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Ye Zhang, Hong Deng, Chao Pan, Yang Hu, Qian Wu, Na Liu, Zhouping Tang Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of China Abstract: Stroke is a clinical disease with high incidence, high disability rate, and high mortality. But effective and safe therapy for stroke remains limited. Adult mesenchymal stromal cells (MSCs) perform a variety of therapeutic functions. MSC delivery improves neurological outcomes in ischemic stroke models via neurorestorative and neuroprotective effects such as angiogenic effects, promoting endogenous proliferation, and reducing apoptosis and inflammation. MSC secretome also showed powerful therapeutic effects as a cell-based therapy in animal experiments. Several clinical trials on MSC implantation via different routes have now been completed in patients with stroke. Although challenges such as immunogenicity of allo-MSCs and large-scale production strategies need to be overcome, MSCs can be considered as a promising potential therapy for ischemic stroke. Keywords: mesenchymal stromal cell, stroke, therapy, transplantation, exosomes

Extraction of methane hydrate from subseafloor reservoir may potentially trigger seabed slides and induce subsidence. To address the problems, it is crucial to properly characterize the phase equilibrium condition of pore hydrate and the shear strength of the soil. As one of the key constitutive components, the phase equilibrium condition enforces a constraint over pore gas pressure, temperature and unhydrated water content. Such a constraint, however, has been traditionally ignored in analyzing the mechanical behavior of hydrate-bearing soil. In this paper, a series of stepwise hydrate dissociation tests was performed, and the phase equilibrium condition of pore hydrate was determined, providing an effective way to evaluate the unhydrated water content during hydrate dissociation. Meanwhile, a series of direct shear tests was also conducted to explore the shear strength characteristics of the soil. It is shown that the shear strength of the hydrate-bearing soil can be significantly influenced by pore gas pressure, unhydrated water content, hydrate saturation and several other factors. In particular, the measured shear strength depends upon the initial water content of the sample, pointing to a potential problem that the shear strength could be wrongly determined if not properly interpreted. A shear strength criterion, which enforces the equilibrium condition of pore hydrate, is developed for hydrate-bearing soil, establishing a link between the equilibrium condition and the shear strength. The proposed equation describes well the shear strength characteristics of hydrate-bearing soils, remarkably unifying the effects of pore pressure, temperature, water content and hydrate saturation.

Propofol, a widely used intravenous anesthetic agent, requires accurate monitoring to ensure therapeutic efficacy and prevent oversedation. Recent developments in modern analytical instrumentation have led to significant breakthroughs in on-line analysis of exhaled breath. This review discusses several sophisticated analytical methods that have been explored for noninvasive, real-time monitoring of propofol concentrations, including proton transfer reaction mass spectrometry, selected ion flow tube mass spectrometry, ion mobility spectrometry, and gas chromatography coupled to surface acoustic wave sensors. These techniques have demonstrated good correlations between plasma and exhaled propofol concentrations and between exhaled propofol concentrations and its cerebral effects. Despite these advances, the use of these technologies in clinical settings is hampered by challenges such as equipment noise, bulkiness, and high cost, as well as limitations related to endotracheal intubation, strong adsorption of propofol to components of the respiratory circuit, variability in respiratory patterns, susceptibility to changes in pulmonary ventilation and blood flow, inconsistencies in calibration methods, and the influence of other drugs and temperature fluctuations on measurement accuracy. Overcoming these technical and procedural challenges is critical to advancing the clinical application of breath analysis for propofol monitoring. This article reviews published studies and summarizes the progress and ongoing challenges in the field.

The size range of respiratory droplets contributing to long-range airborne transmission of infections determines the targeted intervention methods. However, the exact size range remains unknown, and the influencing parameters are also undetermined. Here, we investigated the size-resolved transport and fate of respiratory droplets in four reported venues of COVID-19 outbreaks. We utilised a transient number balance model, a set of expired droplet size distributions, existing formulas for size-resolved settling rates and filtration efficiencies, and a deposition model from the International Commission on Radiological Protection. This enabled us to obtain the size-resolved concentrations of exhaled droplets in indoor air, the size-resolved number of droplet nuclei in the inhaled air, and the number of droplets deposited throughout the respiratory tract. The newly defined airborne transmission size range of expired droplets depends on the effective dilution flow rate of the infection venue under consideration. Three criteria were proposed for determining the sizes of droplets involved in long-range airborne transmission. The airborne transmission droplets typically featured an initial diameter of 0.1–4–6 µm, with an hourly volume generation rate of 0.38–0.42 nL/h per index case in the four venues. This newly estimated volume of airborne transmission droplets provides an essential input into the viral load method for estimating the infectious quanta generation rate. Practical significance: Our size-resolved estimation reveals that only a tiny fraction of expired infectious droplets within an airborne transmission size range survives after the removal effects of ventilation, settling, deactivation, and filtration, as well as the transient dilution effect. These droplets remain in indoor air, potentially contributing to long-range airborne transmission. The airborne transmission size range depends on the size-dependent dilution capacity of a room.

Background: Since the inception of the term “Biomimetics” in 1991, the concept of utilizing natural solutions or deriving inspiration from nature to address contemporary engineering challenges has gained significant attention within the scientific community. Organisms, in order to thrive in harsh environments, have evolved a wide range of micro/nanostructured surfaces, which serve as a rich source of inspiration for the development of artificial micro/nano-structured surfaces. These natural adaptations provide valuable insights and novel pathways for fabricating such surfaces. Aim: To conclude recent advances in micro/nano-structured surfaces from four aspects: biomimetic micro-structured surfaces of plants and animals, properties and applications of biomimetic surfaces, methods of preparations, and their limitation. Key Scientific Concepts:: Artificial micro/nano-structured surfaces inspired by animals and plants are classified and demonstrated according to their living environment. The performances, principles and preparation techniques of natural superhydrophobic surfaces, slippery liquid-infused porous surfaces (SLIPS), anisotropic surfaces, etc. are described in detail. Moreover, the pros and cons of each preparation measures are compared and the challenges developing large-scale, cost-effective surface microstructure preparation processes are pointed out. In the end, the development trends of artificial micro/nano-structured surface are forecasted.

Extracting road network maps for high-resolution remote sensing images is a critical and challenging remote sensing topic, with significant importance for traffic navigation, disaster management, autonomous driving, and urban planning. Although deep learning has demonstrated its powerful feature extraction capabilities in image processing tasks, including road extraction, existing road extraction algorithms still have some limitations. In particular, semantic segmentation-based methods often lack supervision of the connection relationships between roads and topological correctness constraints, resulting in fragmented and poorly connected road network graphs. Moreover, graph-based methods lack effective supervision strategies for vertex misdetection issues. To deal with these issues, we propose a deeply supervised vertex network (DSVNet) for road network graph extraction. First, to effectively supervise road vertices, we design a road vertex supervision module that yields improved vertex prediction accuracy. Second, to merge the benefits of segmentation-based methods and graph-based methods, we establish a parallel semantic segmentation branch based on the vertex querying task, thereby achieving enhanced road extraction accuracy. Furthermore, we introduce deformable attention into the model to boost its performance and computational efficiency. We validate the effectiveness of DSVNet on two large-scale public datasets. A large number of experimental results show that our research approach achieves the best road detection performance.

Study region: Tributaries of the Yellow River, Upper Fen River Basin, China. Study focus: The current research analyzed the streamflow changes resulting from interactions between climate and land use/cover (LULC) under Shared Socioeconomic Pathways (SSPs). The study utilized six General Circulation Models (GCMs) from Climate Model Intercomparison Project-6 (CMIP6) and the Land-Use Harmonization 2 (LUH2) dataset as forcing inputs for the Soil and Water Assessment Tool (SWAT) model. This study aims to quantitatively access the alone and combined effects of climate and LULC changes on future streamflow. New hydrologic insights for the region: The change in future streamflow under the combined effect of climate and LULC exceeded the change observed under the influence of climate or LULC alone in the Fenhe Reservoir Hydrological Station Control Basin (FRCB). The contributions were 72.5 % (SSP126), 73.1 % (SSP245), and 77.2 % (SSP585), respectively. Climate change showed a stronger correlation with future streamflow than LULC changes. Precipitation had the most direct effect on streamflow among the meteorological factors. The expansion of urban land contributes to an increase in streamflow in the source area and southwest tributaries of the FRCB to some extent. The future streamflow will gradually increase in mid-century (2045–2066) under low to high SSP. Adapting effective strategies for the FRCB, can be helpful in water resources planning and management.

The antibodies of outer membrane proteins (OMPs) of bacteria have application value in polyvalent passive vaccines. IgY antibodies can be obtained in large quantities and economically from egg yolk, and have the potential to be applied in aquaculture. The OMPs (OmpAII, OmpW, P5, and Slp) of Aeromonas hydrophila were expressed and purified, and the corresponding IgY antibodies were prepared. Passive immunization to goldfish (Carassius auratus) indicated that the four IgY antibodies had an effective immune protection rate, could activate the innate immune responses, down-regulated the expression of inflammation-related genes (p < 0.05) to reduce inflammatory reactions, down-regulated the expression of antioxidant-related factors (p < 0.05) to reduce antioxidant reactions, protected the integrity of visceral tissue structure, and reduced apoptosis and DNA damage for kidney cells infected by A. hydrophila and Pseudomonas fluorescens. Moreover, the IgY passive (A. hydrophila) and passive cross-protective (P. fluorescens) abilities of OmpW and Slp were higher than those of OmpAII and P5. Thus, the IgY antibodies of OmpW and Slp can be considered as polyvalent vaccine candidates for passive immunization in aquaculture.

Electro-optic (EO) crystals are important material for all-solid-state laser technology, which can be used to fabricate various laser modulators, such as EO switches, laser deflectors, and optical waveguide. The improvements in new high-efficiency EO crystal materials have held great significance to the development of laser technology. Potassium tantalate niobate (KTN) is a popular multifunctional crystal because of its remarkable and excellent quadratic EO effect. KTN EO modulation technology offers numerous advantages, such as high efficiency, good stability, a quick response time, and inertia-free characteristics. In this paper, we summarize the research progress of KTN series crystals systemically, including the theoretical exploration on quadratic EO effect, solid-melt crystal growth technique, comprehensive physical characterization, new physical effect and mechanisms exploration, new EO devices development and design. The EO modulation technique based on the Kerr effect of KTN series crystal offers obvious advantages in reducing the drive voltage and device size, which could better meet the developmental needs of future lasers with a wide wavelength, miniaturization, and integration. This may provide theoretical guidance and an experimental basis for the design and development of new EO crystal devices and promote the development of laser technology.

Shear strength is an essential geotechnical parameter for assessing the landslide potential of loess slopes under rainfall infiltration and farm irrigation conditions on the loess plateau. However, the hydraulic path dependence of shear strength for compacted loess under varying rainfall infiltration conditions has not been thoroughly investigated yet. To this end, a series of direct shear tests and nuclear magnetic resonance (NMR) measurements are carried out on compacted loess. The shear strength tests were continuously implemented on loess specimens under scanning wetting paths besides initial drying paths. The experimental data quantitatively verify the significant effect of hydraulic paths applied to specimens on shear strength of compacted loess. The unique failure envelope of shear strength of loess is identified under the effective stress framework based on intergranular stress, which verifies that the effective stress framework can consider the effect of hydraulic paths on shear strength. Based on the effective stress, a shear strength formula is proposed to characterize shear strengths under varying hydraulic paths, in which the parameters from the soil-water retention curve and shear strength at saturated state are simply required. The proposed shear strength formula can properly predict the measured shear strength data of compacted loess experiencing three hydraulic paths. Furthermore, the distribution curves of transverse relaxation time for pore water in soil under varying hydraulic paths are simultaneously measured using the NMR method. The physical mechanism for the difference in shear strength of loess subjected to different hydraulic paths can be uncovered based on soil-water evolutions in pores in microscale.

With the continuous increase in low altitude flight density, the issue of low altitude navigation safety has attracted widespread attention. Due to the complex low altitude environment, low altitude flight is more susceptible to ground obstacles and weather effects than commercial aviation. In order to ensure the flight safety of helicopters in low altitude airspace, this paper proposes an improved support vector machine based flight conflict detection model. By modeling the conflict network in low altitude flight areas and utilizing Support Vector Machine (SVM) classification features, the safety discrimination of low altitude flight was achieved, ultimately achieving the safety of aircraft in low altitude flight. This article adopts a protected area model that considers the shape of the aircraft as a conflict zone. In order to reduce the complexity of the conflict detection model, an improved ID3 decision tree algorithm and random forest are used to reduce the complexity of the classifier. The study solved the saturation problem of S-type functions in conflict detection models by using more sensitive functions for probability mapping. And use intelligent optimization algorithms to pre train key parameters, achieving efficient conflict detection suitable for low altitude flight.

This study aimed to explore the differences in raw Angelica Sinensis (RAS), wine washing AS (WAS), and wine stir-frying AS (WSAS). The results showed there were differences among the three AS in color and aroma, and 34 aroma compounds were identified. The content determination results revealed the ferulic acid and Z-ligustilide levels of RAS decreased after processing, and those in WAS were higher than in WSAS. Furthermore, 85 representative common components and 37 unique components were tentatively identified in three AS. Finally, the free radical scavenging assay results indicated the antioxidant capacity of RAS was reduced after processing, and the antioxidant capacity of WAS was better than WSAS. Collectively, the RAS undergoes significant changes in color, aromas, components, and antioxidant ability after processing, and the different processing methods also result in significant differences between WAS and WSAS.

The NLRP3 inflammasome’s core and most specific protein, NLRP3, has a variety of functions in inflammation-driven diseases. Costunolide (COS) is the major active ingredient of the traditional Chinese medicinal herb Saussurea lappa and has anti-inflammatory activity, but the principal mechanism and molecular target of COS remain unclear. Here, we show that COS covalently binds to cysteine 598 in NACHT domain of NLRP3, altering the ATPase activity and assembly of NLRP3 inflammasome. We declare COS’s great anti-inflammasome efficacy in macrophages and disease models of gouty arthritis and ulcerative colitis via inhibiting NLRP3 inflammasome activation. We also reveal that the α-methylene-γ-butyrolactone motif in sesquiterpene lactone is the certain active group in inhibiting NLRP3 activation. Taken together, NLRP3 is identified as a direct target of COS for its anti-inflammasome activity. COS, especially the α-methylene-γ-butyrolactone motif in COS structure, might be used to design and produce novel NLRP3 inhibitors as a lead compound.

Brain natriuretic peptide (BNP) belongs to the family of natriuretic peptides, which are responsible for a wide range of actions. Diabetic cardiomyopathy (DCM) is often associated with increased BNP levels. This present research intends to explore the role of BNP in the development of DCM and the underlying mechanisms. Diabetes was induced in mice using streptozotocin (STZ). Primary neonatal cardiomyocytes were treated with high glucose. It was found that the levels of plasma BNP started to increase at 8 weeks after diabetes, which preceded the development of DCM. Addition of exogenous BNP promoted Opa1-mediated mitochondrial fusion, inhibited mitochondrial oxidative stress, preserved mitochondrial respiratory capacity and prevented the development of DCM, while knockdown of endogenous BNP exacerbated mitochondrial dysfunction and accelerated DCM. Opa1 knockdown attenuated the aforementioned protective action of BNP both in vivo and in vitro. BNP-induced mitochondrial fusion requires the activation of STAT3, which facilitated Opa1 transcription by binding to its promoter regions. PKG, a crucial signaling biomolecule in the BNP signaling pathway, interacted with STAT3 and induced its activation. Knockdown of NPRA (the receptor of BNP) or PKG blunted the promoting effect of BNP on STAT3 phosphorylation and Opa1-mediated mitochondrial fusion. The results of this study demonstrate for the first time that there is a rise in BNP during the early stages of DCM as a compensatory protection mechanism. BNP is a novel mitochondrial fusion activator in protecting against hyperglycemia-induced mitochondrial oxidative injury and DCM through the activation of NPRA-PKG-STAT3-Opa1 signaling pathway.

Summary: The abnormal regulation of BMAL1 could lead to the occurrence and progression of various tumors. However, the mechanism of phosphorylation regulation of BMAL1 in tumorigenesis remains poorly understood. In this study, we report a previously unrecognized BMAL1 dephosphorylation pathway that promotes tumor progression. BMAL1 accelerates cell proliferation, migration, and invasion of HT1080 and Calu1 cells. CDK1 binds to BMAL1 through a conserved domain and regulates the dephosphorylation of BMAL1 on Ser42 residues, but not on Ser78 or Thr224, thereby enhancing the oncogenic activity of BMAL1. Dephosphorylation of BMAL1 Ser42 promotes tumor growth and metastasis in mouse subcutaneous transplantation tumor and lung metastatic tumor models. Moreover, UHRF1 is recognized as an important target gene of BMAL1 in cancer cells. Consequently, UHRF1 depletion mimics BMAL1 deficiency with respect to tumor suppression, whereas transfection-enforced re-expression of UHRF1 restores tumor growth in BMAL1-deficient cells. These findings suggest a link between the circadian clock regulator and cancer progression.

Background and aims: Urine ketone bodies have been considered as predictors of stroke in diabetic patients, however, the role of urine ketone bodies in the prognosis of stroke has not been investigated well. This study aimed to investigate the association between urine ketone bodies and adverse outcomes in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA). Methods: This study enrolled 14 015 patients with AIS or TIA who screened for urine ketone bodies from the Third China National Stroke Registry. Status of urine ketone bodies were classified into negative, suspicious positive and positive. The outcomes were all-cause death and poor functional outcomes (modified Rankin Scale [mRS] 2–6/3-6) at 3 months and 1 year. Multivariable Cox proportional hazards regressions and logistic regressions were adopted to explore the associations. Results: Participants with negative, suspicious positive and positive urine ketone bodies were 12979 (92.61%), 480 (3.42%) and 556 (3.97%). After multivariate adjustment, patients with positive urine ketone bodies had a higher risk of all-cause death (hazard ratio, 1.74; confidence interval [CI], 1.07–2.83), a higher proportion of mRS score 2–6 (Odds ratio [OR], 1.85; 95% CI, 1.51–2.27), mRS score 3–6 (OR, 2.00; 95% CI, 1.61–2.48) at 3 months, compared to those with negative urine ketone bodies. Significant associations persisted at 1 year. Furthermore, there was no significant interaction of diabetes status and alcohol use with urine ketone bodies. Conclusions: Positive urine ketone bodies can independently predict all-cause death and poor functional outcomes in patients with AIS or TIA.

Background and aims: High remnant cholesterol is associated with cardiovascular disease (CVD), but whether CVD risk attributable to remnant cholesterol vary between young and later adults remains unknown. The study aimed to assess age differences in the association between remnant cholesterol and CVD. Methods: This prospective study included 95 663 participants without CVD and lipid-lowering treatment at baseline, including 16 254 young adults (age 18–39 years) and 79 409 later adults (age ≥40 years). Individuals were grouped by clinically meaningful remnant cholesterol concentrations of

Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury, and its prognosis depends on the balance between hepatocyte death and regeneration. Sirtuin 6 (SIRT6) has been reported to protect against oxidative stress-associated DNA damage. But whether SIRT6 regulates APAP-induced hepatotoxicity remains unclear. In this study, the protein expression of nuclear and total SIRT6 was up-regulated in mice liver at 6 and 48 h following APAP treatment, respectively. Sirt6 knockdown in AML12 cells aggravated APAP-induced hepatocyte death and oxidative stress, inhibited cell viability and proliferation, and downregulated CCNA1, CCND1 and CKD4 protein levels. Sirt6 knockdown significantly prevented APAP-induced NRF2 activation, reduced the transcriptional activities of GSTμ and NQO1 and the mRNA levels of Nrf2, Ho-1, Gstα and Gstμ. Furthermore, SIRT6 showed potential protein interaction with NRF2 as evidenced by co-immunoprecipitation (Co-IP) assay. Additionally, the protective effect of P53 against APAP-induced hepatocytes injury was Sirt6-dependent. The Sirt6 mRNA was significantly down-regulated in P53−/− mice. P53 activated the transcriptional activity of SIRT6 and exerted interaction with SIRT6. Our results demonstrate that SIRT6 protects against APAP hepatotoxicity through alleviating oxidative stress and promoting hepatocyte proliferation, and provide new insights in the function of SIRT6 as a crucial docking molecule linking P53 and NRF2.

For a long time, ilmenite floatability in strongly acidic pulp has not received enough attention, which violates compliance requirements for the industrial production of ilmenite concentrate. In this present study, decanoic acid was found to be an effective collector, to float ilmenite in strongly acidic pulp (especially for the pH range from 3 to 6). The combination of decanoic acid and oleate proved to be significant in improving ilmenite floatability within a broad pH range, and especially at a pH around 4. The most synergistic and effective result occurred when the ratio of decanoic acid and oleate was 1:2, and the difference in flotation recovery of ilmenite and titanaugite was also increased at a pH around 4. Therefore, the collector scheme with a 1:2 ratio of decanoic acid and oleate was significant in strengthening ilmenite flotation behavior and its selective separation. Keywords: Ilmenite, Decanoic acid, Oleate, Acidic floatability

This paper accompanies the paper titled ''Defining and predicting early recurrence in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy'' presented by the same authors to the European Journal of Surgical Oncology [1]. The present article describes the relevant clinical data of patterns of initial recurrence after curative surgery for rectal cancer with neoadjuvant therapy. This data was collected from the hospital records, Chinese Population Registration and Health Insurance System.

Background: Human are widely exposed to multiple metals, some of which have suspected reproductive toxicity, but no human studies have investigated the developmental effects of prenatal metal exposure. Objectives: We aimed to evaluate the associations between prenatal multiple metal exposure and reproductive development in boys at 2–3 years using multi-pollutant approach. Methods: This prospective study used data of 564 mother–child pairs recruited from the Guangxi Birth Cohort Study. Twenty serum metal concentrations were measured. Least absolute shrinkage and selection operator (LASSO) penalized regression was used to identify independent associations between prenatal multiple metal exposure and testicular volume (TV), and anogenital distance (AGD). Adjusted estimates were then obtained using multiple linear regression analysis, and the regression tree method was used to explore the interactions. Results: Boys in the highest quartile of prenatal lead exposure had a 0.064 mL (95% CI: −0.124, −0.004) smaller ln-transformed TV, 0.060 cm (95% CI: −0.110, −0.011) shorter ln-transformed anopenile distance (AGDap), and 0.115 cm (95% CI: −0.190, −0.039) shorter ln-transformed anoscrotal distance (AGDas) than boys in the lowest quartile (all Ptrend

Nest predation is a major limiting factor of bird reproductive success, and predation by snakes may have particularly adverse effects on passerines. The reed parrotbill (Paradoxornis heudei) is a threatened passerine that inhabits reedbeds in East China, where it faces the risk of population decline due to habitat loss and degradation. Studies on the nest predation of this species are lacking. In this study, we monitored reed parrotbill nests in the core area of the Yancheng Nature Reserve, Jiangsu Province, China. We tracked the final fate of each nest and determined the identity of the predators using infrared cameras. We monitored a total of 13 and 15 active nests in 2017 and 2019, respectively, but only 5 nests were successful. Nest predation was responsible for 22 of 23 nest failures (95.7%). Snakes were the principal predators of the nests, responsible for 19 predation events (86.4%). We used abandoned reed parrotbill nests and quail eggs to create artificial nests. However, the survival rate of the artificial nests (63.3%) was significantly higher than that of the natural nests (11.3%), and rats replaced snakes as the principal predators. The best model indicated that the daily survival rate of reed parrotbill nests decreased with nest age. Our findings suggest that severe snake predation may be an important factor threatening populations of the reed parrotbill, even though the wetland habitat is well protected. The identification of specific nest predators may facilitate the conservation of this near-threatened bird through the development of effective management strategies in reserves. More studies on population estimates of the reed parrotbill and the interactions between this endangered bird and snakes using natural (rather than artificial) nests in different areas are needed. Keywords: Nest predation, Snake, Paradoxornis heudei, Threatened bird, Elaphe anomala

In this article, we report original data on the designation of the primers for full-length cDNA amplification and the internal cDNA amplification of red color-related pigment-binding protein derived from shrimp shell. Data on the color shifts of different soluble proteins under 100 °C 10 min heat treatment and the effects of heating temperatures (from 30 to 100 °C) on the color changes of crude water-soluble proteins are also included in this report. For further details and experimental findings please refer to the article “Isolation and cDNA cloning of a novel red color-related pigment-binding protein derived from the shell of shrimp, Litopenaeus vannamei” (Chuang et al., 2017) [1].

Objectives: Chronic hyperlipidemia and hyperglycemia are characteristic features of type 2 diabetes (T2DM) that are thought to cause or contribute to β-cell dysfunction by “glucolipotoxicity.” Previously we have shown that acute treatment of pancreatic islets with fatty acids (FA) decreases acetylcholine-potentiated insulin secretion. This acetylcholine response is mediated by M3 muscarinic receptors, which play a key role in regulating β-cell function. Here we examine whether chronic FA exposure also inhibits acetylcholine-potentiated insulin secretion using mouse and human islets. Methods: Islets were cultured for 3 or 4 days at different glucose concentration with 0.5 mM palmitic acid (PA) or a 2:1 mixture of PA and oleic acid (OA) at 1% albumin (PA/BSA molar ratio 3.3). Afterwards, the response to glucose and acetylcholine were studied in perifusion experiments. Results: FA-induced impairment of insulin secretion and Ca2+ signaling depended strongly on the glucose concentrations of the culture medium. PA and OA in combination reduced acetylcholine potentiation of insulin secretion more than PA alone, both in mouse and human islets, with no evidence of a protective role of OA. In contrast, lipotoxicity was not observed with islets cultured for 3 days in medium containing less than 1 mM glucose and a mixture of glutamine and leucine (7 mM each). High glucose and FAs reduced endoplasmic reticulum (ER) Ca2+ storage capacity; however, preserving ER Ca2+ by blocking the IP3 receptor with xestospongin C did not protect islets from glucolipotoxic effects on insulin secretion. In contrast, an inhibitor of casein kinase 2 (CK2) protected the glucose dependent acetylcholine potentiation of insulin secretion in mouse and human islets against glucolipotoxicity. Conclusions: These results show that chronic FA treatment decreases acetylcholine potentiation of insulin secretion and that this effect is strictly glucose dependent and might involve CK2 phosphorylation of β-cell M3 muscarinic receptors.

Summary: Histone methylation is essential for regulating gene expression during organogenesis to maintain stem cells and execute a proper differentiation program for their descendants. Here we show that the COMPASS family histone methyltransferase co-factor ASH2L is required for maintaining neural progenitor cells (NPCs) and the production and positioning of projection neurons during neocortex development. Specifically, loss of Ash2l in NPCs results in malformation of the neocortex; the mutant neocortex has fewer neurons, which are also abnormal in composition and laminar position. Moreover, ASH2L loss impairs trimethylation of H3K4 and the transcriptional machinery specific for Wnt-β-catenin signaling, inhibiting the proliferation ability of NPCs at late stages of neurogenesis by disrupting S phase entry to inhibit cell cycle progression. Overexpressing β-catenin after ASH2L elimination rescues the proliferation deficiency. Therefore, our findings demonstrate that ASH2L is crucial for modulating Wnt signaling to maintain NPCs and generate a full complement of neurons during mammalian neocortex development. : Precise orchestration of gene expression dynamics is essential for stem cells to execute a proper differentiation program during organogenesis. Li et al. demonstrate that ASH2L, a core subunit of the COMPASS methyltransferase complex, is critical for maintaining neural progenitor cells and the generation of different neuronal types during mammalian neocortical development. Keywords: ASH2L, COMPASS, Wnt signaling pathway, corticogenesis, H3K4me3, cell cycle, neurogenesis

The pregnane X receptor (PXR) has been well-established as a critical mediator in regulating important drug metabolizing enzymes and transporter proteins, including cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Previous studies identified that PXR served as a molecular target of SUMOylation. However, the impact of SUMOylation of PXR on its transcriptional activity in regulating the expression/activity of the target genes is poorly investigated. In the current study, we established cell-based models of SUMOylated PXR in LS174T cells to investigate the impact of SUMOylation of PXR on regulating the expression/activity of CYP3A4 and P-gp. Our results revealed that rifampicin-induced PXR transactivation of the CYP3A4 and P-gp promoter was suppressed by SUMOylation of PXR in reporter gene assay. The mRNA and protein expression of CYP3A4 and P-gp was also suppressed. Moreover, CYP3A4 enzymatic assay and Rho123 intracellular assay revealed that rifampicin-induced CYP3A4 and P-gp activity was also suppressed by SUMOylated PXR. Our data collectively indicated for the first time that SUMOylation of PXR exerts suppressive effect on rifampicin-induced expression and activity of CYP3A4 and P-gp, which suggest that alteration in the SUMOylation status of PXR will be expected to affect the CYP3A4 mediated drug metabolism and P-gp mediated drug transport.

Objectives: Hyperglycemia and elevated blood lipids are the presumed precipitating causes of β-cell damage in T2DM as the result of a process termed “glucolipotoxicity”. Here, we tested whether glucolipotoxic pathophysiology is caused by defective bioenergetics using islets in culture. Methods: Insulin secretion, respiration, ATP generation, fatty acid (FA) metabolite profiles and gene expression were determined in isolated islets treated under glucolipotoxic culture conditions. Results: Over time, chronic exposure of mouse islets to FAs with glucose leads to bioenergetic failure and reduced insulin secretion upon stimulation with glucose or amino acids. Islets exposed to glucolipotoxic conditions displayed biphasic changes of the oxygen consumption rate (OCR): an initial increase in baseline and Vmax of OCR after 3 days, followed by decreased baseline and glucose stimulated OCR after 5 days. These changes were associated with lower islet ATP levels, impaired glucose-induced ATP generation, a trend for reduced mitochondrial DNA content and reduced expression of mitochondrial transcription factor A (Tfam). We discovered the accumulation of carnitine esters of hydroxylated long chain FAs, in particular 3-hydroxytetradecenoyl-carnitine. Conclusions: As long chain 3-hydroxylated FA metabolites are known to uncouple heart and brain mitochondria [53–55], we propose that under glucolipotoxic condition, unsaturated hydroxylated long-chain FAs accumulate, uncouple and ultimately inhibit β-cell respiration. This leads to the slow deterioration of mitochondrial function progressing to bioenergetics β-cell failure.

Abstract.: The pregnane X receptor (PXR, NR1I2), a member of the nuclear receptor superfamily, is activated by a number of clinically prescribed drugs and herbal extracts. The inducible expression of several important cytochrome P450 (CYP450) enzymes has been shown to be regulated by the activation of PXR in the liver. In the current study, reporter gene–transfected cells were used to identify potential antagonists of PXR. Here, we showed that resveratrol (RES), a natural polyphenolic compound could significantly suppress the rifampicin-induced PXR transactivation of the CYP3A4 promoter. Treatment of hPXR–over-expressed cells with RES reduced the rifampicin-inducible expression of CYP3A4 in a concentration-dependent manner. Moreover, the induction of mRNA and protein expression of CYP3A11 by pregnenolone 16α-carbonitrile was also significantly reduced when RES was applied in primary cultures of mouse hepatocytes. Taking together, these findings suggest that RES can attenuate the PXR-mediated induction of CYP3A enzyme. Therefore, it would be possible for RES to antagonize the elevation in CYP3A-mediated drug metabolism by identified PXR activators. Keywords:: pregnane X receptor, CYP3A, resveratrol, rifampicin, antagonist

Microcystin-leucine-arginine (MC-LR) produced by cyanobacterial harmful algal blooms are hazardous materials. However, the toxicity and mechanisms of continuous exposure to MC-LR on the occurrence of osteoporosis remains poorly documented. In this study, to mimic the chronic influences of MC-LR on the bone tissues in humans, an animal model was constructed in which mice were treated with MC-LR through drinking water at an environmentally relevant level (1-30 μg/L) for 6 months. MC-LR was enriched in the skeletal system, leading to the destruction of bone microstructure, the decrease of bone trabecular number, the reduction of osteoblasts, the enhanced content of lipid droplets, and the activation of osteoclasts, which is the characteristic of osteoporosis. Herein, we revealed ferroptosis is a vital mechanism of osteoblast death in mouse models of MC-LR. MC-LR exposure activates AMPK/ULK1 signaling, further promotes ferritin selective autophagy, causes free iron release and lipid peroxidation deposition, and eventually leads to ferroptosis of osteoblasts. Importantly, the use of AMPK or ferroptosis inhibitors in vivo markedly reduced MC-LR-induced osteoblast death and impaired osteogenic differentiation. Interestingly, MC-LR exposure promotes iron uptake in bone marrow macrophages through the TF-TFR1 pathway, leading to its transformation to TRAP-positive pre-osteoclast cells, thereby promoting bone resorption. Overall, our data innovatively revealed the core mechanism of MC-LR-induced osteoporosis, providing the bi-directional regulation of MC-LR on osteoblast-osteoclast from the perspective of iron homeostasis imbalance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Antiviral drugs are widely used, yet their potential risks during early development, particularly within the central nervous system, remain contentious. Oseltamivir phosphate (OSE), a commonly prescribed antiviral, is increasingly detected in various environments. However, its toxicity to organisms and the underlying mechanisms are not well understood. In this study, we employed the zebrafish model to evaluate the developmental neurotoxic effects of OSE at environmentally and therapeutically relevant doses, through high-throughput behavioral analysis, in vivo two-photon imaging, transcriptomic sequencing, pharmacological intervention, and biochemical and molecular assays. Our results indicated that OSE exposure increased heart rate and induced pericardial edema in zebrafish larvae. Additionally, OSE-exposed larvae exhibited hyperactive behavior, impaired social interactions, and reduced habitual learning capacity. Although OSE at our selected levels did not significantly affect neuron count in the brain, it activated neuroinflammatory responses, altered blood vessel morphology, modulated neurotransmitter levels and the expression of neurodevelopment-related genes. Transcriptomic analysis revealed upregulation of mitochondria-related genes associated with oxidative phosphorylation. Further assessments of mitochondrial function demonstrated altered activities of respiratory chain complexes, reduced mitochondrial membrane potential (MMP), and decreased ATP content. Notably, co-treatment with mitochondrial protectants acetyl-l-carnitine-hydrochloride (ALC) or nicotinamide riboside (NR) effectively mitigated OSE-induced neurobehavioral disorders. These findings suggest that overuse of OSE can pose neurodevelopmental risks for both humans and animals, potentially attributable to mitochondrial dysfunction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

With the increasing prevalence of microplastics (MPs) in the environment, human health has become a growing concern. After entering the human body, MPs accumulate in the kidneys, indicating that the kidneys are their major target organs. This study investigated nephrotoxicity associated with MPs, with a specific focus on polystyrene (PS) MPs and amino-functionalized polystyrene (PS-NH 2 ) MPs. Although previous studies have documented the nephrotoxic effects associated with short-term exposure to MPs, the mechanisms of kidney toxicity caused by chronic long-term exposure to MPs remain largely unclear. In animal models, mice were exposed to MPs (10 mg/L) at concentrations that are accessible to humans, administered via drinking water over a period of six months. These findings indicate that MPs can induce renal fibrosis by facilitating the onset of inflammation and accumulation of a substantial number of inflammatory cells. Our in vitro study showed that long-term exposure to MPs (60 μg/mL) induced ferroptosis in renal tubular epithelial cells via ferritinophagy and secreted TGF-β1, leading to renal fibroblast activation. Conversely, the application of Fer-1, a ferroptosis inhibitor, prevents ferroptosis in renal epithelial cells and reverses the activation of renal fibroblasts. Our study identified a novel toxicity mechanism for renal fibrosis induced by MPs exposure, offering new insights into the detrimental effects of environmental MPs on human health., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Herein, the intricate molecular interplay between human serum albumin (HSA) and tungsten disulfide quantum dots (WS 2 QDs) was probed using spectroscopic techniques and sophisticated molecular simulation methods. Fluorescence spectroscopy demonstrated that under physiological conditions, WS 2 QDs forge a non-fluorescent ground-state complex with HSA, facilitated by hydrogen bonding and van der Waals forces, ultimately resulting in the static quenching of the protein's intrinsic fluorescence. Complementary site competition experiments and molecular docking simulations reinforced a precise 1: 1 binding stoichiometry, predominantly targeting HSA's Site I. Three-dimensional fluorescence spectroscopy revealed that WS 2 QDs perturb the HSA polypeptide backbone, subtly modifying the microenvironment surrounding aromatic amino acid residues. This alteration was further corroborated by circular dichroism spectroscopy, marked by a decrease in helical content and a transition towards irregular peptide conformations. Thermal stability assays illuminated the reduced thermal resilience of the HSA - WS 2 QD complex. Laser confocal microscopy coupled with thioflavin T staining yielded compelling evidence that WS 2 QDs effectively inhibit amyloid fibril formation in both HSA and lysozyme, underscoring their potential as potent anti-amyloidogenic agents. This comprehensive study offers pivotal insights into multifaceted impact of WS 2 QDs on protein structure and function, thereby expanding their horizon of potential applications within the burgeoning field of nanomedicine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Coronary heart disease (CHD) poses a significant threat to patients' health, with stable angina pectoris (SAP) being prevalent among individuals with CHD. This study aims to evaluate the effects of Traditional Chinese Exercise (TCE) on the physical and mental well-being, as well as the quality of life, of patients suffering from SAP., Methods: We searched databases including China National Knowledge Infrastructure (CNKI), Wanfang, China Science and Technology Journal Database, PubMed, Web of Science, Cochrane and Embase for randomised controlled trials evaluating the effects of TCE on patients with SAP. Effect sizes and heterogeneity were calculated using RevMan 5.3 software., Results: A total of 14 studies involving 1,288 participants were included in the analysis. Most studies were assessed to have a moderate risk of bias. The pooled results indicated that TCE significantly improved the 6-Minute Walk Test scores of patients with SAP (MD = 35.48, 95 % CI: 23.66-47.29, P < 0.001), enhanced scores across various dimensions of the Seattle Angina Questionnaire (P < 0.05), and reduced levels of depression (MD = -6.32, 95 % CI: -9.13 to -3.51, P < 0.001) and anxiety (MD = -6.41, 95 % CI: -9.18 to -3.64, P < 0.001) among SAP patients. Additionally, the Egger's test revealed no significant publication bias across the outcomes (P > 0.05)., Conclusion: TCE significantly enhances the physical and mental health of SAP patients, leading to improved quality of life. Future studies with larger sample sizes and high methodological quality are needed to further evaluate the clinical efficacy of TCE., Competing Interests: Declaration of competing interest All authors have declared that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Antibiotics and microplastics (MPs) often coexist in facility agriculture soils due to the prevalent use of animal manure and plastic films. However, their combined impacts on the rhizosphere environment of lettuce remain unclear. This study assessed the effects of individual and combined exposure to polyethylene (PE) MPs (2 g·kg -1 ) and oxytetracycline (OTC) (0, 5, 50, and 150 mg·kg -1 ) on the growth of lettuce seedlings and enzyme activities, physicochemical properties, metabolite profiles and bacterial communities of rhizosphere soil of lettuce. Exposure to 150 mg·kg -1 OTC, either individually or combined, significantly increased lettuce seedling shoot biomass. All treatments decreased chlorophyll and carotenoid contents. Combined exposure notably increased the Simpson's index of rhizosphere bacterial communities and altered community composition. The number of differential genera of rhizosphere was less than that of non-rhizosphere. Combined exposure significantly changed both rhizosphere and non-rhizosphere metabolite profiles. Soil organic matter emerged as the key environmental factor influencing bacterial community variation. Mantel tests revealed strong positive associations between total potassium and rhizosphere bacterial communities under combined exposure. The correlation network identified stearic acid and palmitic acid as the core metabolites in the rhizosphere. These findings offer valuable insights into the impact of OTC combined with PE MPs on lettuce rhizosphere environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Mariculture tail water is characterized as the low C/N ratios and thus blocks the conventional heterotrophic denitrification process due to insufficient carbon source. Therefore, oligotrophic marine bacteria with heterotrophic nitrification and aerobic denitrification (HN-AD) are urgently required to bioaugment aerobic biological filter. In this study, Marinobacter alkaliphilus SBY-1 was isolated and confirmed optimal nitrate removal capacity at a rate of 716 mg/L·d without ammonia production or nitrite accumulation under initial nitrate concentration of 800 mg/L, pH 7, salinity 20 ‰, sodium acetate as the carbon source, and low C/N ratios of 3.6. SBY-1 also demonstrated heterotrophic nitrification capability with a maximum ammonia removal rate reaching 69.21 % when ammonia was used as the nitrogen source. The enzymes involved in the HN-AD process including ammonia monooxygenase (AMO), nitrate reductase (NR), and nitrite reductase (NIR) were all detected in SBY-1 with superior activity observed for NR and NIR. Additionally, analysis of EPS and auto-aggregation revealed that SBY-1 exhibited excellent auto-aggregation ability under high influent nitrogen concentration conditions, making it more suitable for biofilm formation and further application in biofilm-based denitrification process. Genome analysis identified genes associated with Nar, Nap, Nas, Nir, Nif, Nrt, Nrf, Nor, Nos which confirmed that SBY-1 possessed a complete HN-AD pathway for nitrogen metabolism. The predicted nitrogen metabolism pathway of SBY-1 was NO 3 - -N → NO 2 - . These findings provide new insights into the efficient removal of nitrate by SBY-1 under lower C/N conditions.2 O → N 2 . These findings provide new insights into the efficient removal of nitrate by SBY-1 under lower C/N conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

WD repeat-containing protein 5 (WDR5) is a scaffolding protein involved in critical protein-protein interactions and a promising target for therapeutic development. Novel small-molecule ligands targeting WDR5 were identified using the DELopen platform, a free-access DNA-encoded chemical library (DEL) for academic research. Through off-DNA structure-activity relationship studies and photoaffinity labeling, two promising initial leads, DBL-6-13 and DBL-6-33, were identified as new binders of WDR5. These compounds exhibited moderate to good binding affinities and were confirmed to bind the WIN-site through co-crystal structure analysis. Our findings demonstrate the utility of DEL technology in identifying ligands for challenging targets like WDR5, particularly within an academic research setting using the DELopen platform. The identified WDR5 ligands offer a foundation for further optimization and exploration as chemical probes for WDR5 research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. In fact, none of the authors in this work is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for Bioorganic Chemistry., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Transarterial chemoembolization (TACE) based neoadjuvant therapy was proven effective in hepatocellular carcinoma (HCC). Recently, tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) also showed promise in HCC treatment. However, the prognostic benefits associated with these treatments remain uncertain. This study aimed to explore the relationship between pathologic response and prognostic features in HCC patients who received neoadjuvant therapy., Methods: HCC patients who received TACE either with or without TKIs/ICIs as neoadjuvant therapy before liver resection were retrospectively collected from the First Affiliated Hospital, Zhejiang University School of Medicine in China. Pathologic response was determined by calculating the proportion of non-viable area within the tumor. Major pathologic response (MPR) was defined as the presence of non-viable tumor cells reaching a minimum of 90 %. Complete pathologic response (CPR) was characterized by the absence of viable cells observed in the tumor., Results: A total of 481 patients meeting the inclusion criteria were enrolled, with 76 patients (15.8 %) achieving CPR and 179 (37.2 %) reaching MPR. The median recurrence-free survival (mRFS) in the CPR + MPR group was significantly higher than the non-MPR group (31.3 vs. 25.1 months). The difference in 3-year overall survival (OS) rate was not significant (90.2 % vs. 87.6 %). Multivariate Cox regression analysis identified failure to achieve MPR (hazard ratio = 1.548, 95 % confidence interval: 1.122-2.134; P = 0.008), HBsAg positivity (HR = 1.818, 95 % CI: 1.062-3.115, P = 0.030), multiple lesions (HR = 2.278, 95 % CI: 1.621-3.195, P < 0.001), and baseline tumor size > 5 cm (HR = 1.712, 95 % CI: 1.031-2.849, P = 0.038) were independent risk factors for RFS. Subgroup analysis showed that 67 of 93 (72.0 %) patients who received the combination of TACE, TKIs, and ICIs achieved MPR + CPR., Conclusions: In individuals who received TACE-based neoadjuvant therapy for HCC, failure to achieve MPR emerges as an independent risk factor for RFS. Notably, the combination of TACE, TKIs, and ICIs demonstrated the highest rate of MPR., Competing Interests: Competing interest No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article., (Copyright © 2024. Published by Elsevier B.V.)