Relationship between exposure to fine particulate matter and cardiovascular risk factors and the modifying effect of socioeconomic status: a cross-sectional study in Beijing, China.

Accumulating research suggested that long-term exposure to fine particulate matter (PM2.5) is related to cardiovascular disease (CVD). However, evidence regarding the relationship between PM2.5 and CVD risk factors remains inconsistent. We hypothesized that this association may be partially modified by socioeconomic status (SES). To investigate the relationships and to test the modifying effect of SES, we included baseline data for 21,018 adults from September 2017 to May 2018. PM2.5 concentrations were determined by employing an amalgamation of linear measurements obtained from monitoring stations located near the participants' residential and workplace addresses. We assessed SES across several domains, including income, education, and occupation levels, as well as through a composite SES index. The results indicated that for every 10 µg/m3 increase in PM2.5 exposure, the risk of hypercholesterolemia, hyperbetalipoproteinemia, diabetes, and hyperhomocysteinemia (HHcy) increased by 7.7% [Odds ratio (OR) = 1.077, 95% Confidence Interval (CI) = 1.011, 1.146], 19.6% (OR = 1.196, 95% CI = 1.091, 1.312), 4.2% (OR = 1.042, 95% CI = 1.002, 1.084), and 17.1% (OR = 1.171, 95% CI = 1.133, 1.209), respectively. Compared to the high SES group, those with low SES are more prone to hypercholesterolemia, hyperbetalipoproteinemia, diabetes, and HHcy. Notably, the disparities in SES appear significant in the relationship between PM2.5 exposure and hypercholesterolemia as well as hyperbetalipoproteinemia. But for diabetes and HHcy, the modification effect of SES on PM2.5 shows an inconsistent pattern. In conclusion, the results confirm the association between PM2.5 and cardiovascular risk factors and low SES significantly amplified the adverse PM2.5 effect on dyslipidemia. It is crucial to emphasize a need to improve the socioeconomic inequality among adults in Beijing and contribute to the understanding of the urgency in protecting the health of vulnerable groups.

Physical Frailty, Genetic Predisposition, and Incident Heart Failure.

Background: There is growing interest in the intersection of frailty and heart failure (HF); however, large-sample longitudinal studies in the general population are lacking. Objectives: The goal of this study was to examine the longitudinal relationship between frailty and incident HF, and whether age and genetic predisposition could modify this association. Methods: This prospective cohort study included 340,541 participants (45.7% male; mean age 55.9 ± 8.1 years) free of HF at baseline in the UK Biobank. Frailty was assessed by using the Fried frailty phenotype and included weight loss, exhaustion, low physical activity, slow gait speed, and low grip strength. The weighted polygenetic risk score was calculated. Cox models were used to estimate these associations and the interaction between the 2 factors. Results: During a median 14.1 years of follow-up, 7,590 patients with HF were documented. Compared with nonfrail participants, both prefrail and frail participants had a positive association with the risk of incident HF (prefrail HR: 1.40 [95% CI: 1.17-1.67]; frail HR: 2.07 [95% CI: 1.67-2.57]). Exhaustion (HR: 1.21; 95% CI: 1.03-1.43), slow gait speed (HR: 1.62; 95% CI: 1.39-1.90), and low grip strength (HR: 1.31; 95% CI: 1.14-1.51) were associated with a greater risk of incident HF. Furthermore, genetic susceptibility did not significantly modify the associations (P interaction = 0.094), and the association was significantly strengthened in younger participants (P interaction = 0.008). Conclusions: Frailty status was associated with a higher risk of incident HF independent of genetic risk. A younger population may be more susceptible to HF when exposed to frailty. Whether the modification of frailty status represents another avenue for preventing HF warrants further investigation.

[Clincopathological analysis of 171 patients with osteochondroma and malignant transformation in maxillofacial bone].

PURPOSE: To investigate the clinical and pathological features of osteochondroma in maxillofacial region, and to summarize the clinicopathological features of rare osteochondroma malignant transformation in order to provide clinical guidance. METHODS: From January 2018 to September 2023, a total of 171 patients with osteochondroma were retrospectively collected in Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. Their preoperative CT and clinicopathological features were analyzed. RESULTS: Of the 171 patients with osteochondroma in maxillofacial bone, 66%（113/171） were females and 34% were male. Their age ranged from 11-76 with an average age was 44 years old. Of the 171 cases, 95.3%（163/171）in mandible condyle, 4%(7/171) in mandible processus coronoideus, and 0.5%（1/171） in zygomatic arch. The imaging findings showed that the thickness of cartilaginous cap was less than 1 cm in 98%（159/161） cases with condyle lesions. Only 2 cases(2/171, 1.1%) had malignant transformation. One was diagnosed with secondary chondrosarcoma, another developed low-grade osteosarcoma. CONCLUSIONS: Osteochondroma in maxillofacial region mostly occurs in females, and most commonly located in condylar process, with a malignant change rate of 1.1%, which is similar to that of other parts of the body. Imaging findings have important guiding significance for the diagnosis of osteochondroma malignant change.

Tremendous and infrequently adenoid cystic carcinoma of the breast without any metastasis for more than 20 years: A case report.

RATIONALE: Breast adenoid cystic carcinoma is an extremely rare tumor that is incompletely understood, accounting for less than <0.1% of all breast cancers, with an average diameter of 3 cm, and it is extremely rare to see a large, non-metastatic breast adenoid cystic carcinoma with a diameter of about 30 cm. Since this disease is extremely rare, there are few reports in the literature and limited data on clinical diagnosis and treatment. We present a case of a 71-year-old woman with a large, non-metastatic adenoid cystic carcinoma of the left breast and share our opinion on the diagnosis and treatment of this case. PATIENT CONCERNS: A 71-year-old woman with a 20-year-old left breast mass with local bleeding and rupture for 1 hour presented to our hospital for further diagnosis and treatment. A computed tomography scan showed a large soft tissue mass shadow in the left breast and malignancy was considered. Subsequently, tissue aspiration pathology was performed and the results confirmed adenoid cystic carcinoma of the breast. DIAGNOSIS: Intraoperative pathology results of radical mastectomy for left breast cancer diagnosed adenoid cystic carcinoma of the breast and immunohistochemistry results of triple-negative breast cancer. INTERVENTIONS AND OUTCOMES: Treatment of adenoid cystic carcinoma of the breast included neoadjuvant chemotherapy for breast cancer, radical mastectomy of the left breast, and postoperative chemotherapy. Initially, neoadjuvant chemotherapy for breast cancer was performed, and the TAC regimen was used to successfully reduce the size of the tumor and gain access to surgical treatment for breast cancer. The patient has recovered well after the surgery, with no wound infection or ulceration, and is now waiting for the patient's physical function to recover for postoperative chemotherapy, with no obvious discomfort. LESSONS: Adenoid cystic carcinoma tumors are usually around 3 cm; such a huge 30 cm adenoid cystic carcinoma of the breast is extremely rare, and it is extremely rare to find a breast malignancy that has not developed regional lymph node and distant metastases for more than 20 years. Clinicians must remain vigilant for early breast malignancies at a high age of incidence and conduct further research for diagnosis to avoid delays.

Dental pulp stem cells-derived cannabidiol-treated organoid-like microspheroids show robust osteogenic potential via upregulation of WNT6.

Dental pulp stem cells (DPSC) have shown osteogenic and bone regenerative potential. Improving the in situ bone regeneration potential of DPSC is crucial for their application as seed cells during bone defect reconstruction in clinics. This study aimed to develop DPSC-derived organoid-like microspheroids as effective seeds for bone tissue engineering applications. DPSC osteogenic microspheroids (70 µm diameter) were cultured in a polydimethylsiloxane-mold-based agarose-gel microwell-culture-system with or without cannabidiol (CBD)-treatment. Results of in vitro studies showed higher osteogenic differentiation potential of microspheroids compared with 2D-cultured-DPSC. CBD treatment further improved the osteogenic differentiation potential of microspheroids. The effect of CBD treatment in the osteogenic differentiation of microspheroids was more pronounced compared with that of CBD-treated 2D-cultured-DPSC. Microspheroids showed a higher degree of bone regeneration in nude mice calvarial bone defect compared to 2D-cultured-DPSC. CBD-treated microspheroids showed the most robust in situ bone regenerative potential compared with microspheroids or CBD-treated 2D-cultured-DPSC. According to mRNA sequencing, bioinformatic analysis, and confirmation study, the higher osteogenic potential of CBD-treated microspheroids was mainly attributed to WNT6 upregulation. Taken together, DPSC microspheroids have robust osteogenic potential and can effectively translate the effect of in vitro osteoinductive stimulation during in situ bone regeneration, indicating their application potential during bone defect reconstruction in clinics.

Exosomes derived from endothelial progenitor cells ameliorate LPS-induced brain microvascular endothelial cells injury by delivering miR-126a-5p.

Endothelial progenitor cells (EPCs) play a crucial role in maintaining vascular health and aiding in the repair of damaged blood vessels. However, the specific impact of EPCs-derived exosomes on vascular endothelial cell injury caused by lipopolysaccharide (LPS) remains inadequately understood. This study aims to explore the potential benefits of EPC-exosomes in mitigating LPS-induced vascular injury and to elucidate the underlying mechanism. Initially, EPCs were isolated from mouse peripheral blood, and their identity was confirmed through flow cytometry and immunocytochemistry. Subsequently, the exosomes derived from EPCs were identified using transmission electron microscopy (TEM) and western blot analysis. A sepsis model was induced by subjecting brain microvascular endothelial cells (BMECs) to LPS-induced injury. Both EPC and their exosomes demonstrated a significant increase in BMECs proliferation, reduced apoptosis, decreased levels of pro-inflammatory factors (TNF-α, IL-6, and caspase-3), and enhanced sprouting and angiogenesis of BMECs. Notable, the Exosomes demonstrated a more pronounced impact on these parameters. Furthermore, both EPCs and Exosomes exhibited significantly increased levels of miR-126a-5p, with the Exosomes showing a more substantial enhancement. These findings suggest that supplementing exosomal miR-126a-5p from EPCs can provide protective effects on BMECs, offering a potential therapeutic option for treating sepsis-induced microvascular endothelial cell injury.

Chip-scale high-performance photonic microwave oscillator.

Optical frequency division based on bulk or fiber optics provides unprecedented spectral purity for microwave oscillators. To extend the applications of this approach, the challenges are to develop miniaturized oscillators without trading off phase noise performance. Here, we report a chip-scale high-performance photonic microwave oscillator based on integrated electro-optical frequency division. Dual distributed-feedback lasers are co-self-injection locked to a single silicon nitride spiral resonator to provide a record-high-stability, fully on-chip optical reference. An integrated electro-optical frequency comb based on a thin-film lithium niobate phase modulator chip is leveraged to perform optical-to-microwave frequency division. The resulting integrated photonic microwave oscillator achieves a record-low phase noise for chip-scale oscillators. The results represent a major advance in high-performance, integrated photonic microwave oscillators for applications including signal processing, radar, timing, and coherent communications.

A study on the classification of complexly shaped cultivated land considering multi-scale features and edge priors.

Obtaining accurate cultivated land distribution data is crucial for sustainable agricultural development. The current cultivated land extraction studies mainly analyze crops on a regular shape and a small block scale. Aiming at the problem of fragmentation of plots in complexly shaped cultivated land leads to variable scales and blurred edges and the difficulty of extracting the context information by kernel convolution operation of the CNN-based model. We propose a complexly shaped farmland extraction network considering multi-scale features and edge priors (MFEPNet). Specifically, we design a context cross-attention fusion module to couple the local-global features extracted by the two-terminal path CNN-transformer network, which obtains more accurate cultivated land plot representations. This paper constructs the relation maps through a multi-scale feature reconstruction module to realize multi-scale information compensates by combining the gated weight parameter based on information entropy. Additionally, we design a texture-enhanced edge module, which uses the attention mechanism to fuse the edge information of texture feature extraction and the reconstructed feature map to enhance the edge features. In general, the network effectively reduces the influence of variable scale, blurred edges, and limited global field of view. The novel model proposed in this paper is compared with classical deep learning models such as UNet, DeeplabV3 +, DANet, PSPNet, RefineNet, SegNet, ACFNet, and OCRNet on the regular and irregular farmland datasets divided by IFLYTEK and Netherlands datasets. The experimental results show that MFEPNet achieves 92.40 % and 91.65 % MIoU on regular and irregular farmland datasets, which is better than the benchmark experimental model.

TRB3 Promotes Cataract Progression through Endoplasmic Reticulum Stress-mediated Mitochondrial Dysfunction and Cell Apoptosis.

Cataracts are characterized as a disease affecting lens opacity. Endoplasmic reticulum (ER) stress can cause lens epithelial cell (LEC) dysfunction, affecting normal lens transparency and function, but the role of Tribbles 3 (TRB3), an inducible gene of ER stress, in cataracts is poorly understood. This study explored how TRB3 promotes cataract progression through ER stress. We administered a subcutaneous injection of sodium selenite at a dosage of 3.46 mg/kg to rats to create an animal model of cataracts. Additionally, we exposed rat LEC cells to 0.01 µM tunicamycin (TM) for 24 h to establish a cell model of ER stress. The detection of related genes and proteins was performed via RT‒qPCR and Western blot techniques. Flow cytometry, along with JC-1, TUNEL, and HE staining, was employed to assess damage to cells and lens tissues. This study revealed that TRB3 was abnormally highly expressed in both a cataract rat model and an ER stress cell model. Knocking down TRB3 has a similar effect as treatment with an ER stress inhibitor, effectively reversing the ER stress and apoptosis induced by TM. This effect includes increasing the mitochondrial membrane potential in LEC cells, lowering reactive oxygen species (ROS) levels, increasing ATP production, suppressing the expression of the apoptosis-related proteins Bax and C-caspase-3, increasing Bcl-2 expression, and decreasing apoptosis. Furthermore, TRB3 knockdown improved the pathological conditions of rat lenses and inhibited mitochondrial dysfunction and cell apoptosis to relieve the development of cataracts in rats. Mechanistically, CHOP promotes the expression of TRB3 by binding to the TRB3 promoter, thereby activating ER stress, leading to mitochondrial dysfunction and cell apoptosis in LEC cells and accelerating the development of cataracts. According to our findings, targeting TRB3 expression inhibition could emerge as a novel approach for cataract therapy.

Longitudinal assessment of glymphatic changes following mild traumatic brain injury: Insights from perivascular space burden and DTI-ALPS imaging.

Introduction: Traumatic brain injury (TBI) even in the mild form may result in long-lasting post-concussion symptoms. TBI is also a known risk to late-life neurodegeneration. Recent studies suggest that dysfunction in the glymphatic system, responsible for clearing protein waste from the brain, may play a pivotal role in the development of dementia following TBI. Given the diverse nature of TBI, longitudinal investigations are essential to comprehending the dynamic changes in the glymphatic system and its implications for recovery. Methods: In this prospective study, we evaluated two promising glymphatic imaging markers, namely the enlarged perivascular space (ePVS) burden and Diffusion Tensor Imaging-based ALPS index, in 44 patients with mTBI at two early post-injury time points: approximately 14 days (14Day) and 6-12 months (6-12Mon) post-injury, while also examining their associations with post-concussion symptoms. Additionally, 37 controls, comprising both orthopedic patients and healthy individuals, were included for comparative analysis. Results: Our key findings include: (1) White matter ePVS burden (WM-ePVS) and ALPS index exhibit significant correlations with age. (2) Elevated WM-ePVS burden in acute mTBI (14Day) is significantly linked to a higher number of post-concussion symptoms, particularly memory problems. (3) The increase in the ALPS index from acute (14Day) to the chronic (6-12Mon) phases in mTBI patients correlates with improvement in sleep measures. Furthermore, incorporating WM-ePVS burden and the ALPS index from acute phase enhances the prediction of chronic memory problems beyond socio-demographic and basic clinical information. Conclusion: ePVS burden and ALPS index offers distinct values in assessing glymphatic structure and activity. Early evaluation of glymphatic function could be crucial for understanding TBI recovery and developing targeted interventions to improve patient outcomes.

Joint effects of physical frailty and traditional cardiovascular risk factor control on cardiovascular disease in patients with diabetes.

OBJECTIVES: Physical frailty has been found to increase the risk of multiple adverse outcomes including cardiovascular disease (CVD) in diabetic patients, but whether this could be modified by traditional risk factor control remains unknown. We aimed to explore the joint and interaction effects of frailty and traditional risk factor control on the risk of CVD. DESIGN: A population-based cohort study. SETTING AND PARTICIPANTS: We included 15,753 participants with type 2 diabetes at baseline from UK Biobank. MEASUREMENTS: Physical frailty was assessed by Fried criteria's frailty phenotype. The degree of risk factor control was determined by the numbers of the following factors controlled within the target range, including glycated hemoglobin, blood pressure, low-density lipoprotein cholesterol, smoking, and kidney condition. Incident CVD included coronary heart disease, stroke, or heart failure. Cox proportional hazard models were used to assess the individual and joint effects of frailty and risk factor control on the risk of CVD. RESULTS: After a median follow-up of 13.5 years, 1129 incident CVD events were observed. Compared with non-frailty, both prefrailty and frailty were significantly associated with increased risk of CVD (HR 1.22, 95% CI [1.13, 1.31] for pre-frailty and 1.70 [1.53, 1.90] for frailty). For the joint effects, participants with frailty and a low degree of risk factor control (control of 0-1 risk factors) had the highest risk of CVD (2.92 [2.04, 4.17]) compared to those with non-frailty and optimal risk factor control (control of 4-5 risk factors). Moreover, a significant additive interaction between frailty and risk factor control was observed, with around 3.8% of CVD risk attributed to the interactive effects. CONCLUSIONS: Both prefrailty and frailty were associated with a higher risk of CVD in participants with type 2 diabetes. Moreover, physical frailty could interact with the degree of risk factor control in an additive manner to increase the CVD risk.

Identification of a novel xanthine oxidoreductase inhibitor for hyperuricemia treatment with high efficacy and safety profile.

Hyperuricemia is with growing incidence and of high risk to develop into gout and other metabolic diseases. The key enzyme catalyzing uric acid synthesis, xanthine oxidoreductase (XOR) is a vital target for anti-hyperuricemic drugs, while XOR inhibitors characterized as both potent and safe are currently in urgent need. In this study, a novel small molecule compound, CC15009, was identified as a specific XOR inhibitor. CC15009 exerted strongest in vitro XOR inhibitory activity among current XOR inhibitors. It also showed favorable dose-dependent uric acid-lowering effects in two different XOR substrate-induced hyperuricemic mouse models, which was significantly superior than the current first-line drug, allopurinol. Mechanically, the direct binding of CC15009 against XOR was confirmed by molecular docking and SPR analysis. The inhibition mode was competitive and reversible. Besides, the potential antioxidant activity of CC15009 was indicated by its strong inhibitory activity against the oxidized isoform of XOR, which reduced ROS generation as the byproduct. Regarding the safety concerns of current XOR inhibitors, especially in cardiovascular risks, the safety of CC15009 was comprehensively evaluated. No significant abnormality was observed in the acute, subacute toxicity tests and mini-AMES test. Notably, there was no obvious inhibition of CC15009 against cardiac ion channels, including hERG, Nav1.5, Cav1.2 at the concentration of 30 µM, indicating its lower cardiovascular risk. Taken together, our results supported CC15009 as a candidate of high efficacy and safety profile to treat hyperuricemia through direct XOR inhibition.

Redox-Neutral Coupling of Allyl Alcohols with Trifluoromethyl Ketones via Synergistic Ni-Ti Bimetallic Catalysis.

A redox-neutral coupling of allyl alcohols with trifluoromethyl ketones has been developed via Ni-Ti bimetallic catalysis. This innovative method allows for the efficient synthesis of various ß-tertiary trifluoromethyl alcohol-substituted ketones with yields of up to 98%. The reaction is scalable and compatible with a wide range of substrates, including complex bioactive molecules. Mechanistic studies suggest that the rate-determining step involving ß-H elimination and the presence of the Ti-based Lewis acid, as well as a hydroxyl group on the substrates, is crucial for driving the reactivity of this transformation.

The Involvement of the Ventral Tegmental Area in the Electroacupuncture Alleviation of Anxiety-Like Behaviors Induced by Chronic Restraint Stress in Mice.

Emotional stress is a significant environmental risk factor for various mental health disabilities, such as anxiety. Electroacupuncture (EA) has been demonstrated to have pronounced anxiolytic effects. However, the neural mechanisms underlying these effects and their contribution to behavioral deficits remain poorly understood. Here, we addressed these issues using a classical mouse anxiety model induced by chronic restraint stress (CRS).Anxiety-like behaviors were evaluated with the open field test and elevated plus maze. Neuronal activation in various brain regions was marked using c-Fos, followed by calculations of interregional correlation to characterize a network that became functionally active following EA at the HT7 acupoint (EA-HT7). We selected the hub regions and further investigated their functions and connections in regulating anxiety-like behaviors by using a combination of chemogenetic manipulations and behavioral testing. CRS exposure induced anxiety-like behaviors. Interestingly, EA-HT7 mitigated these behavioral abnormalities. The c-Fos expression in 30 brain areas revealed a vital brain network for acupuncture responsiveness in naïve mice. Neural activity in the NAcSh (nucleus accumbens shell), BNST (bed nucleus of the stria terminalis), VMH (Ventromedial Hypothalamus), ARC (arcuate nucleus), dDG (dorsal dentate gyrus), and VTA (ventral tegmental area) was significantly altered following acupuncture. Notably, both c-Fos immunostaining and brain functional connectivity analysis revealed the significant activation of VTA following EA-HT7. Interestingly, blocking the VTA eliminated the anxiolytic effects of EA-HT7, whereas chemogenetic activation of the VTA replicated the therapeutic effects of EA-HT7. EA-HT7 has demonstrated benefits in treating anxiety and enhances brain functional connectivity. The VTA is functionally associated with the anxiolytic effects of EA-HT7.

The SDF-1/CXCR4 axis is involved in adipose-derived stem cell migration.

BACKGROUND: Intravenous injection of adipose-derived stem cells (ADSCs) can improve the urinary function of stress urinary incontinence (SUI) model rats and C-X-C chemokine receptor type 4 (CXCR4)-positive ADSCs are found in urethral tissues. The CXCR4 ligand stromal cell-derived factor-1 (SDF-1) is highly expressed in urinary incontinence model rats. In this study, we investigated the involvement of the SDF-1/CXCR4 axis in the homing of ADSCs. METHODS: ADSCs were isolated from rats and purified. The levels of CXCR4 and CXCR7 were determined by western blot analysis and immunofluorescence assays following stimulation with SDF-1. Hypoxia conditioning was performed to treat the cells in vitro, following which the messenger RNA (mRNA) and protein level of SDF-1, CXCR4, and CXCR7 were estimated. RESULTS: We found that CXCR4 and CXCR7 were expressed in ADSCs at passage zero (P0), P1, and P3, and the expression of both increased after SDF-1 stimulation. The level of expression of the mRNAs and proteins of SDF-1, CXCR4, and CXCR7 in ADSCs was higher after hypoxic conditioning. We then knocked down CXCR4 or CXCR7 using small interfering RNAs and found that the mRNA levels of CXCR4 and CXCR7 were considerably downregulated in the si-CXCR4/7-transfected cells. We also found that the SDF-1/CXCR4 axis was required for the migration of ADSCs. The phosphorylation levels of Janus kinase (JAK), protein kinase B (AKT), and extracellular regulated protein kinase significantly increased in SDF-1-stimulated ADSCs. However, the migration of ADSCs was suppressed when the corresponding specific inhibitors were used to block JAK and AKT signaling or silence CXCR4, whereas no significant change was observed in the migratory ability of ADSCs when the ERK pathway was blocked or CXCR7 was silenced. CONCLUSIONS: The SDF-1/CXCR4 axis is involved in the migration of ADSCs and may play a role in the migrate of ADSCs in SUI.

Microbial community structure in an uranium-rich acid mine drainage site: implication for the biogeochemical release of uranium.

The generation of acid mine drainage (AMD) characterized by high acidity and elevated levels of toxic metals primarily results from the oxidation and dissolution of sulfide minerals facilitated by microbial catalysis. Although there has been significant research on microbial diversity and community composition in AMD, as well as the relationship between microbes and heavy metals, there remains a gap in understanding the microbial community structure in uranium-enriched AMD sites. In this paper, water samples with varying levels of uranium pollution were collected from an abandoned stone coal mine in Jiangxi Province, China during summer and winter, respectively. Geochemical and high-throughput sequencing analyses were conducted to characterize spatiotemporal variations in bacterial diversity and community composition along pollution groups. The results indicated that uranium was predominantly concentrated in the AMD of new pits with strong acid production capacity, reaching a peak concentration of 9,370 µg/L. This was accompanied by elevated acidity and concentrations of iron and total phosphorus, which were identified as significant drivers shaping the composition of bacterial communities, rather than fluctuations in seasonal conditions. In an extremely polluted environment (pH < 3), bacterial diversity was lowest, with a predominant presence of acidophilic iron-oxidizing bacteria (such as Ferrovum), and a portion of acidophilic heterotrophic bacteria synergistically coexisting. As pollution levels decreased, the microbial community gradually evolved to cohabitation of various pH-neutral heterotrophic species, ultimately reverting back to background level. The pH was the dominant factor determining biogeochemical release of uranium in AMD. Acidophilic and uranium-tolerant bacteria, including Ferrovum, Leptospirillum, Acidiphilium, and Metallibacterium, were identified as playing key roles in this process through mechanisms such as enhancing acid production rate and facilitating organic matter biodegradation.

Association patterns of ketone bodies with the risk of adverse outcomes according to diabetes status.

AIM: To investigate the associations between ketone bodies (KB) and multiple adverse outcomes including cardiovascular disease (CVD), chronic kidney disease (CKD) and all-cause mortality according to diabetes status. METHODS: This prospective study included 222 824 participants free from CVD and CKD at baseline from the UK Biobank. Total KB including ß-hydroxybutyrate, acetoacetate and acetone were measured by nuclear magnetic resonance. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between KB and adverse outcomes among participants with normoglycaemia, prediabetes and type 2 diabetes, respectively. RESULTS: During a mean follow-up of 14.1 years, 24 088 incident CVD events (including 17 303 coronary heart disease events, 5172 stroke events and 5881 heart failure [HF] events), 8605 CKD events and 15 813 deaths, were documented. Higher total KB significantly increased the risk of HF among participants with normoglycaemia (HR, 1.32 [95% CI, 1.17-1.49], per 10-fold increase in total KB) and prediabetes (1.35 [1.04-1.76]), and increased the risk of CKD among those with normoglycaemia (1.20 [1.09-1.33]). Elevated KB levels were associated with an increased risk of all-cause mortality across the glycaemic spectrum (1.32 [1.23-1.42] for normoglycaemia, 1.45 [1.24-1.71] for prediabetes and 1.47 [1.11-1.94] for diabetes). Moreover, a significant additive interaction between KB and diabetes status was observed on the risk of death (P = .009), with 4.9% of deaths attributed to the interactive effects. CONCLUSIONS: Our study underscored the variation in association patterns between KB and adverse outcomes according to diabetes status and suggested that KB could interact with diabetes status in an additive manner to increase the risk of mortality.

Ultrafast Super-Resolution Imaging Exploiting Spontaneous Blinking of Static Excimer Aggregates.

Single-molecule localization methods have been popularly exploited to obtain super-resolved images of biological structures. However, the low blinking frequency of randomly switching emission states of individual fluorophores greatly limits the imaging speed of single-molecule localization microscopy (SMLM). Here we present an ultrafast SMLM technique exploiting spontaneous fluorescence blinking of cyanine dye aggregates confined to DNA framework nanostructures. The DNA template guides the formation of static excimer aggregates as a "light-harvesting nanoantenna", whereas intermolecular excitation energy transfer (EET) between static excimers causes collective ultrafast fluorescence blinking of fluorophore aggregates. This DNA framework-based strategy enables the imaging of DNA nanostructures with 12.5-fold improvement in speed compared to conventional SMLM. Further, we demonstrate the use of this strategy to track the movement of super-resolved DNA nanostructures for over 20 min in a microfluidic system. Thus, this ultrafast SMLM holds great potential for revealing the dynamic processes of biomacromolecules in living cells.

TOX2 nuclear-cytosol translocation is linked to leukemogenesis of acute T-cell leukemia by repressing TIM3 transcription.

Nuclear factors TOX and TOX2 upregulate TIM3 expression and lead to T-cell exhaustion in malignancies. Here, we demonstrate two distinct TIM3 expression patterns (high & low) with high TOX and TOX2 levels in T-cell acute lymphoblastic leukemia (T-ALL) specimens and cell lines. However, the mechanisms regulated by TOX and TIM3 signaling in leukemogenesis are unclear. We found that TOX and TOX2 proteins each directly upregulated HAVCR2 transcription, while the cellular localization of TOX2 was different in Jurkat and MOLT3 cells (nucleus) and lymphoblastic cell T2 and normal T cells (cytoplasm). Nuclear TOX and TOX2 formed a protein complex and repressed HAVCR2 promoter activity by recruiting transcriptional corepressor LCOR and deacetylase HDAC3. The nuclear-cytosol translocation of TOX2 was deacetylation-dependent and cooperatively mediated by deacetylase Sirt1 and kinase TBK1. Radiation damage induced TOX2 nuclear translocation and decreased Sirt1, TIM3, and caspase 1 expression in normal T cells. Accordingly, knockdown of TOX, TOX2 or LCOR; HDAC3 inhibition; or TIM3 overexpression induced Jurkat cell apoptosis in vitro and slow growth in vivo. Thus, our findings demonstrate a novel regulatory mechanism involving TOX-TOX2 and the TIM3 pathway in the leukemogenesis of T-ALL.

3-Hydroxyneocryptolepine, a new indoloquinoline alkaloid from the roots of Cryptolepis sanguinolenta (Lindl.) Schltr.

Phytochemical investigations of the African ethnomedicinal plant Cryptolepis sanguinolenta (Lindl.) Schltr. (Apocynaceae) have yielded only a small number of rare naturally occurring indoloquinoline alkaloids. Our recent work has resulted in the isolation of a new indoloquinoline named 3-hydroxyneocryptolepine, which was obtained from an ethanolic extract of the roots. The structure of the compound was elucidated based on 1D and 2D NMR as well as HRESIMS spectral evidence. LDL uptake promotion activity of the compound in HepG2 cells was not significant.