealed a linear range for CEA detection spanning 0.01-32 ng/mL, with a remarkably low detection limit of 0.0023 ng/mL. Similarly, for CA15-3 detection, the linear range extended from 0.1 to 320 U/mL, with a low detection limit of 0.014 U/mL. The proposed strategy introduces new avenues for the development of highly efficient, cost-effective, and user-friendly PEC sensors. Furthermore, it holds promising prospects for early clinical diagnosis, contributing to potential breakthroughs in medical detection and ultimately improving patient outcomes.

Multifaceted role and regulation of aquaporins for efficient stomatal movements.

Stomata are micropores on the leaf epidermis that allow carbon dioxide (CO2) uptake for photosynthesis at the expense of water loss through transpiration. Stomata coordinate the plant gas exchange of carbon and water with the atmosphere through their opening and closing dynamics. In the context of global climate change, it is essential to better understand the mechanism of stomatal movements under different environmental stimuli. Aquaporins (AQPs) are considered important regulators of stomatal movements by contributing to membrane diffusion of water, CO2 and hydrogen peroxide. This review compiles the most recent findings and discusses future directions to update our knowledge of the role of AQPs in stomatal movements. After highlighting the role of subsidiary cells (SCs), which contribute to the high water use efficiency of grass stomata, we explore the expression of AQP genes in guard cells and SCs. We then focus on the cellular regulation of AQP activity at the protein level in stomata. After introducing their post-translational modifications, we detail their trafficking as well as their physical interaction with various partners that regulate AQP subcellular dynamics towards and within specific regions of the cell membranes, such as microdomains and membrane contact sites.

A new method to measure aquaporin-facilitated membrane diffusion of hydrogen peroxide and cations in plant suspension cells.

Plant aquaporins (AQPs) facilitate the membrane diffusion of water and small solutes, including hydrogen peroxide (H2 O2 ) and, possibly, cations, essential signalling molecules in many physiological processes. While the determination of the channel activity generally depends on heterologous expression of AQPs in Xenopus oocytes or yeast cells, we established a genetic tool to determine whether they facilitate the diffusion of H2 O2 through the plasma membrane in living plant cells. We designed genetic constructs to co-express the fluorescent H2 O2 sensor HyPer and AQPs, with expression controlled by a heat shock-inducible promoter in Nicotiana tabacum BY-2 suspension cells. After induction of ZmPIP2;5 AQP expression, a HyPer signal was recorded when the cells were incubated with H2 O2 , suggesting that ZmPIP2;5 facilitates H2 O2 transmembrane diffusion; in contrast, the ZmPIP2;5W85A mutated protein was inactive as a water or H2 O2 channel. ZmPIP2;1, ZmPIP2;4 and AtPIP2;1 also facilitated H2 O2 diffusion. Incubation with abscisic acid and the elicitor flg22 peptide induced the intracellular H2 O2 accumulation in BY-2 cells expressing ZmPIP2;5. We also monitored cation channel activity of ZmPIP2;5 using a novel fluorescent photo-switchable Li+ sensor in BY-2 cells. BY-2 suspension cells engineered for inducible expression of AQPs as well as HyPer expression and the use of Li+ sensors constitute a powerful toolkit for evaluating the transport activity and the molecular determinants of PIPs in living plant cells.

Activation pattern of the coronary sinus facilitates the differentiation for ventricular outflow tract arrhythmias.

INTRODUCTION: The accuracy of surface ECG algorithms for predicting the origin of outflow tract ventricular arrhythmias (OT-VAs) might be questioned. Intracardiac electrograms recorded at anatomic landmarks could provide new predictive insights. We aim to evaluate the efficacy of a novel criterion utilizing the activation pattern of the coronary sinus (CS) in localizing OT-VAs, including VAs originating from the right ventricular outflow tract (RVOT), endocardial left ventricular outflow tract (Endo-LVOT), and epicardial left ventricular outflow tract (Epi-LVOT). METHODS: We measured the ventricular activation time of the mitral annulus (MA) from the onset of the earliest QRS complex of VAs to the initial deflection over the isoelectric line at local signals, namely the QRS-MA interval. The activation at 3 and 12 o'clock of the MA was recorded as the QRS-MA3 and QRS-MA12 intervals, respectively. Their predictive values were compared to previous ECG algorithms. RESULTS: A total of 68 patients with OT-VAs were enrolled (51 for development and 17 for validation). From early to late, the ventricular activation sequences at MA12 were as follows: Epi-LVOT, Endo-LVOT, and RVOT. In LBBB morphology OT-VAs, the QRS-MA12 interval was significantly earlier for LVOT origins than RVOT origins. In the combined cohort of development and validation cohort, a cut-off value of ≤10 ms predicted the LVOT origin with a sensitivity of 100% and specificity of 78%. The QRS-MA12 interval ≤ -24 ms additionally predicted epicardial LVOT sites of origin. CONCLUSIONS: The QRS-MA interval could accurately differentiate the OT-VAs localization.

The prognostic value of the stress hyperglycemia ratio for all-cause and cardiovascular mortality in patients with diabetes or prediabetes: insights from NHANES 2005-2018.

BACKGROUND: The Stress hyperglycemia ratio (SHR) is a novel marker reflecting the true acute hyperglycemia status and is associated with clinical adverse events. The relationship between SHR and mortality in patients with diabetes or prediabetes is still unclear. This study aimed to investigate the predictive value of the SHR for all-cause and cardiovascular mortality in patients with diabetes or prediabetes. METHODS: This study included 11,160 patients diagnosed with diabetes or prediabetes from the National Health and Nutrition Examination Survey (2005-2018). The study endpoints were all-cause and cardiovascular mortality, and morality data were extracted from the National Death Index (NDI) up to December 31, 2019. Patients were divided into SHR quartiles. Cox proportion hazards regression was applied to determine the prognostic value of SHR. Model 1 was not adjusted for any covariates. Model 2 was adjusted for age, sex, and race. Model 3 was adjusted for age, sex, race, BMI, smoking status, alcohol use, hypertension, CHD, CKD, anemia, and TG. RESULTS: During a mean follow-up of 84.9 months, a total of 1538 all-cause deaths and 410 cardiovascular deaths were recorded. Kaplan-Meier survival analysis showed the lowest all-cause mortality incidence was in quartile 3 (P < 0.001). Multivariate Cox regression analyses indicated that, compared to the 1st quartile, the 4th quartile was associated with higher all-cause mortality (model 1: HR = 0.89, 95% CI 0.74-10.7, P = 0.226; model 2: HR = 1.24, 95% CI 1.03-1.49, P = 0.026; model 3: HR = 1.30, 95% CI 1.08-1.57, P = 0.006). The 3rd quartile was associated with lower cardiovascular mortality than quartile 1 (model 1: HR = 0.47, 95% CI 0.32-0.69, P < 0.001; model 2: HR = 0.66, 95% CI 0.45-0.96, P = 0.032; model 3: HR = 0.68, 95% CI 0.46-0.99, P = 0.049). There was a U-shaped association between SHR and all-cause mortality and an L-shaped association between SHR and cardiovascular mortality, with inflection points of SHR for poor prognosis of 0.87 and 0.93, respectively. CONCLUSION: SHR is related to all-cause and cardiovascular mortality in patients with diabetes or prediabetes. SHR may have predictive value in those patients.

Temporal compressive edge imaging enabled by a lensless diffuser camera.

Lensless imagers based on diffusers or encoding masks enable high-dimensional imaging from a single-shot measurement and have been applied in various applications. However, to further extract image information such as edge detection, conventional post-processing filtering operations are needed after the reconstruction of the original object images in the diffuser imaging systems. Here, we present the concept of a temporal compressive edge detection method based on a lensless diffuser camera, which can directly recover a time sequence of edge images of a moving object from a single-shot measurement, without further post-processing steps. Our approach provides higher image quality during edge detection, compared with the "conventional post-processing method." We demonstrate the effectiveness of this approach by both numerical simulation and experiments. The proof-of-concept approach can be further developed with other image post-processing operations or versatile computer vision assignments toward task-oriented intelligent lensless imaging systems.

Association of Regular Opioid Use With Incident Dementia and Neuroimaging Markers of Brain Health in Chronic Pain Patients: Analysis of UK Biobank.

OBJECTIVES: We aimed to investigate the association of regular opioid use, compared with non-opioid analgesics, with incident dementia and neuroimaging outcomes among chronic pain patients. DESIGN: The primary design is a prospective cohort study. To triangulate evidence, we also conducted a nested case-control study analyzing opioid prescriptions and a cross-sectional study analyzing neuroimaging outcomes. SETTING AND PARTICIPANTS: Dementia-free UK Biobank participants with chronic pain and regular analgesic use. MEASUREMENTS: Chronic pain status and regular analgesic use were captured using self-reported questionnaires and verbal interviews. Opioid prescription data were obtained from primary care records. Dementia cases were ascertained using primary care, hospital, and death registry records. Propensity score-matched Cox proportional hazards analysis, conditional logistic regression, and linear regression were applied to the data in the prospective cohort, nested case-control, and cross-sectional studies, respectively. RESULTS: Prospective analyses revealed that regular opioid use, compared with non-opioid analgesics, was associated with an increased dementia risk over the 15-year follow-up (Hazard ratio [HR], 1.18 [95% confidence interval (CI): 1.08-1.30]; Absolute rate difference [ARD], 0.44 [95% CI: 0.19-0.71] per 1000 person-years; Wald χ2 = 3.65; df = 1; p <0.001). The nested case-control study suggested that a higher number of opioid prescriptions was associated with an increased risk of dementia (1 to 5 prescriptions: OR = 1.21, 95% CI: 1.07-1.37, Wald χ2 = 3.02, df = 1, p = 0.003; 6 to 20: OR = 1.27, 95% CI: 1.08-1.50, Wald χ2 = 2.93, df = 1, p = 0.003; more than 20: OR = 1.43, 95% CI: 1.23-1.67, Wald χ2 = 4.57, df = 1, p < 0.001). Finally, neuroimaging analyses revealed that regular opioid use was associated with lower total grey matter and hippocampal volumes, and higher white matter hyperintensities volumes. CONCLUSION: Regular opioid use in chronic pain patients was associated with an increased risk of dementia and poorer brain health when compared to non-opioid analgesic use. These findings imply a need for re-evaluation of opioid prescription practices for chronic pain patients and, if further evidence supports causality, provide insights into strategies to mitigate the burden of dementia.

Synergistic effect of Ag@CN with BiVO4 in a unique Z-type heterojunction for enhancing photoelectrochemical water splitting performance.

In the realm of photoelectrochemical technology, the enhancement of photogenerated charge carrier separation is pivotal for the advancement of energy conversion performance. Carbon nitride (CN) is established as a photocatalytic material with significant potential and exhibits unique advantages in addressing the issue of rapid recombination of photogenerated carriers. This study utilized an efficient in situ doping method that combined Mo,W-doped BiVO4 (Mo,W:BVO) with silver-loaded CN (Ag@CN), yielding an all-solid-state Mo,W:BVO/Ag@CN heterostructure that effectively augments the separation efficiency of electron-hole pairs. Through the annealing process, Ag@CN was uniformly coated within the Mo,W:BVO thin film, significantly enlarging the interface contact area to enhance visible light absorption and photogenerated carrier movement. The results of the photoelectrochemical tests showed that the Mo,W:BVO/Ag@CN heterostructure had the highest photocurrent and charge transfer efficiency, which were 6.4 times and 3.6 times higher respectively than those of the unmodified Mo,W:BVO. Our research elucidates the interactions within all-solid-state Z-scheme heterojunctions, outlining strategic approaches for crafting innovative and superior photocatalytic systems.

Genetically engineered nanovesicles mobilize synergistic antitumor immunity by ADAR1 silence and PDL1 blockade.

Growing evidence has proved that RNA editing enzyme ADAR1, responsible for detecting endogenous RNA species, was significantly associated with poor response or resistance to immune checkpoint blockade (ICB) therapy. Here, a genetically engineered nanovesicle (siAdar1-LNP@mPD1) was developed as an RNA interference nano-tool to overcome tumor resistance to ICB therapies. Small interfering RNA against ADAR1 (siAdar1) was packaged into a lipid nanoparticle (LNP), which was further coated with plasma membrane extracted from the genetically engineered cells overexpressing PD1. siAdar1-LNP@mPD1 could block the PD1/PDL1 immune inhibitory axis by presenting the PD1 protein on the coating membranes. Furthermore, siAdar1 could be effectively delivered into cancer cells by the designed nanovesicle to silence ADAR1 expression, resulting in an increased type I/II interferon (IFN-ß/γ) production and making the cancer cells more sensitive to secreted effector cytokines such as IFN-γ with significant cell growth arrest. These integrated functions confer siAdar1-LNP@mPD1 with robust and comprehensive antitumor immunity, as evidenced by significant tumor growth regression, abscopal tumor prevention, and effective suppression of lung metastasis, through a global remodeling of the tumor immune microenvironment. Overall, we provided a promising translatable strategy to simultaneously silence ADAR1 and block PDL1 immune checkpoint to boost robust antitumor immunity.

Relationship between biological rhythm dysregulation and suicidal ideation in patients with major depressive disorder.

BACKGROUND: Although the disturbance of circadian rhythms represents a significant clinical feature of major depressive disorder (MDD), the relationship between biological rhythm disturbances and the severity of suicidal ideation in individuals with MDD remains unclear. We aimed to explore the characteristics of different biological rhythm dimensions in MDD and their association with the severity of depressive symptoms and suicidal ideation. METHODS: A total of 50 MDD patients and 50 healthy controls were recruited and their general information was collected. The severity of depressive symptoms was assessed with the 17-item Hamilton Depression Rating Scale (HDRS17). The intensity of suicidal ideation was evaluated with the Beck Scale for Suicide Ideation (BSS). The Chinese version of the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) scale was utilized to assess the participants' biological rhythm dysregulation. Multiple logistic regression analysis was conducted to explore the relationship between biological rhythm and the risk of MDD. Multiple linear regression analysis was performed in the MDD group to investigate the relationship between different biological rhythm dimensions and suicide ideation. RESULTS: Significant differences were observed between the MDD group and the control group in total BRIAN score (Z=-5.41, P < 0.001) as well as scores for each dimension. After adjusting for confounding factors, multiple logistic regression analysis revealed a significant association between total BRIAN score and the presence of MDD (OR = 1.20, 95% CI = 1.10-1.29, P < 0.001), as well as between scores in different BRIAN dimensions and the presence of MDD (activity: OR = 1.47, 95% CI = 1.24-1.74, P < 0.001; sleep: OR = 1.52, 95% CI = 1.28-1.79, P < 0.001; social: OR = 1.80, 95% CI = 1.32-2.46, P < 0.001; eating pattern: OR = 1.34, 95% CI = 1.12-1.60, P = 0.001). In patients with MDD, linear regression analysis demonstrated a positive relationship between BSS scores and BRIAN eating pattern scores (ß = 0.34, P = 0.022), even after adjusting for demographic factors and the severity of depression. CONCLUSIONS: Patients with MDD exhibited significantly higher levels of dysregulation in all four biological rhythm dimensions compared to healthy controls and the degree of dysregulation was associated with the severity of depression. More importantly, dysregulation of eating pattern may increase the intensity of suicidal ideation in MDD, thus elevating the risk of suicide.

A thermo-sensitive hydrogel with prominent hemostatic effect prevents tumor recurrence via anti-anoikis-resistance.

Tumor cells can survive when detached from the extracellular matrix (ECM) or lose cell-cell connections, a phenomenon known as anoikis-resistance (AR). AR is closely associated with tumor cell metastasis and recurrence, enabling tumor cells to disseminate, migrate, and invade after detachment. To address this issue, a novel intervention method combining intraoperative hemostasis with multifunctional nanozyme driven-enhanced chemodynamic therapy (ECDT) has been proposed, which holds the potential to weaken the AR capability of tumor cells and suppress tumor recurrence. Here, a nanocomposite containing a dendritic mesoporous nanoframework with Cu2+ was developed using an anion-assisted approach after surface PEG grafting and glucose oxidase (GOx) anchoring (DMSN-Cu@GOx/PEG). DMSN-Cu@GOx/PEG was further encapsulated in a thermal-sensitive hydrogel (H@DMSN-Cu@GOx/PEG). DMSN-Cu@GOx/PEG utilizes its high peroxidase (POD) activity to elevate intracellular ROS levels, thereby weakening the AR capability of bladder cancer cells. Additionally, through its excellent catalase (CAT) activity, DMSN-Cu@GOx/PEG converts the high level of hydrogen peroxide (H2O2) catalyzed by intracellular GOx into oxygen (O2), effectively alleviating tumor hypoxia, downregulating hypoxia-inducible factor-1α (HIF-1α) expression, inhibiting epithelial-mesenchymal transition (EMT) processes, and ultimately suppressing the migration and invasion of bladder cancer cells. Interestingly, in vivo results showed that the thermosensitive hydrogel H@DMSN-Cu@GOx/PEG could rapidly gel at body temperature, forming a gel film on wounds to eliminate residual tumor tissue after tumor resection surgery. Importantly, H@DMSN-Cu@GOx/PEG exhibited excellent hemostatic capabilities, effectively enhancing tissue coagulation during post-tumor resection surgery and mitigating the risk of cancer cell dissemination and recurrence due to surgical bleeding. Such hydrogels undoubtedly possess strong surgical application. Our developed novel nanosystem and hydrogel can inhibit the AR capability of tumor cells and prevent recurrence post-surgery. This study represents the first report of using dendritic mesoporous silica-based nanoreactors for inhibiting the AR capability of bladder cancer cells and suppressing tumor recurrence post-surgery, providing a new avenue for developing strategies to impede tumor recurrence after surgery.

The impact of triglyceride glucose-body mass index on all-cause and cardiovascular mortality in elderly patients with diabetes mellitus: evidence from NHANES 2007-2016.

BACKGROUND: The relationship between triglyceride glucose-body mass index (TyG-BMI) index and mortality in elderly patients with diabetes mellitus (DM) are still unclear. This study aimed to investigate the association between TyG-BMI with all-cause and cardiovascular mortality among elderly DM patients in the United States (US). METHODS: Patients aged over 60 years with DM from the National Health and Nutrition Examination Survey (2007-2016) were included in this study. The study endpoints were all-cause and cardiovascular mortality and the morality data were extracted from the National Death Index (NDI) which records up to December 31, 2019. Multivariate Cox proportional hazards regression model was used to explore the association between TyG-BMI index with mortality. Restricted cubic spline was used to model nonlinear relationships. RESULTS: A total of 1363 elderly diabetic patients were included, and were categorized into four quartiles. The mean age was 70.0 ± 6.8 years, and 48.6% of them were female. Overall, there were 429 all-cause deaths and 123 cardiovascular deaths were recorded during a median follow-up of 77.3 months. Multivariate Cox regression analyses indicated that compared to the 1st quartile (used as the reference), the 3rd quartile demonstrated a significant association with all-cause mortality (model 2: HR = 0.64, 95% CI 0.46-0.89, P = 0.009; model 3: HR = 0.65, 95% CI 0.43-0.96, P = 0.030). Additionally, the 4th quartile was significantly associated with cardiovascular mortality (model 2: HR = 1.83, 95% CI 1.01-3.30, P = 0.047; model 3: HR = 2.45, 95% CI 1.07-5.57, P = 0.033). The restricted cubic spline revealed a U-shaped association between TyG-BMI index with all-cause mortality and a linear association with cardiovascular mortality, after adjustment for possible confounding factors. CONCLUSIONS: A U-shaped association was observed between the TyG-BMI index with all-cause mortality and a linear association was observed between the TyG-BMI index with cardiovascular mortality in elderly patients with DM in the US population.