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Abstract Sepsis-associated encephalopathy (SAE) is a frequent and severe complication in septic patients, characterized by diffuse brain dysfunction resulting from systemic inflammation. Accurate prediction of long-term mortality in these patients is critical for improving clinical outcomes and guiding treatment strategies. We conducted a retrospective cohort study using the MIMIC IV database to identify adult patients diagnosed with SAE. Patients were randomly divided into a training set (70%) and a validation set (30%). Least absolute shrinkage and selection operator regression and multivariate logistic regression were employed to identify significant predictors of 1-year mortality, which were then used to develop a prognostic nomogram. The model’s discrimination, calibration, and clinical utility were assessed using the area under the receiver operating characteristic curve (AUC), calibration plots, and decision curve analysis, respectively. A total of 3,882 SAE patients were included in the analysis. The nomogram demonstrated strong predictive performance with AUCs of 0.881 (95% CI: 0.865, 0.896) in the training set and 0.859 (95% CI: 0.830, 0.888) in the validation set. Calibration plots indicated good agreement between predicted and observed 1-year mortality rates. The decision curve analysis showed that the nomogram provided greater net benefit across a range of threshold probabilities compared to traditional scoring systems such as Glasgow Coma Scale and Sequential Organ Failure Assessment. Our study presents a robust and clinically applicable nomogram for predicting 1-year mortality in SAE patients. This tool offers superior predictive performance compared to existing severity scoring systems and has significant potential to enhance clinical decision-making and patient management in critical care settings.

Abstract This review explores the intricate roles of metal ions—iron, copper, zinc, and selenium—in glioma pathogenesis and immune evasion. Dysregulated metal ion metabolism significantly contributes to glioma progression by inducing oxidative stress, promoting angiogenesis, and modulating immune cell functions. Iron accumulation enhances oxidative DNA damage, copper activates hypoxia-inducible factors to stimulate angiogenesis, zinc influences cell proliferation and apoptosis, and selenium modulates the tumor microenvironment through its antioxidant properties. These metal ions also facilitate immune escape by upregulating immune checkpoints and secreting immunosuppressive cytokines. Targeting metal ion pathways with therapeutic strategies such as chelating agents and metalloproteinase inhibitors, particularly in combination with conventional treatments like chemotherapy and immunotherapy, shows promise in improving treatment efficacy and overcoming resistance. Future research should leverage advanced bioinformatics and integrative methodologies to deepen the understanding of metal ion-immune interactions, ultimately identifying novel biomarkers and therapeutic targets to enhance glioma management and patient outcomes.

Abstract Severe traumatic bleeding may lead to extremely high mortality rates, and early intervention to stop bleeding plays as a critical role in saving lives. However, rapid hemostasis in deep non-compressible trauma using a highly water-absorbent hydrogel, combined with strong tissue adhesion and bionic procoagulant mechanism, remains a challenge. In this study, a DNA hydrogel (DNAgel) network composed of natural nucleic acids with rapid water absorption, high swelling and instant tissue adhesion is reported, like a band-aid to physically stop bleeding. The excellent swelling behavior and robust mechanical performance, meanwhile, enable the DNAgel band-aid to fill the defect cavity and exert pressure on the bleeding vessels, thereby achieving compression hemostasis for deep tissue bleeding sites. The neutrophil extracellular traps (NETs)-inspired DNAgel network also acts as an artificial DNA scaffold for erythrocytes to adhere and aggregate, and activates platelets, promoting coagulation cascade in a bionic way. The DNAgel achieves lower blood loss than commercial gelatin sponge (GS) in male rat trauma models. In vivo evaluation in a full-thickness skin incision model also demonstrates the ability of DNAgel for promoting wound healing. Overall, the DNAgel band-aid with great hemostatic capacity is a promising candidate for rapid hemostasis and wound healing.

Background: Chronic respiratory diseases (CRDs) are among the top three causes of human mortality. The relationship between modifiable environmental risk factor of noise and risk of mortality in CRDs is unclear. We investigated the longitudinal association between environmental noise exposure and cause-specific mortality in individuals with CRDs, considering the modifying effect of air pollution. Methods: Residential noise exposure was modelled using Common Noise Assessment Methods in Europe. Information on death causes were acquired from death registry data. Cox proportional-hazards models were used to estimate effect sizes. Results: Among 41,222 participants selected from UK Biobank with CRDs in baseline, a total of 3618 death cases occurred during an average follow-up of 12 years with mortality density of 7.16 per 1000 person years. Exposure with highest noise level (> percentile 90) were associated with 22 % (Hazard ratio [HR] = 1.22, 95 % confidence interval [CI]: 1.05, 1.42), 71 % (HR = 1.71, 95 % CI: 1.14, 2.56), and 84 % (HR = 1.84, 95 % CI: 1.10, 3.07) increased risks for all-cause, respiratory disease (RD)-cause, and COPD-cause mortalities, separately. Both multiplicative and additive interactions was found between air pollution and noise with the risk of RD-cause mortality. Participants with high air pollution and noise exposure were associated with a 101 % (HR = 2.01, 95 % CI: 1.10, 3.66) increased risk of RD-cause mortality. Conclusion: It is imperative to mitigate noise exposure as a preventive measure against incident mortality in individuals with CRDs.

Abstract Background Mitochondria play essential roles in tumorigenesis; however, little is known about the contribution of mitochondrial DNA (mtDNA) to esophageal squamous cell carcinoma (ESCC). Whole-genome sequencing (WGS) is by far the most efficient technology to fully characterize the molecular features of mtDNA; however, due to the high redundancy and heterogeneity of mtDNA in regular WGS data, methods for mtDNA analysis are far from satisfactory. Methods Here, we developed a likelihood-based method dMTLV to identify low-heteroplasmic mtDNA variants. In addition, we described fNUMT, which can simultaneously detect non-reference nuclear sequences of mitochondrial origin (non-ref NUMTs) and their derived artifacts. Using these new methods, we explored the contribution of mtDNA to ESCC utilizing the multi-omics data of 663 paired tumor-normal samples. Results dMTLV outperformed the existing methods in sensitivity without sacrificing specificity. The verification using Nanopore long-read sequencing data showed that fNUMT has superior specificity and more accurate breakpoint identification than the current methods. Leveraging the new method, we identified a significant association between the ESCC overall survival and the ratio of mtDNA copy number of paired tumor-normal samples, which could be potentially explained by the differential expression of genes enriched in pathways related to metabolism, DNA damage repair, and cell cycle checkpoint. Additionally, we observed that the expression of CBWD1 was downregulated by the non-ref NUMTs inserted into its intron region, which might provide precursor conditions for the tumor cells to adapt to a hypoxic environment. Moreover, we identified a strong positive relationship between the number of mtDNA truncating mutations and the contribution of signatures linked to tumorigenesis and treatment response. Conclusions Our new frameworks promote the characterization of mtDNA features, which enables the elucidation of the landscapes and roles of mtDNA in ESCC essential for extending the current understanding of ESCC etiology. dMTLV and fNUMT are freely available from https://github.com/sunnyzxh/dMTLV and https://github.com/sunnyzxh/fNUMT , respectively.

Abstract Living organisms ranging from bacteria to animals have developed their own ways to accumulate and store phosphate during evolution, in particular as the polyphosphate (polyP) granules in bacteria. Degradation of polyP into phosphate is involved in phosphorus cycling, and exopolyphosphatase (PPX) is the key enzyme for polyP degradation in bacteria. Thus, understanding the structure basis of PPX is crucial to reveal the polyP degradation mechanism. Here, it is found that PPX structure varies in the length of ɑ‐helical interdomain linker (ɑ‐linker) across various bacteria, which is negatively correlated with their enzymatic activity and thermostability – those with shorter ɑ‐linkers demonstrate higher polyP degradation ability. Moreover, the artificial DrPPX mutants with shorter ɑ‐linker tend to have more compact pockets for polyP binding and stronger subunit interactions, as well as higher enzymatic efficiency (kcat/Km) than that of DrPPX wild type. In Deinococcus‐Thermus, the PPXs from thermophilic species possess a shorter ɑ‐linker and retain their catalytic ability at high temperatures (70 °C), which may facilitate the thermophilic species to utilize polyP in high‐temperature environments. These findings provide insights into the interdomain linker length‐dependent evolution of PPXs, which shed light on enzymatic adaption for phosphorus cycling during natural evolution and rational design of enzyme.

Abstract Protocell fitness under extreme prebiotic conditions is critical in understanding the origin of life. However, little is known about protocell’s survival and fitness under prebiotic radiations. Here we present a radioresistant protocell model based on assembly of two types of coacervate droplets, which are formed through interactions of inorganic polyphosphate (polyP) with divalent metal cation and cationic tripeptide, respectively. Among the coacervate droplets, only the polyP-Mn droplet is radiotolerant and provides strong protection for recruited proteins. The radiosensitive polyP-tripeptide droplet sequestered with both proteins and DNA could be encapsulated inside the polyP-Mn droplet, and form into a compartmentalized protocell. The protocell protects the inner nucleoid-like condensate through efficient reactive oxygen species’ scavenging capacity of intracellular nonenzymic antioxidants including Mn-phosphate and Mn-peptide. Our results demonstrate a radioresistant protocell model with redox reaction system in response to ionizing radiation, which might enable the protocell fitness to prebiotic radiation on the primitive Earth preceding the emergence of enzyme-based fitness. This protocell might also provide applications in synthetic biology as bioreactor or drug delivery system.

The world’s first 1.3 GHz cryomodule containing eight 9-cell superconducting radio-frequency (rf) cavities treated by medium-temperature furnace baking (mid-T bake) was developed at the Institute of High Energy Physics, Chinese Academy of Sciences. The 9-cell cavities in the cryomodule achieved an unprecedented high average intrinsic quality factor (Q_{0}) of 3.8×10^{10} at 16 MV/m and 3.6×10^{10} at 21 MV/m in the horizontal test. The cryomodule can operate stably up to a total continuous wave rf voltage greater than 193 MV, with an average cavity usable accelerating gradient of more than 23 MV/m. The results significantly exceed the specifications of Circular Electron Positron Collider and Dalian advanced light source and the other high repetition rate free electron laser facilities [Linac Coherent Light Source II (LCLS-II), LCLS-II-high energy, Shanghai High Repetition Rate X-ray FEL and Extreme Light Facility, Shenzhen Superconducting Soft X-Ray Free Electron Laser, etc.]. There is evidence that the mid-T bake cavity may not require fast cooldown or long processing time in the cryomodule. This paper reviews the cryomodule performance and discusses some important issues in cryomodule assembly and testing.

Abstract COVID-19 has seriously threatened public health, and transdermal vaccination is an effective way to prevent pathogen infection. Microneedles (MNs) can damage the stratum corneum to allow passive diffusion of vaccine macromolecules, but the delivery efficiency is low, while iontophoresis can actively promote transdermal delivery but fails to transport vaccine macromolecules due to the barrier of the stratum corneum. Herein, we developed a wearable iontophoresis-driven MN patch and its iontophoresis-driven device for active and efficient transdermal vaccine macromolecule delivery. Polyacrylamide/chitosan hydrogels with good biocompatibility, excellent conductivity, high elasticity, and a large loading capacity were prepared as the key component for vaccine storage and active iontophoresis. The transdermal vaccine delivery strategy of the iontophoresis-driven MN patch is “press and poke, iontophoresis-driven delivery, and immune response”. We demonstrated that the synergistic effect of MN puncture and iontophoresis significantly promoted transdermal vaccine delivery efficiency. In vitro experiments showed that the amount of ovalbumin delivered transdermally using the iontophoresis-driven MN patch could be controlled by the iontophoresis current. In vivo immunization studies in BALB/c mice demonstrated that transdermal inoculation of ovalbumin using an iontophoresis-driven MN patch induced an effective immune response that was even stronger than that of traditional intramuscular injection. Moreover, there was little concern about the biosafety of the iontophoresis-driven MN patch. This delivery system has a low cost, is user-friendly, and displays active delivery, showing great potential for vaccine self-administration at home.

Experimental extraction of Zak phase from band structures of a Su-Schrieffer-Heeger model in the synthetic frequency dimension, constructed by two coupled ring resonators with bichromatic modulations of different amplitudes.

Abstract Background Nanoplastics have been recently found widely distributed in our natural environment where ubiquitously bacteria are major participants in various material cycles. Understanding how nanoplastics interact with bacterial cell membrane is critical to grasp their uptake processes as well as to analyze their associated risks in ecosystems and human microflora. However, little is known about the detailed interaction of differentially charged nanoplastics with bacteria. The present work experimentally and theoretically demonstrated that nanoplastics enter into bacteria depending on the surface charges and cell envelope structural features, and proved the shielding role of membrane lipids against nanoplastics. Results Positively charged polystyrene nanoplastics (PS-NH2, 80 nm) can efficiently translocate across cell membranes, while negatively charged PS (PS-COOH) and neutral PS show almost no or much less efficacy in translocation. Molecular dynamics simulations revealed that the PS-NH2 displayed more favourable electrostatic interactions with bacterial membranes and was subjected to internalisation through membrane penetration. The positively charged nanoplastics destroy cell envelope of Gram-positive B. subtilis by forming membrane pore, while enter into the Gram-negative E. coli with a relatively intact envelope. The accumulated positively charged nanoplastics conveyed more cell stress by inducing a higher level of reactive oxygen species (ROS). However, the subsequently released membrane lipid-coated nanoplastics were nearly nontoxic to cells, and like wise, stealthy bacteria wrapped up with artifical lipid layers became less sensitive to the positively charged nanoplastics, thereby illustrating that the membrane lipid can shield the strong interaction between the positively charged nanoplastics and cells. Conclusions Our findings elucidated the molecular mechanism of nanoplastics’ interaction and accumulation within bacteria, and implied the shielding and internalization effect of membrane lipid on toxic nanoplastics could promote bacteria for potential plastic bioremediation. Graphical Abstract

BackgroundSchizophrenia (SCZ) is a heterogeneous psychiatric disorder, with significant contribution from genetic factors particularly for chronic cases with negative symptoms and cognitive deficits. To date, Genome Wide Association Studies (GWAS) and exome sequencing have associated SCZ with a number of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs), but there is still missing heritability. Medium-sized structural variants (SVs) are difficult to detect using SNP arrays or second generation sequencing, and may account for part of the missing heritability of SCZ.Aims and objectivesTo identify SVs associated with severe chronic SCZ across the whole genome.Study design10 multiplex families with probands suffering from chronic SCZ with negative symptoms and cognitive deficits were recruited, with all their affected members demonstrating uni-lineal inheritance. Control subjects comprised one affected member from the affected lineage, and unaffected members from each paternal and maternal lineage.MethodsThird generation sequencing was applied to peripheral blood samples from 10 probands and 5 unaffected controls. Bioinformatic tools were used to identify SVs from the long sequencing reads, with confirmation of findings in probands by short-read Illumina sequencing, Sanger sequencing and visual manual validation with Integrated Genome Browser.ResultsIn the 10 probands, we identified and validated 88 SVs (mostly in introns and medium-sized), within 79 genes, which were absent in the 5 unaffected control subjects. These 79 genes were enriched in 20 biological pathways which were related to brain development, neuronal migration, neurogenesis, neuronal/synaptic function, learning/memory, and hearing. These identified SVs also showed evidence for enrichment of genes that are highly expressed in the adolescent striatum.ConclusionA substantial part of the missing heritability in SCZ may be explained by medium-sized SVs detectable only by third generation sequencing. We have identified a number of such SVs potentially conferring risk for SCZ, which implicate multiple brain-related genes and pathways. In addition to previously-identified pathways involved in SCZ such as neurodevelopment and neuronal/synaptic functioning, we also found novel evidence for enrichment in hearing-related pathways and genes expressed in the adolescent striatum.

Abstract Background Diabetic patients are more vulnerable to skeletal complications. Peroxisome proliferators-activated receptor (PPAR) β/δ has a positive regulatory effect on bone turnover under physiologic glucose concentration; however, the regulatory effect in diabetes mellitus has not been investigated yet. Herein, we explored the effects of PPARβ/δ agonist on the regeneration of diabetic bone defects and the osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) under a pathological high-glucose condition. Methods We detected the effect of PPARβ/δ agonist on osteogenic differentiation of rBMSCs in vitro and investigated the bone healing process in diabetic rats after PPARβ/δ agonist treatment in vivo. RNA sequencing was performed to detect the differentially expressed genes and enriched pathways. Western blot was performed to detect the autophagy-related protein level. Laser confocal microscope (LSCM) and transmission electron microscope (TEM) were used to observe the formation of autophagosomes. Results Our results demonstrated that the activation of PPARβ/δ can improve the osteogenic differentiation of rBMSCs in high-glucose condition and promote the bone regeneration of calvarial defects in diabetic rats, while the inhibition of PPARβ/δ alleviated the osteogenic differentiation of rBMSCs. Mechanistically, the activation of PPARβ/δ up-regulates AMPK phosphorylation, yielding mTOR suppression and resulting in enhanced autophagy activity, which further promotes the osteogenic differentiation of rBMSCs in high-glucose condition. The addition of AMPK inhibitor Compound C or autophagy inhibitor 3-MA inhibited the osteogenesis of rBMSCs in high-glucose condition, suggesting that PPARβ/δ agonist promotes osteogenic differentiation of rBMSCs through AMPK/mTOR-regulated autophagy. Conclusion In conclusion, our study demonstrates the potential role of PPARβ/δ as a molecular target for the treatment of impaired bone quality and delayed bone healing in diabetic patients for the first time.

Abstract Nanoplastics are emerging pollutants of global concern. Agricultural soil is becoming a primary sink for nanoplastics generated from plastic debris. The uptake and accumulation of nanoplastics by crops contaminate the food chain and pose unexpected risks to human health. However, whether nanoplastics can enter grains and their impact on the grains of crop grown in contaminated soil is still unknown. Here, the translocation of polystyrene nanoplastics (PS‐NPs) in crops, including peanut (Arachis hypogaea L.) and rice (Oryza sativa L.) is investigated. It is demonstrated PS‐NPs translocation from the root and accumulation in the grains at the maturation stage. The treatment with PS‐NPs (250 mg kg−1) increases the empty‐shell numbers of rice grain by 35.45%, thereby decreasing the seed‐setting rate of rice by 3.02%, and also decreases the average seed weight of peanuts by 3.45%. Moreover, PS‐NPs exerted adverse effects on nutritional quality, such as decreasing the content of mineral elements, amino acids, and unsaturated fatty acids. To the knowledge, this is the first report of the presence of nanoplastics in the grains of crop plants grown in soil containing nanoplastics, and the results highlight the impact of nanoplastics on the yield and nutritional quality of crop grains.

As human–computer interaction has become increasingly popular, haptic technology has become a research topic of great interest, since vibration perception, as a type of haptic feedback, can enhance user experience during an interaction. However, the high power consumption of existing drivers makes them unsuitable for use in portable devices. In this paper, a bidirectional four-switch buck–boost converter (FSBBC) and Proportional–Integral (PI)–Proportional (P) feedback control are proposed to implement a driver in a high-capacitance piezoelectric actuator which is capable of recovering the energy stored in the high-capacitance load and increasing efficiency. The FSBBC offers an extended input voltage range, rendering significant technological advantages in diverse applications such as automobiles, laptops, and smartphones. By implementing specific control strategies, the FSBBC not only outperforms conventional buck–boost converters in boosting performance, but also ensures that the output and input voltages retain the same polarity. This effectively addresses the polarity inversion challenge inherent to traditional buck–boost circuits. Within the FSBBC, the significant reduction in voltage stress endured by the MOSFET effectively minimizes system costs and size and enhances reliability. The proposed system was simulated in Simulink, which was combined with testing on a field-programmable gate array (FPGA). The driver is capable of driving capacitors of up to 2.9 μF, with 80 Vpp output and 2.75% total harmonic distortion (THD) observed in the test.

For the issues of the poor stability of the furrow opener depth, large soil backfill depth, and inconsistent furrow shape on a no-till seeder for planting green manure between rows of orchards in South Xinjiang, a double-disc, corrugated furrow opener is designed. This paper analyzes the law of soil movement between corrugated double-disc and traditional double-disc furrow openers using the discrete element method (DEM) and concludes that the corrugation width and number of corrugations on the corrugated double-disc furrow opener are the primary factors affecting furrowing operation. When the number of corrugations is sixteen, the forward speed is six kilometers per hour, and when the corrugation width is seventeen and a half millimeters, the simulation operation parameters are optimal. The soil-bin validation experiment results are as follows: Under the condition of an 80 mm furrow depth, the stability of the average furrow depth is enhanced by 3.54%, the working resistance and the average disrupted soil area are increased by 26.16 N and 220 mm2, respectively, and the backfill depth is decreased by 10.98 mm. The operation effect of a double-disc furrow opener with corrugated discs is enhanced by the high stability of the furrow depth, low working resistance, and small backfill depth. This study provides a theoretical foundation for the design and optimization of the furrow opener components of a no-till seeder for planting green manure between rows of orchards.

Abstract The BEPCII project is for upgrading the Beijing Electron Positron Collider to reach a higher luminosity. The cryogenic system has been firstly designed and deployed in BEPCII, which provides cooling capacity for SRF cavities, SCQ and SSM. The cryogenic control system consists of Siemens PLC for the refrigerator control and “PLC + IOC” for superconducting device control. The BEPCII machine commissioning with beam started in October 2006. This paper describes the design and the development of the cryogenic control system.

Abstract Background With increasing cancer incidence and decreasing cancer mortality, there is a growing need for a valid and culturally adapted tool to measure health-related quality of life in children with cancer. This study validated the DISABKIDS Chronic Generic Module (DCGM-37) in Chinese children and adolescents with cancer. Methods The DCGM-37 was translated and adapted for use in China following the guidelines from its copyright holders. In total, 140 children and adolescents with cancer and their guardians were included in this cross-sectional study. Internal consistency and test-retest reliability were evaluated. Convergent validity was examined using Pearson correlation between the DCGM-37 and the PedsQL 4.0 Generic Core Scale. Dimensionality was clarified using exploratory factor analysis. Discriminant validity was evaluated by comparing DCGM-37 scores by sex, age, family income, and clinical characteristics. Results Internal consistency (Cronbach’s alpha 0.91) and test–retest reliability were good (intraclass correlation coefficient 0.87, 95% confidence interval 0.73–0.94). Strong correlations between the DCGM-37 and the PedsQL 4.0 (r = 0.83) suggest good convergent validity. Six factors explained 51.94% of the total variance. Children with leukemia scored higher than those with sarcoma in all subscales (effect size ranged from 0.39 to 0.83), especially the “social exclusion” subscales (effect size 0.83). Small to moderate differences (effect size ranged from 0.38 to 0.58) were observed by sex, age, and family income. Neither floor nor ceiling effects were observed. Conclusion The DCGM-37 is reliable and valid for measuring health-related quality of life in Chinese children and adolescents with cancer.

Smartphone-powered drug delivery device A device developed by researchers in China uses a microneedle array to efficiently and painlessly deliver precise doses of insulin and can be used by patients without help from medical staff. The new system was developed by a team led by Xi Xie and Lelun Jiang of Sun Yat-Sen University. The array of microneedles is pressed against the skin to create micro-holes and then automatically retracted. A mild electric current then drives charged nanovesicles carrying insulin through the holes. The circuit is powered and controlled via a smartphone, which can alter the intensity of the current to determine the dosage of insulin delivered. The team showed that the device effectively delivered insulin to a diabetic rat model with no obvious harmful effects. It thus offers a powerful tool for efficient, controllable, and convenient delivery of macromolecular drugs.

ObjectivesTo investigate differences in behavioral and psychological symptoms of dementia (BPSD) and caregiver distress caused between older adults with dementia living in the community and in nursing homes.DesignA comparative cross-sectional study.Setting and ParticipantsParticipants were recruited from outpatient clinics of a tertiary psychiatric hospital and dementia units of a nursing home in Guangzhou, China.MethodsNeuropsychiatric Inventory was used to assess symptoms and caregiver distress. Dementia severity was determined using the Clinical Dementia Rating.ResultsThis study included 157 community and 112 nursing home residents with dementia. Clinically significant symptoms (item score ≥ 4) were found in 88.5% of the former and 75% of the latter. Caregivers of 79.6% of the former and 26.8% of the latter reported that at least one of these caused them moderate-to-severe distress (distress score ≥ 3). Among the community patients, anxiety was the most frequent “very severe” symptom, while sleep disorders and agitation caused the most frequent “very severe” caregiver distress. After controlling for dementia severity and medication use, family caregiving remained an independent risk predictor for clinically significant symptoms and moderate-to-severe caregiver distress. The prediction of caregiver distress based on symptom scores varied across caregiver types and individual symptoms (R2 0.36–0.82). Group differences in clinically significant symptoms and moderate-to-severe caregiver distress showed at the stage of moderate-to-severe dementia.Conclusions and ImplicationsTailored management strategies to relieve family caregivers’ BPSD-induced distress are needed, especially at the stage of moderate-to-severe dementia. An effective service system should be established for supporting family caregivers to cope with BPSD.

Inhibitors of the BET family proteins are limited by their potency and oral bio-availability. Here, the authors report a new BET inhibitor, NHWD-870, with improved potency compared to previous BET inhibitors, and show that it suppresses BRD4 and targets tumour associated macrophages.

Gravi-A nanoparticles, composed of retinyl propionate (RP) and hydroxypinacolone retinoate (HPR), were prepared by encapsulating the two using the high-pressure homogenization technique. The nanoparticles are effective in anti-wrinkle treatment with high stability and low irritation. We evaluated the effect of different process parameters on nanoparticle preparation. Supramolecular technology effectively produced nanoparticles with spherical shapes with an average size of 101.1 nm. The encapsulation efficiency was in the 97.98–98.35% range. The system showed a sustained release profile for reducing the irritation caused by Gravi-A nanoparticles. Furthermore, applying lipid nanoparticle encapsulation technology improved the transdermal efficiency of the nanoparticles, thereby allowing these to penetrate deep into the dermis layer to achieve precise and sustained release of active ingredients. Gravi-A nanoparticles can be extensively and conveniently used in cosmetics and other related formulations by direct application.

Diabetic osteoporosis is a common complication in diabetic patients, leading to increased fracture risk and impaired bone healing. As a member of the peroxisome proliferator-activated receptor (PPAR) family, PPARβ/δ agonist is suggested as a therapeutic target for the treatment of metabolic syndrome, and has been reported to positively regulate bone turnover by improving osteogenesis. However, its regulatory role in diabetic osteoporosis has not been reported yet. Here, we explored the therapeutic effects and potential mechanisms of PPARβ/δ agonist to the osteoporotic phenotypes of diabetic mice. Our results indicated that the osteoporotic phenotypes could be significantly ameliorated in diabetic mice by the administration of PPARβ/δ agonists. In vitro experiments suggested that PPARβ/δ agonist treatment could alleviate the abnormal increase of osteoclast activity in diabetic mice by rectifying high glucose-mediated macrophage dysfunction instead of directly inhibiting osteoclast differentiation. Mechanistically, Angptl4 may act as a downstream target of PPARβ/δ to regulate macrophage polarization. In conclusion, our study demonstrates the potential of PPARβ/δ agonist as a therapeutic target for the treatment of osteoporosis and immune homeostasis disorder in diabetic patients.

Chronic obstructive pulmonary disease (COPD) is a highly heterogeneous disease. Emphysematous phenotype is the most common and critical phenotype, which is characterized by progressive lung destruction and poor prognosis. However, the underlying mechanism of this structural damage has not been completely elucidated. A total of 12 patients with COPD emphysematous phenotype (COPD-E) and nine patients with COPD non-emphysematous phenotype (COPD-NE) were enrolled to determine differences in differential abundant protein (DAP) expression between both groups. Quantitative tandem mass tag–based proteomics was performed on lung tissue samples of all patients. A total of 29 and 15 lung tissue samples from patients in COPD-E and COPD-NE groups, respectively, were used as the validation cohort to verify the proteomic analysis results using western blotting. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted for DAPs. A total of 4,343 proteins were identified, of which 25 were upregulated and 11 were downregulated in the COPD-E group. GO and KEGG analyses showed that wound repair and retinol metabolism–related pathways play an essential role in the molecular mechanism of COPD emphysematous phenotype. Three proteins, namely, KRT17, DHRS9, and FMO3, were selected for validation. While KRT17 and DHRS9 were highly expressed in the lung tissue samples of the COPD-E group, FMO3 expression was not significantly different between both groups. In conclusion, KRT17 and DHRS9 are highly expressed in the lung tissue of patients with COPD emphysematous phenotype. Therefore, these proteins might involve in wound healing and retinol metabolism in patients with emphysematous phenotype and can be used as phenotype-specific markers.

Background: The mechanisms underlying differences in the susceptibility to chronic obstructive pulmonary disease (COPD) exacerbations between patients are not well understood. Recent studies have shown that the patients with frequent COPD exacerbations is related to specific protein expression in lung tissue. Anterior gradient 3 (AGR3) is expressed in airway epithelial cells in the lung and proteomic analysis revealed that its expression is decreased in patients with frequent COPD exacerbations. Moreover, the loss of epithelial integrity might facilitate trans-epithelial permeability of pathogens in such patients. This study was performed to determine that AGR3 protein play a role in COPD frequency exacerbators.Methods: Human lung tissues were collected from current-smoking patients (Control; n = 15) as well as patients with infrequent COPD exacerbations (IFCOPD; n = 18) and frequent COPD exacerbations (FCOPD; n = 8). While AGR3 protein expression was measured by immunohistochemistry and western blotting, AGR mRNA expression was determined by real time quantitative polymerase chain reaction (RT-qPCR). Furthermore, adherent junctions (AJs) and tight junctions (TJs) protein expression in human lung tissues were measured by immunohistochemistry. The effects of cigarette smoke extract (CSE) on AJ and TJ protein and mRNA expression in BEAS-2B cells were assessed by western blotting and RT-qPCR. In addition, the effect of AGR3 overexpression and knockdown on AJ and TJ protein expression was determined.Results: AGR3 was mainly expressed in the airway epithelium and AGR3-positive products were localized in the cytoplasm. Western blotting and RT-qPCR results showed that AGR3 protein (p = 0.009) and mRNA (p = 0.04) expression in the FCOPD group was significantly lower than that in the IFCOPD group. Moreover, E-cadherin, occludin, and zonula occludens-1 (ZO-1) expression was lower in the FCOPD group than in the IFCOPD group. The protein and mRNA expression of E-cadherin, occludin, and ZO-1 was decreased within 24 h post-CSE exposure. AGR3 overexpression rescued CSE-induced downregulation of E-cadherin, occludin, and ZO-1.Conclusion: Difference in AGR3 expression in the lung tissue might be correlated with increased susceptibility to COPD exacerbation. AGR3 can prevent CSE-induced downregulation of E-cadherin, occludin, and ZO-1 in airway epithelial cells. Loss of AGR3 might promote viral and bacterial infection and induce immune inflammation to increase COPD exacerbation.

Fresh two-dimensional molybdenum disulfide (MoS2) absorbs the hydrocarbon contaminations in the ambient air and makes surface aging. To understand how the surface aging influences the interactions between MoS2 and biomolecules is important in the biomedical applications. Here, employing all-atom molecular dynamics simulations, we investigated the interactions of the fresh and aged MoS2 nanosheets with the lipid membranes of different components. Our results demonstrate that both the fresh and aged MoS2 nanosheets can spontaneously insert into the bilayer membranes. However, the fresh MoS2 nanosheet displays significantly stronger interaction and then has a larger penetration depth than the aged counterpart, regardless of the lipid components. The calculations of potential mean forces through the umbrella sampling further confirm that the insertion of fresh MoS2 into the lipid membranes is more energetically favorable. Moreover, we found that the fresh MoS2 nanosheet can cause a larger damage to the integrity of lipid membranes than the aged one. This work provides insightful understandings of the surface-aging-dependent interactions of the MoS2 nanosheets with biomembranes, which could facilitate the design of novel MoS2-based nanodevices with advanced surface properties.

The LKB1/AMPK is crucial for maintaining cellular homeostasis and is often deregulated in tumours. Here, the authors show that the ribosylation of LKB1 by tankyrase-RNF146 axis results in attenuation of LKB1 pathway activation.

The objective of this study was to investigate the effects of simvastatin (SIM) on lipid metabolism disorders and gut microbiota in high-fat diet-induced hyperlipidemic rats. The obtained results revealed that feeding rats with SIM (20 mg/kg/day) significantly decreased serum lipid level and inhibited hepatic lipid accumulation and steatosis. Histological analysis further indicated that SIM reduced lipid deposition in adipocytes and hepatocytes in comparison with that of the HFD group. The underlying mechanisms of SIM administration against HFD-induced hyperlipidemia were also studied by UPLC-Q-TOF/MS-based liver metabonomics coupled with pathway analysis. Metabolic pathway enrichment analysis of liver metabolites with significant difference in abundance indicated that fatty acids metabolism and amino acid metabolism were the main metabolic pathways altered by SIM administration. Meanwhile, operational taxonomic units (OTUs) analysis revealed that oral administration of SIM altered the composition of gut microbiota, including Ruminococcaceae (OTU960) and Lactobacillus (OTU152), and so on. Furthermore, SIM treatment also regulated the mRNA levels of the genes involved in lipid and cholesterol metabolism. Immunohistochemistry (IHC) analysis of the liver-related proteins (CD36, CYP7A1 and SREBP-1C) showed that oral administration of SIM could regulate the levels of the protein expression related to hepatic lipid metabolism.

In order to achieve the optimized design of a cased telescoped ammunition (CTA) interior ballistic design, a genetic algorithm was introduced into the optimal design of CTA interior ballistics with coupling the CTA interior ballistic model. Aiming at the interior ballistic characteristics of a CTA gun, the goal of CTA interior ballistic design is to obtain a projectile velocity as large as possible. The optimal design of CTA interior ballistic is carried out using a genetic algorithm by setting peak pressure, changing the chamber volume and gun powder charge density. A numerical simulation of interior ballistics based on a 35 mm CTA firing experimental scheme was conducted and then the genetic algorithm was used for numerical optimization. The projectile muzzle velocity of the optimized scheme is increased from 1168 m/s for the initial experimental scheme to 1182 m/s. Then four optimization schemes were obtained with several independent optimization processes. The schemes were compared with each other and the difference between these schemes is small. The peak pressure and muzzle velocity of these schemes are almost the same. The result shows that the genetic algorithm is effective in the optimal design of the CTA interior ballistics. This work will be lay the foundation for further CTA interior ballistic design. Keywords: Cased telescoped ammunition, Interior ballistics, Gunpowder, Optimization genetic algorithm

To date, only approximately 20 drugs synthesized with small molecules have been approved by the FDA for use in traditional transdermal patches (TTP) owing to the extremely low permeation rate of the skin barrier for macromolecular drugs. A novel touch-actuated microneedle array patch (TMAP) was developed for transdermal delivery of liquid macromolecular drugs. TMAP is a combination of a typical TTP and a solid microneedle array (MA). High doses of liquid drug formulations, especially heat-sensitive compounds can be easily filled and stored in the drug reservoir of TMAPs. TMAP can easily penetrate the skin and automatically retract from it to create microchannels through the stratum corneum (SC) layer using touch-actuated ‘press and release’ actions for passive permeation of liquid drugs. Comparison of subcutaneous injection, TTP, solid MA, and dissolvable MA, indicated that insulin-loaded TMAP exhibited the best hypoglycemic effect on type 1 diabetic rats. A ‘closed-loop’ permeation control was also provided for on-demand insulin delivery based on feedback of blood glucose levels (BGLs). Twenty IU-insulin-loaded TMAP maintained the type 1 diabetic rats in a normoglycemic state for approximately 11.63 h, the longest therapeutic duration among all previously reported results on microneedle-based transdermal patches. TMAP possesses excellent transdermal drug delivery capabilities.

Large-scale fast charging of electric vehicles (EVs) probably causes voltage deviation problems in the distribution network. Installing energy storage systems (ESSs) in the fast-charging stations (FCSs) and formulating appropriate active power plans for ESSs is an effective way to reduce the local voltage deviation problem. Some deterministic centralized strategies used for ESSs at FCSs are proposed to solve the voltage deviation problem mentioned above. However, the randomness of the EV load is very large, which can probably reduce the effects of deterministic centralized strategies. A fast and reliable centralized strategy considering the randomness of the EV load for ESSs is a key requirement. Therefore, we propose in this paper a day-ahead scheduling strategy with the aim of maximizing the probability of the nodal voltage change being smaller than a preset limit at the observation node. In the proposed strategy, the uncertainty of EV load is taken into account and the probability of the voltage change of an observation node is quantified by a proposed analytic assessment model (AMM). Furthermore, a voltage change optimization model (VCOM) based on a novel control parameter β is proposed, where β can be used as a constraint to suppress the nodal voltage change at the observation node. Finally, the IEEE 33-bus test system is used to verify the effectiveness of the proposed day-ahead ESS strategy.

In recent years, the orderly charging of electric vehicles (EVs) in commercial parking has become a meaningful research topic due to the increasing number of EVs, especially for parking lots close to workplaces and serving fixed users. In this paper, a parking lot energy management system integrated with energy storage system (ESS) and photovoltaic (PV) system is established. The concept of energy price tag (EPT) is introduced to define the price of all energy storage devices, and the priority order between PV, ESS, EVs, and power grid is established. Taking the minimization of charging cost as the optimization objective, the charging plans of ESS, EVs, and buildings are optimized considering the constraints of EVs user demand and PV power. By comparing the simulation results of four cases, it is proven that this strategy can reduce the charging cost and improve the consumption rate of PV.

Abstract Background Pichia pastoris is one of the most important cell factories for production of industrial enzymes and heterogenous proteins. The genome-scale metabolic model of high quality is crucial for comprehensive understanding of the P. pastoris metabolism. Methods In this paper, we upgraded P. pastoris genome-scale metabolic model based on the combination of latest genome annotations and literatures. Then the performance of the new model was evaluated using the Cobra Toolbox v2.0. Results Compared with the recently published model iMT1026, the reaction number in the new model iRY1243 was increased from 2035 to 2407 and the metabolite number was increased from 1018 to 1094. Accordingly, the unique ORF number was increased from 1026 to 1243. To improve the metabolic functions of P. pastoris genome-scale metabolic model, the biosynthesis pathways of vitamins and cofactors were carefully added. iRY1243 showed good performances when predicting the growth capability on most of the reported carbon and nitrogen sources, the metabolic flux distribution with glucose as a sole carbon source, the essential and partially essential genes, and the effects of gene deletion or overexpression on cell growth and S-adenosyl-l-methionine production. Conclusion iRY1243 is an upgraded P. pastoris genome-scale metabolic model with significant improvements in the metabolic coverage and prediction ability, and thus it will be a potential platform for further systematic investigation of P. pastoris metabolism.

Background: Natural 2-phenylethanol (2-PE) is an important flavoring that emits the aroma of roses. During biotransformation, the aroma quality of natural 2-PE is affected by its main by-products, which include butanol, isobutyric acid, butyric acid, and isovaleric acid. Thus, controlling undesirable by-product formation can reduce the effect of odor on 2-PE aroma quality. Results: 2-PE was produced through biotransformation using l-phenylalanine as a substrate and glucose as a carbon source. Ascorbic acid was added to the system to improve the redox reaction and suppress the generation of by-products. Principal component analysis of the aroma quality of 2-PE was performed using an electronic nose. Similarity analysis revealed that the effects of four by-products on 2-PE aroma quality may be ranked in the following order: isovaleric acid > butyric acid > isobutyric acid > butanol. The sample that exhibited the best similarity to the standard 2-PE sample (99.19%) was the sample to which ascorbic acid had been added during glucose metabolism. Conclusions: 2-PE produced through the addition of ascorbic acid exhibited the closest aroma similarity to the standard 2-PE sample.

Pseudorabies virus (PRV), a member of the Herpesviridae, is the causative agent of an acute infectious disease in a variety of animals. The emergence of a novel variant strain brought huge economic losses to the pig industry since classical vaccine strains were not completely effective against variant strains. Therefore, the development of new anti-pseudorabies virus drugs and vaccines is of great significance for the treatment and prevention of pseudorabies. In this study, we found that germacrone, one of the major components of the essential oils extracted from Rhizoma Curcuma, was able to effectively inhibit PRV replication in a dose-dependent manner in vitro. Germacrone showed antiviral activity against PRV in the early phase of the viral replication cycle. Moreover, we found that germacrone does not directly kill the virus, nor does it affect the expression of the PRV receptor protein nectin-1, nectin-2, and CD155. Our results suggest germacrone could be used as an efficient microbicide or immunomodulatory agent in the control of the emerging variant PRV.

It takes electric vehicles (EVs) a long time to charge, which is bound to influence the charging experience of vehicle owners. At the same time, large-scale charging behavior also brings about large load pressure on, and elevates the overload risk of, the power distribution network. To solve these problems, we proposed a high-efficiency charging service system based on charging reservation and charging pile binding services. The system can shorten the average charging time of EVs and improve the average immediate utilization rate of new energy sources at charging stations (CSs). In addition, the system also guarantees that the EVs are charged within the allowable range of the capacity of the distribution network and avoids overloading of the distribution network caused by the charging of EVs. The key support for the utility of the system is rooted in the three-level CS selection model and the CS energy control algorithm (CSECA) proposed in the research. Finally, the proposed model and algorithm were verified to be valid through numerous simulation experiments.

Lake Taihu has undergone severe eutrophication in the past three decades, and harmful cyanobacteria blooms occur nearly every year in Meiliang Bay at the north end of the lake. To elucidate the potential relationship between seasonal nutrient limitation and phytoplankton proliferation, a 20-year (1991-2012) time series of nutrient limitation in Meiliang Bay was analyzed for deviations between trophic state index (TSI) parameters. Results showed that patterns of nutrient limitation in Meiliang Bay were distinctly seasonal, where phytoplankton growth was generally phosphorus (P)-limited in winter and spring, but nitrogen (N)-limited mainly occurred in summer and fall. This general pattern, however, shifted into N limitation across the four seasons during the mid-1990s because a rapid increase in industrialization led to a significant rise in the input of N and P from inflowing tributaries. The initial patterns were restored by environmental regulation in the end of 1990s, including the Zero Actions plan. Using routine monitoring data, a generalised additive model (GAM) with time and deviations between trophic state indexes for nitrogen and phosphorus (TSIN-TSIP) as explanatory variables was used to explore which nutrient was responsible for limitation of phytoplankton chlorophyll-a (Chl-a) in different seasons. Surprisingly, the model revealed a weak N limitation (TSIN-TSIP = -10) corresponded to peak values of Chl-a in summer-autumn season, which is probably because the phytoplankton community is co-limited by N & P during the period. The shift of nutrition limitation during winter-spring would partially explain high values of Chl-a throughout 1996. This study suggests that seasonal patterns of nutrient limitation must be considered to develop effective management measures to control cyanobacterial blooms.

The isothermal curing of polymethacrylimide (PMI) is studied through the use of dynamic mechanical analysis (DMA). Based on the growth rate of measured dynamic mechanical property, the relative conversion is defined to investigate the evolution of storage modulus E′ at different curing temperatures. Hsich’s nonequilibrium thermodynamic fluctuation theory, Avrami equation, and isoconversional methods are used to analyze isothermal cure kinetics of PMI. The results show that there are different increase modes of E′ at low temperature range and high temperature range, respectively. In low temperature range, the relative conversion curves include a transitional stage which is found to be strongly frequency-dependent, but this stage is not observed in the relative conversion curve in high temperature range. During the isothermal curing process, the relative evolution of E′ can be described by Hsich’s nonequilibrium thermodynamic fluctuation theory and Avrami equation. Moreover, the values and evolutions of activation energy are different in two temperature ranges, which suggest that the curing mechanism probably has changed.

Salinity is among the environmental factors that affect plant growth and development and constrain agricultural productivity. Salinity stress triggers increases in cytosolic free Ca(2+) concentration ([Ca(2+)]i) via Ca(2+) influx across the plasma membrane. Salinity stress, as well as other stresses, induces the production of reactive oxygen species (ROS). It is well established that ROS also triggers increases in [Ca(2+)]i. However, the relationship and interaction between salinity stress-induced [Ca(2+)]i increases and ROS-induced [Ca(2+)]i increases remain poorly understood. Using an aequorin-based Ca(2+) imaging assay we have analyzed [Ca(2+)]i changes in response to NaCl and H2O2 treatments in Arabidopsis thaliana. We found that NaCl and H2O2 together induced larger increases in [Ca(2+)]i in Arabidopsis seedlings than either NaCl or H2O2 alone, suggesting an additive effect on [Ca(2+)]i increases. Following a pre-treatment with either NaCl or H2O2, the subsequent elevation of [Ca(2+)]i in response to a second treatment with either NaCl or H2O2 was significantly reduced. Furthermore, the NaCl pre-treatment suppressed the elevation of [Ca(2+)]i seen with a second NaCl treatment more than that seen with a second treatment of H2O2. A similar response was seen when the initial treatment was with H2O2; subsequent addition of H2O2 led to less of an increase in [Ca(2+)]i than did addition of NaCl. These results imply that NaCl-gated Ca(2+) channels and H2O2-gated Ca(2+) channels may differ, and also suggest that NaCl- and H2O2-evoked [Ca(2+)]i may reduce the potency of both NaCl and H2O2 in triggering [Ca(2+)]i increases, highlighting a feedback mechanism. Alternatively, NaCl and H2O2 may activate the same Ca(2+) permeable channel, which is expressed in different types of cells and/or activated via different signaling pathways.