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Yunfeng Han,1 Long Xi,1,2 Fang Leng,3 Chenjie Xu,3 Ying Zheng1 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, 999078, People’s Republic of China; 2School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China; 3Department of Biomedical Engineering, City University of Hong Kong, Hong Kong SAR, People’s Republic of ChinaCorrespondence: Ying Zheng; Chenjie Xu, Tel +853 88224687 ; +852 34424169, Fax +853 28841358, Email yzheng@umac.mo; chenjie.xu@cityu.edu.hkPurpose: Psoriasis is a chronic and recurrent inflammatory dermatitis characterized by T cell imbalance and abnormal keratinocyte proliferation. MicroRNAs (miRNAs) hold promise as therapeutic agents for this disease; however, their clinical application is hindered by poor stability and limited skin penetration. This study demonstrates the utilization of Framework Nucleic Acid (FNA) for the topical delivery of miRNAs in psoriasis treatment.Methods: By utilizing miRNA-125b as the model drug, FNA-miR-125b was synthesized via self-assembly. The successful synthesis and stability of FNA-miR-125b in bovine fetal serum (FBS) were verified through gel electrophoresis. Subsequently, flow cytometry was employed to investigate the cell internalization on HaCaT cells, while qPCR determined the effects of FNA-miR-125b on cellular functions. Additionally, the skin penetration ability of FNA-miR-125b was assessed. Finally, a topical administration study involving FNA-miR-125b cream on imiquimod (IMQ)-induced psoriasis mice was conducted to evaluate its therapeutic efficacy.Results: The FNA-miR-125b exhibited excellent stability, efficient cellular internalization, and potent inhibition of keratinocyte proliferation. In the psoriasis mouse model, FNA-miR-125b effectively penetrated the skin tissue, resulting in reduced epidermal thickness and PASI score, as well as decreased levels of inflammatory cytokines. Keywords: psoriasis, topical delivery, miRNA-125b, framework nucleic acid, FNA

Zhifen Qiao,1,* Shiyi Huang,1,* Fang Leng,1,2 Yu Bei,2 Yingzhi Chen,2 Minjie Chen,2 Yunfeng Hu,3 Yadong Huang,1,2 Qi Xiang1,2 1Institute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, 510632, People’s Republic of China; 2Biopharmaceutical R&D Center of Jinan University, Guangzhou, 510632, People’s Republic of China; 3The First Affiliated Hospital of Jinan University, Department of Dermatology, Guangzhou, 510632, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qi XiangInstitute of Biomedicine and Guangdong Provincial Key Laboratory of Bioengineering Medicine, Jinan University, Guangzhou, 510632, People’s Republic of ChinaTel +86-020-8556-3234Email txiangqi@jnu.edu.cnBackground: Sensitive skin (SS) is easily irritated by various environmental stimuli, and epidemiological surveys surprisingly find that self-perceived SS is widespread worldwide.Objective: To investigate whether SS is linked to changes in the skin bacterial population using 16S rRNA sequencing and bioinformatic analysis.Patients and Methods: According to both the Huaxi SS Questionnaire and Lactic Acid Stimulation Test, 60 female volunteers in Guangzhou were classified into normal skin (NS) and SS groups. Skin barrier parameters were assessed by the CK skin tester. The DNA of the bacterial flora on the facial skin surface was extracted and was subjected to 16S rRNA sequencing.Results: The skin hydration was significantly lower in the SS group compared to the NS group (P =0.032). Based on 16S rRNA sequencing and bioinformatic analysis, the number of operational taxonomic units (OTUs) significantly decreased in the SS group (P =0.0235, SS vs NS). The relative abundance of Neisseriaceae in SS group decreased significantly (P < 0.05, SS vs NS), while that of Neisseria (within the Neisseriaceae family) increased significantly (P < 0.05, SS vs NS).Conclusion: SS is accompanied by a decrease in species diversity and richness, which may be relevant to the weakening of the microbial barrier (due to the increase of Neisseria or the decrease of Neisseriaceae). Thus, corresponding treatment for Neisseriaceae may be a new idea in the treatment of SS.Keywords: sensitive skin, 16S rRNA sequencing, bacterial, skin microbiome, skin barrier

RPKI Relying party needs to synchronizing data from repository periodically to verify information. In general, Rsync and RRDP are the two common means to complete data synchronization, however, each of them has related problems. In order to solve these problems, through analyzingthe way for synchronizing data from repository by the relying party, a mathematical model was established. Furthermore, based on the current problems faced by the two synchronization means, an improved RPKI data synchronization scheme was proposed. The advantages and disadvantages of the improved scheme were analyzed in detail, as well as the applicable scenarios. The improved scheme could provide a reference for optimizing the deployment and application of RPKI.

Rice husk ash is a kind of volcanic ash material with high silicon. This also provides a feasibility for rice husk ash as cement-based auxiliary cementing material. China is rich in rice husk resources, and the rice husk ash is stacked. Using rice husk ash (RHA) instead of traditional cementitious materials can effectively solve the environmental pollution caused by the accumulation of rice husk ash. Domestic and international scholar have added rice husk ash as mineral admixture to concrete, but the utilization rate is very low. In order to increase the added value of rice husk ash, the high silicon property of rice husk ash was used to solidify soil. The application range of solidified soil is wide, the requirements for materials are not high, and the functions are different, which can realize the extensive use of rice husk ash. This paper summarizes the literature on comprehensive utilization of rice husk ash at home and abroad, systematically expounds the physicochemical properties and production process of rice husk ash, introduces the application of rice husk ash in solidified soil, and points out the unsolved problems in this field, which provides a direction for the further development.

This paper discusses the seismic analysis of concrete dams with consideration of material nonlinearity. Based on a consistent rate-dependent model and two thermodynamics-based models, two thermodynamics-based rate-dependent constitutive models were developed with consideration of the influence of the strain rate. They can describe the dynamic behavior of concrete and be applied to nonlinear seismic analysis of concrete dams taking into account the rate sensitivity of concrete. With the two models, a nonlinear analysis of the seismic response of the Koyna Gravity Dam and the Dagangshan Arch Dam was conducted. The results were compared with those of a linear elastic model and two rate-independent thermodynamics-based constitutive models, and the influences of constitutive models and strain rate on the seismic response of concrete dams were discussed. It can be concluded from the analysis that, during seismic response, the tensile stress is the control stress in the design and seismic safety evaluation of concrete dams. In different models, the plastic strain and plastic strain rate of concrete dams show a similar distribution. When the influence of the strain rate is considered, the maximum plastic strain and plastic strain rate decrease.

Abstract Background A high concentration of cisplatin (CDDP) induces apoptosis in many tumor cell lines. CDDP has been administered by infusion to avoid severe toxicity. Recently, it has been reported that changes in survivin expression or function may lead to tumor sensitization to chemical and physical agents. The aim of this study was to determine whether a dominant-negative mouse survivin mutant could enhance the anti-tumor activity of CDDP. Methods A plasmid encoding the phosphorylation-defective dominant-negative mouse survivin threonine 34→alanine mutant (survivin T34A) complexed to a DOTAP-chol liposome (Lip-mS) was administered with or without CDDP in Lewis Lung Carcinoma (LLC) cells and in mice bearing LLC tumors, and the effects on apoptosis, tumor growth and angiogenesis were assessed. Data were analyzed using one-way analysis of variance(ANOVA), and a value of P < 0.05 was considered to be statistically significant. Results LLC cells treated with a combination of Lip-mS and CDDP displayed increased apoptosis compared with those treated with Lip-mS or CDDP alone. In mice bearing LLC tumors and treated with intravenous injections of Lip-mS and/or CDDP, combination treatment significantly reduced the mean tumor volume compared with either treatment alone. Moreover, the antitumor effect of Lip-mS combined with CDDP was greater than their anticipated additive effects. Conclusion These data suggest that the dominant-negative survivin mutant, survivin T34A, sensitized LLC cells to chemotherapy of CDDP. The synergistic antitumor activity of the combination treatment may in part result from an increase in the apoptosis of tumor cells, inhibition of tumor angiogenesis and induction of a tumor-protective immune response.

Macrophage polarization facilitates the inflammatory response and intensified fibrosis in the silicosis microenvironment by a mechanism related to macrophage pyroptosis, although the upstream target remains poorly defined. Currently, there are few reports on the development of drugs that alleviate macrophage polarization by dampening pyroptosis. The present study aims to explore the mechanics of silica mediating macrophage polarization and to investigate whether quercetin (Que) can depolarize macrophages with this mechanism. Silica processing led to prominent M1 polarization of macrophages. Additionally, significant macrophage polarization could be detected in the lung tissue of mice with airway-perfused silica. Further investigation turned out that pronounced mitochondria damage, mtDNA cytoplasmic ectomy, and pyroptosis occurred in response to silica. Nevertheless, Que treatment could effectively attenuate silica-induced mitochondria damage and pyroptosis as demonstrated in vitro and in vivo. Further exploration presented Que could bind to TOM70 and restore silica-induced mitochondrial damage. More importantly, the M1 polarization of macrophage was depressed with the co-treatment of Que and silica, wherein the inflammatory response and pulmonary fibrosis were also mitigated without obvious damage to vital organs. In conclusion, these findings proved that silica leads to mitochondrial damage, thereby evoking pyroptosis and promoting macrophage M1 polarization. Que could bind to TOM70 and restore its function, suppressing mitochondrial damage and pyroptosis, and depolarizing macrophages to reduce fibrosis, which provides a promising strategy for silicosis treatment in the future., 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 The Authors. Published by Elsevier Inc. All rights reserved.)

Ultrasonic-mediated plasmid transformation is a promising microbial transformation strategy with broad application prospects that has attracted interest across various fields. Limited research exists on developing a quantitative model to understand the relationship between transformation efficiency and ultrasonic power. Within the ultrasonic range that did not damage plasmids, the maximum transformation efficiency reached at 4.84 × 10 5 CFU/μg DNA. A kinetic model based on changes in membrane permeability was utilized to determine the membrane permeability at different power levels. The results indicated a linear correlation between ultrasonic power, transformation efficiency, and membrane permeability within a specific range. A quantitative relationship model was established based on ultrasonic power and transformation efficiency in E. coli. Electron microscopy revealed that E. coli cells subjected to ultrasonic treatment exhibited pore formation and cellular expansion. Furthermore, the integrity of the bacterial membrane was compromised as ultrasonic power increased. Nine genes associated with the functional terms of cell membrane components and transmembrane transport were identified in E. coli DH5α. According to qRT-PCR results, genes with these functions (including cusC, uidC, tolQ, tolA, ompC, yaiY) play crucial roles in ultrasound-mediated transformation of E. coli DH5α. This study suggested that ultrasound-mediated transformation in E. coli DH5α is not a simple physical-chemical process but rather involves the regulation of responsive membrane-related genes. This research establishes the groundwork for future comprehensive investigations into the molecular mechanism of ultrasound-mediated transformation and provides insights for the application of ultrasound technology in genetic engineering and related fields., 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.)

Bolivia has abundant pebbles, while the supply of crushed stone is limited and unstable. Thus, the resource utilization of local pebble as a coarse aggregate and the guarantee of concrete durability are the key scientific issues in the Sucre Highway Project. In this paper, a comparative analysis was conducted of the performance of crushed stone concrete and pebble concrete. Additionally, the impact of fly ash on the water permeability resistance of concrete was investigated. The results indicate that the apparent density, bulk density, and void ratio of pebbles are lower than those of crushed stone, and the aggregate gradation of pebbles is dispersed. The type of aggregate is the primary factor influencing the splitting tensile strength of concrete, with the main failure modes of pebble concrete being slurry cracking, aggregate crushing, and interface debonding. While aggregate and fly ash have a minor effect on compressive strength, they significantly impact flexural tensile strength; however, all concretes meet the requirements for extra-heavy, very heavy, and heavy traffic load levels. In terms of impermeability, fly ash effectively mitigates the negative impact of aggregate type on the impermeability of concrete. These findings support the application of pebble concrete in the highway project.

Codonopsis pilosula , commonly known as Dangshen, is a valuable medicinal plant, but its slow growth and susceptibility to environmental stress pose challenges for its cultivation. In pursuit of sustainable agricultural practices to enhance the yield and quality of Dangshen, the present study isolated a bacterial strain exhibiting plant growth-promoting potential from the rhizosphere of C. pilosula . This strain was subsequently identified as Bacillus licheniformis YB06. Assessment of its plant growth-promoting attributes revealed the potential of B. licheniformis YB06 as a biofertilizer. Whole-genome sequencing of B. licheniformis YB06 revealed a genome size of 4,226,888 bp with a GC content of 46.22%, harboring 4325 predicted protein-coding sequences. Genomic analysis of B. licheniformis YB06 revealed a diverse array of genes linked to induced systemic resistance (ISR) and plant growth-promoting (PGP) traits, encompassing phytohormone production, nitrogen assimilation and reduction, siderophore biosynthesis, phosphate solubilization, biofilm formation, synthesis of PGP-related amino acids, and flagellar motility. Seed germination assays demonstrated the positive effects of B. licheniformis YB06 on the germination and growth of C. pilosula seedlings. Furthermore, we explored various fertilization regimes, particularly the B. licheniformis YB06-based biofertilizer, were investigated for their impact on the structure and diversity of the C. pilosula rhizosphere soil bacterial community. Our findings revealed that fertilization significantly impacted soil bacterial composition and diversity, with the combined application of B. licheniformis YB06-based biofertilizer and organic fertilizer exhibiting a particularly pronounced enhancement of rhizosphere bacterial community structure and diversity. This study represents the first report on the beneficial effects of B. licheniformis YB06 on both the growth of C. pilosula and the composition of its rhizosphere soil microbial community. These findings provide a theoretical foundation and practical guidance for the development of novel bio-organic compound fertilizers, thereby contributing to the sustainable cultivation of C. pilosula .

Background: Sepsis is a heterogeneous syndrome. This study aimed to identify new sepsis sub-phenotypes using plasma cortisol trajectory., Methods: This retrospective study included patients with sepsis admitted to the intensive care unit of Zhongshan Hospital Fudan University between March 2020 and July 2022. A group-based cortisol trajectory model was used to classify septic patients into different sub-phenotypes. The clinical characteristics, biomarkers, and outcomes were compared between sub-phenotypes., Results: A total of 258 patients with sepsis were included, of whom 186 were male. Patients were divided into two trajectory groups: the lower-cortisol group (n = 217) exhibited consistently low and slowly declining cortisol levels, while the higher-cortisol group (n = 41) showed relatively higher levels in comparison. The 28-day mortality (65.9% vs.16.1%, P < 0.001) and 90-day mortality (65.9% vs. 19.8%, P < 0.001) of the higher-cortisol group were significantly higher than the lower-cortisol group. Multivariable Cox regression analysis showed that the trajectory sub-phenotype (HR = 5.292; 95% CI 2.218-12.626; P < 0.001), APACHE II (HR = 1.109; 95% CI 1.030-1.193; P = 0.006), SOFA (HR = 1.161; 95% CI 1.045-1.291; P = 0.006), and IL-1β (HR = 1.001; 95% CI 1.000-1.002; P = 0.007) were independent risk factors for 28-day mortality. Besides, the trajectory sub-phenotype (HR = 4.571; 95% CI 1.980-10.551; P < 0.001), APACHE II (HR = 1.108; 95% CI 1.043-1.177; P = 0.001), SOFA (HR = 1.270; 95% CI 1.130-1.428; P < 0.001), and IL-1β (HR = 1.001; 95% CI 1.000-1.001; P = 0.015) were also independent risk factors for 90-day mortality., Conclusion: This study identified two novel cortisol trajectory sub-phenotypes in patients with sepsis. The trajectories were associated with mortality, providing new insights into sepsis classification., (© 2024. The Author(s).)

Uveal melanoma is the most common intraocular malignant tumor in adults. For patients presenting with cataracts and glaucoma, it is recommended to assess whether an intraocular lesion is present as the primary cause. The present study describes the case of a 52-year-old man with primary intraocular malignant melanoma. The patient experienced painless vision loss in the right eye for 1 year, with recent onset of eye swelling and pain in the week prior to seeking medical attention. A slit-lamp examination revealed a shallow anterior chamber in the right eye, a visibly opaque lens and a faint reflection of the tumor surface in the vitreous humor. In addition, the intraocular pressure of this eye was >60 mmHg. Magnetic resonance imaging revealed a large tumor behind the lens measuring 16×18×14 mm. Pathological examination confirmed the diagnosis of malignant melanoma. No BRCA-associated protein-1 somatic mutation was detected, whereas germline mutations of MutL protein homolog 1, RAD54 like, and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 were identified. Extensive systemic examination excluded the possibility that the tumors originated from another part of the body. The present case report highlights the crucial role of slit-lamp examination in the detection of ocular tumors. It is advocated that for patients presenting with cataracts, attention should be paid to the possibility of intraocular tumors. Meticulous slit-lamp microscopy may reveal a reflection of the surface of a malignant melanoma, preventing misdiagnosis., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Wang et al.)

Single-cell RNA sequencing (scRNA-seq) has emerged as a valuable tool for studying cellular heterogeneity in various fields, particularly in virological research. By studying the viral and cellular transcriptomes, the dynamics of viral infection can be investigated at a single-cell resolution. However, limited studies have been conducted to investigate whether RNA transcripts from clinical samples contain substantial amounts of viral RNAs, and a specific computational framework for efficiently detecting viral reads based on scRNA-seq data has not been developed. Hence, we introduce DVsc, an open-source framework for precise quantitative analysis of viral infection from single-cell transcriptomics data. When applied to approximately 200 diverse clinical samples that were infected by more than 10 different viruses, DVsc demonstrated high accuracy in systematically detecting viral infection across a wide array of cell types. This innovative bioinformatics pipeline could be crucial for addressing the potential effects of surreptitiously invading viruses on certain illnesses, as well as for designing novel medicines to target viruses in specific host cell subsets and evaluating the efficacy of treatment. DVsc supports the FASTQ format as an input and is compatible with multiple single-cell sequencing platforms. Moreover, it could also be applied to sequences from bulk RNA sequencing data. DVsc is available at http://62.234.32.33:5000/DVsc., (© The Author(s) 2024. Published by Oxford University Press and Science Press on behalf of the Beijing Institute of Genomics, Chinese Academy of Sciences / China National Center for Bioinformation and Genetics Society of China.)

Paraphoma chrysanthemicola , an endophytic fungus isolated from the roots of Codonopsis pilosula , influences salicylic acid (SA) levels. The interaction mechanism between SA and P. chrysanthemicola within C. pilosula remains elusive. To elucidate this, an experiment was conducted with four treatments: sterile water (CK), P. chrysanthemicola (FG), SA, and a combination of P. chrysanthemicola with salicylic acid (FG+SA). Results indicated that P. chrysanthemicola enhanced plant growth and counteracted the growth inhibition caused by exogenous SA. Physiological analysis showed that P. chrysanthemicola reduced carbohydrate content and enzymatic activity in C. pilosula without affecting total chlorophyll concentration and attenuated the increase in these parameters induced by exogenous SA. Secondary metabolite profiling showed a decrease in soluble proteins and lobetyolin levels in the FG group, whereas SA treatment led to an increase. Both P. chrysanthemicola and SA treatments decreased antioxidase-like activity. Notably, the FG group exhibited higher nitric oxide (NO) levels, and the SA group exhibited higher hydrogen peroxide (H 2 O 2 ) levels in the stems. This study elucidated the intricate context of the symbiotic dynamics between the plant species P. chrysanthemicola and C. pilosula , where an antagonistic interaction involving salicylic acid was prominently observed. This antagonism was observed in the equilibrium between carbohydrate metabolism and secondary metabolism. This equilibrium had the potential to engage reactive oxygen species (ROS) and nitric oxide (NO).

Enterobacter cloacae is an emerging pathogen isolated in healthcare-associated infections. A major virulence factor of this bacterium is the type VI secretion system (T6SS). The genome of E. cloacae harbors two T6SS gene clusters (T6SS-1 and T6SS-2), and the functional characterization of both systems showed that these two T6SSs are not expressed under the same conditions. Here, we report that the major histone-like protein HU positively regulates the expression of both T6SSs and, therefore, the function that each T6SS exerts in E. cloacae . Single deletions of the genes encoding the HU subunits ( hupA and hupB ) decreased mRNA levels of both T6SS. In contrast, the hupA hupB double mutant dramatically affected the T6SS expression, diminishing its transcription. The direct binding of HU to the promoter regions of T6SS-1 and T6SS-2 was confirmed by electrophoretic mobility shift assay. In addition, single and double mutations in the hup genes affected the ability of inter-bacterial killing, biofilm formation, adherence to epithelial cells, and intestinal colonization, but these phenotypes were restored when such mutants were trans -complemented. Our data broaden our understanding of the regulation of HU-mediated T6SS in these pathogenic bacteria., Importance: T6SS is a nanomachine that functions as a weapon of bacterial destruction crucial for successful colonization in a specific niche. Enterobacter cloacae expresses two T6SSs required for bacterial competition, adherence, biofilm formation, and intestinal colonization. Expression of T6SS genes in pathogenic bacteria is controlled by multiple regulatory systems, including two-component systems, global regulators, and nucleoid proteins. Here, we reported that the HU nucleoid protein directly activates both T6SSs in E. cloacae , affecting the T6SS-related phenotypes. Our data describe HU as a new regulator involved in the transcriptional regulation of T6SS and its impact on E. cloacae pathogenesis., Competing Interests: The authors declare no conflict of interest.

Objective: Prompt and effective wound repair is an essential strategy to promote recovery and prevent infection in patients with various types of trauma. Platelets can release a variety of growth factors upon activation to facilitate revascularization and tissue repair, provided that their activation is uncontrollable. The present study is designed to explore the selective activation of platelets by photodynamic and photothermal effects (PDE/PTE) as well as the trauma repair mediated by PDE/PTE., Materials and Methods: In the current research, platelets were extracted from the blood of mice. Indocyanine green (ICG) was applied to induce PDE/PTE. The uptake of ICG by platelets was detected by laser confocal microscopy and flow cytometry. The cellular integrity was measured by microscopy. The reactive oxygen species (ROS) generation and temperature of platelets were assayed by 2,7-Dichlorodihydrofluorescein diacetate (DCFH-DA) and temperature detector. The activation of platelets was measured by western blots (WB), dynamic light scattering (DLS), and scanning electron microscopy (SEM). The release of growth factor was detected by enzyme-linked immuno sorbent assay (Elisa), wherein the in vitro cell proliferation was investigated by 5-Ethynyl-2'-deoxyuridine (EDU) assay. The wound infection rates model and histological examination were constructed to assay the ICG-loaded platelet-mediated wound repair., Results: Platelets could load with ICG, a kind of photodynamic and photothermal agent, as carriers and remain intact. Near-infrared (NIR) laser irradiation of ICG-loaded platelets (ICG@PLT) facilitated higher temperature and ROS generation, which immediately activated ICG@PLT, as characterized by increased membrane p-selectin (CD62p), cyclooxygenase-2 (COX-2), thromboxane A2 receptor (TXA2R) expression, elevated hydrated particle size, and prominent aggregation in platelets. Further investigation revealed that massive insulin-like growth factor (IGF) and platelet-derived growth factor (PDGF) were released from the activated ICG@PLT, which also promoted the proliferation of endothelial cells and keratinocytes in co-culture. In consequence, activated platelets and increased neovascularization could be observed in rats with wound infection treated by ICG@PLT in the presence of NIR. More impressively, the hydrogel containing ICG@PLT accelerated wound healing and suppressed inflammation under NIR, exhibiting excellent wound repair properties., Conclusion: Taken together, the current work identified that platelets could be activated by PDE/PTE and thereby release growth factor, potentiating wound repair in a controlled manner., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Child and maternal malnutrition (CMM) caused heavy disability-adjusted life years (DALY) and deaths globally. It is crucial to understand the global burden associated with CMM in order to prioritize prevention and control efforts. We performed a comprehensive analysis of the global DALY and deaths attributable to CMM from 1990 to 2019 in this study., Methods: The age-standardized CMM related burden including DALY and death from 1990 to 2019 were accessed from the Global Burden of Disease study 2019 (GBD 2019). The changing trend were described by average annual percentage change (AAPC). The relationship between sociodemographic factors and burden attributable to CMM were explored by generalized linear model (GLM)., Results: Globally, in 2019, the age-standardized DALY and death rates of CMM were 4,425.24/100,000 (95% UI: 3,789.81/100,000-5,249.55/100,000) and 44.72/100,000 (95% UI: 37.83/100,000-53.47/100,000), respectively. The age-standardized DALY rate (AAPC = -2.92, 95% CI: -2.97% to -2.87%) and death rates (AAPC = -3.19, 95% CI: -3.27% to -3.12%) presented significantly declining trends during past 30 years. However, CMM still caused heavy burden in age group of <28 days, Sub-Saharan Africa and low SDI regions. And, low birth weight and short gestation has identified as the primary risk factors globally. The GLM indicated that the highly per capita gross domestic product, per capita current health expenditure, physicians per 1,000 people were contributed to reduce the burden attributable to CMM., Conclusion: Although global burden attributable to CMM has significantly declined, it still caused severe health burden annually. To strengthen interventions and address resources allocation in the vulnerable population and regions is necessary., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Pi, Leng and Shen.)

Macromolecular crowding, manifested by high concentrations of proteins and nucleic acids in living cells, significantly influences biological processes such as enzymatic reactions. Studying these reactions in vitro, using agents such as polyetthylene glycols (PEGs) and polyvinyl alcohols (PVAs) to mimic intracellular crowding conditions, is essential due to the notable differences from enzyme behaviors observed in diluted aqueous solutions. In this article, we studied Mycobacterium tuberculosis (Mtb) DNA gyrase under macromolecular crowding conditions by incorporating PEGs and PVAs into the DNA supercoiling reactions. We discovered that high concentrations of potassium glutamate, glycine betaine, PEGs, and PVA substantially stimulated the DNA supercoiling activity of Mtb DNA gyrase. Steady-state kinetic studies showed that glycine betaine and PEG400 significantly reduced the K M of Mtb DNA gyrase and simultaneously increased the V max or k cat of Mtb DNA gyrase for ATP and the plasmid DNA molecule. Molecular dynamics simulation studies demonstrated that PEG molecules kept the ATP lid of DNA gyrase subunit B in a closed or semiclosed conformation, which prevented ATP molecules from leaving the ATP-binding pocket of DNA gyrase subunit B. The stimulation of the DNA supercoiling activity of Mtb DNA gyrase by these molecular crowding agents likely results from a decrease in water activity and an increase in excluded volume., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

FOXP3 is a transcription factor that is essential for the development of regulatory T cells, a branch of T cells that suppress excessive inflammation and autoimmunity 1-5 . However, the molecular mechanisms of FOXP3 remain unclear. Here we here show that FOXP3 uses the forkhead domain-a DNA-binding domain that is commonly thought to function as a monomer or dimer-to form a higher-order multimer after binding to T n G repeat microsatellites. The cryo-electron microscopy structure of FOXP3 in a complex with T 3 G repeats reveals a ladder-like architecture, whereby two double-stranded DNA molecules form the two 'side rails' bridged by five pairs of FOXP3 molecules, with each pair forming a 'rung'. Each FOXP3 subunit occupies TGTTTGT within the repeats in a manner that is indistinguishable from that of FOXP3 bound to the forkhead consensus motif (TGTTTAC). Mutations in the intra-rung interface impair T n G repeat recognition, DNA bridging and the cellular functions of FOXP3, all without affecting binding to the forkhead consensus motif. FOXP3 can tolerate variable inter-rung spacings, explaining its broad specificity for T n G-repeat-like sequences in vivo and in vitro. Both FOXP3 orthologues and paralogues show similar T n G repeat recognition and DNA bridging. These findings therefore reveal a mode of DNA recognition that involves transcription factor homomultimerization and DNA bridging, and further implicates microsatellites in transcriptional regulation and diseases., (© 2023. The Author(s).)

Paraphoma chrysanthemicola is a newly identified endophytic fungus. The focus of most studies on P. chrysanthemicola has been on its isolation, identification and effects on plants. However, the limited genomic information is a barrier to further research. Therefore, in addition to studying the morphological and physiological characteristics of P. chrysanthemicola , we sequenced its genome and compared it with that of Paraphoma sp. The results showed that sucrose, peptone and calcium phosphate were suitable sources of carbon, nitrogen and phosphorus for this strain. The activities of amylase, cellulase, chitosanase, lipase and alkaline protease were also detected. Sequencing analysis revealed that the genome of P. chrysanthemicola was 44.1 Mb, with a scaffold N50 of 36.1 Mb and 37,077 protein-coding genes. Gene Ontology (GO) annotation showed that mannose-modified glycosylation was predominant in monosaccharide utilisation. The percentage of glycoside hydrolase (GH) modules was the highest in the carbohydrate-active enzymes database (CAZy) analysis. Secondary metabolite-associated gene cluster analysis identified melanin, dimethylcoprogen and phyllostictine A biosynthetic gene clusters (>60% similarity). The results indicated that P. chrysanthemicola had a mannose preference in monosaccharide utilisation and that melanin, dimethylcoprogen and phyllostictine A were important secondary metabolites for P. chrysanthemicola as an endophytic fungus.

Cytidine is an important kind of nucleoside that can be applied to drug development and food industry. Cytidine sulfate is one of its popular forms, which is promising as a medicinal intermediate, especially in antiviral and antitumor drugs. Product refining is the key point of industrial development, and crystallization is a significant way of refining. In this work, the solubility of cytidine sulfate in pure water from 278.15 to 328.15 K and in water-ethanol binary solvents at 298.15 K was measured by the UV spectroscopic method. The solubility data were correlated with temperature and solvent composition using the modified Apelblat, van't Hoff, and CNIBS/R-K equations. On this basis, we investigated and compared three crystallization processes, and the coupling method was developed to prepare crystals with a large particle size, concentrated distribution, and high yield and packing density. In addition, the structure and stability of the products were characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, thermogravimetric analysis, differential scanning calorimetry, and dynamic vapor sorption analysis. It was found that cytidine sulfate has only one crystal form in our research process, and the product of coupling crystallization is stable and favorable for industrial development., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background: Neurodevelopmental disorders (NDDs) are associated with altered development of the brain especially in childhood. Copy number variants (CNVs) play a crucial role in the genetic aetiology of NDDs by disturbing gene expression directly at linear sequence or remotely at three-dimensional genome level in a tissue-specific manner. Despite the substantial increase in NDD studies employing whole-genome sequencing, there is no specific tool for prioritising the pathogenicity of CNVs in the context of NDDs., Methods: Using an XGBoost classifier, we integrated 189 features that represent genomic sequences, gene information and functional/genomic segments for evaluating genome-wide CNVs in a neuro/brain-specific manner, to develop a new tool, neuroCNVscore. We used Human Phenotype Ontology to construct an independent NDD-related set., Results: Our neuroCNVscore framework (https://github.com/lxsbch/neuroCNVscore) achieved high predictive performance (precision recall=0.82; area under curve=0.85) and outperformed an existing reference method SVScore. Notably, the predicted pathogenic CNVs showed enrichment in known genes associated with autism., Conclusions: NeuroCNVscore prioritises functional, deleterious and pathogenic CNVs in NDDs at whole genome-wide level, which is important for genetic studies and clinical genomic screening of NDDs as well as for providing novel biological insights into NDDs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Rhizosphere soil physicochemical, endophytic fungi have an important role in plant growth. A large number of endophytic fungi play an indispensable role in promoting plant growth and development, and they can provide protection for host plants by producing a variety of secondary metabolites to resist and inhibit plant pathogens. Due to the terrain of Gansu province is north-south and longitudinal, different climatic conditions, altitude, terrain and growth environment will affect the growth of Codonopsis pilosula, and the changes in these environmental factors directly affect the quality and yield of C. pilosula in different production areas. However, In C. pilosula, the connection between soil nutrients, spatiotemporal variation and the community structure of endophytic fungi isolated from C. pilosula roots has not been well studied., Results: Seven hundred six strains of endophytic fungi were obtained using tissue isolation and the hyphaend-purification method from C. pilosula roots that picked at all seasons and six districts (Huichuan, HC; Longxi, LX; Zhangxian, ZX; Minxian, MX; Weiyuan, WY; and Lintao, LT) in Gansu Province, China. Fusarium sp. (205 strains, 29.04%), Aspergillus sp. (196 strains, 27.76%), Alternaria sp. (73 strains, 10.34%), Penicillium sp. (58 strains, 8.22%) and Plectosphaerella sp. (56 strains, 7.93%) were the dominant genus. The species composition differed from temporal and spatial distribution (Autumn and Winter were higher than Spring and Summer, MX and LT had the highest similarity, HC and LT had the lowest). physical and chemical of soil like Electroconductibility (EC), Total nitrogen (TN), Catalase (CAT), Urease (URE) and Sucrase (SUC) had significant effects on agronomic traits of C. pilosula (P < 0.05). AK (Spring and Summer), TN (Autumn) and altitude (Winter) are the main driving factors for the change of endophytic fungal community. Moreover, geographic location (such as altitude, latitude and longitude) also has effects on the diversity of endophytic fungi., Conclusions: These results suggested that soil nutrients and enzyme, seasonal variation and geographical locations have an impact on shaping the community structure of culturable endophytic fungi in the roots of C. pilosula and its root traits. This suggests that climatic conditions may play a driving role in the growth and development of C. pilosula., (© 2023. The Author(s).)

BES1, as the most important transcription factor responsible for brassinolide (BR) signaling, has been confirmed to play a significant role in regulating plant growth and the improvement of stress resistance. The transcriptional regulatory mechanism of BES1 has been well elucidated in several plants, such as Arabidopsis thaliana (A. thaliana), Triticum aestivum L. (T. aestivum), and Oryza sativa L. (O. sativa). Nevertheless, the genome-wide analysis of the BES1 family in Vitis vinifera L. (V. vinifera). has not been comprehensively carried out. Thus, we have conducted a detailed analysis and identification of the BES1 transcription factors family in V. vinifera; a total of eight VvBES1 genes was predicted, and the phylogenetic relationships, gene structures, and Cis-acting element in their promoters were also analyzed. BES1 genes have been divided into three groups (I, II and III) based on phylogenetic relationship analysis, and most of VvBES1 genes were in group III. Also, we found that VvBES1 genes was located at seven of the total nineteen chromosomes, whereas VvBES1-2 (Vitvi04g01234) and VvBES1-5 (Vitvi18g00924) had a collinearity relationship, and their three copies are well preserved. In addition, the intron-exon model of VvBES1 genes were mostly conserved, and there existed several Cis-acting elements related to stress resistance responsive and phytohormones responsive in BES1s genes promoter. Moreover, the BES1 expressions were different in different V. vinifera organs, and BES1 expressions were different in different V. vinifera varieties under saline-alkali stress and heat stress, the expression of VvBES1 also changed with the prolongation of saline-alkali stress treatment time. The above findings could not only lay a primary foundation for the further validation of VvBES1 function, but could also provide a reference for molecular breeding in V. vinifera., (© 2023. The Author(s).)

In this paper, we report an efficient approach for the direct fluoroalkylthiolation of indoles with iodofluoroethane in the presence of Na 2 S 2 O 4 . In this work, we employed readily available iodofluoroethane and Na 2 S 2 O 4 as fluoroalkylthiolation reagents, featuring mild conditions and a wide range of indole substrates. In addition, fluoroalkylthiolated 2,3'-biindole derivatives can also be prepared by this method., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Introduction: Interval colorectal cancer identified before the next surveillance colonoscopy was more likely to be located in the proximal colon. This study aimed to determine whether a second examination of the proximal colon could increase the adenoma detection rate (ADR)., Methods: Patients undergoing colonoscopy for any indications were recruited for the study. After the colonoscopy was completed with the first standard forward view examination of the proximal colon, patients were randomized to either the intervention group, in which the proximal colon was once again inspected, or the control group, in which the proximal colon was inspected once. The primary outcome was the proximal colon ADR., Results: A total of 840 patients were enrolled for intention-to-treat analysis (intervention group, n = 420; control group, n = 420). The proximal colon ADR in the intervention group was significantly higher than that in the control group (35.7% vs 25.2%, P = 0.001). The whole-colon ADR was also higher in the intervention group than in the control group (44.0% vs 34.0%, P = 0.003). The higher ADR in the intervention group was also confirmed by the per-protocol analysis. Older age, adenoma detected on the first proximal colon examination, and longer total proximal colon withdrawal time were independent factors for detecting ≥1 adenoma on the second withdrawal from the proximal colon., Discussion: The second examination of the proximal colon significantly increased the proximal colon ADR and whole-colon ADR in patients undergoing colonoscopy for any indication., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Economic development and infrastructure improvement will inevitably lead to the accumulation of construction waste and tailings, which has not only a huge impact on the environment but is also a waste of resources. Recycling these resources and making green concrete is an effective way to solve these problems. In this study, the salt spray erosion characteristics and erosion mechanism of tailings recycled concrete (TRC) with polypropylene fibers were studied through macro and micro methods. The results showed that its compressive strength and splitting tensile strength increased at first and then decreased, with the optimum content of 0.6-0.9%, and the strength increase coefficient reached its maximum value at the erosion period being 14 d to 28 d. Under the same erosion cycle, when the fiber content was low (≤0.6-0.9%), the erosion depth hardly fluctuated. While the fiber content changed from 0.6% to 1.2%, the erosion depth and curing ability (erosion for 90 days) increased by 16.29% and 11.20%, which implied that its erosion resistance decreased sharply. Through SEM microscopic analysis, it could be observed that when the fiber content was low, the matrix structure and porosity had little change; while the fiber content was excessive, the porosity increased greatly. The longer the erosion period was, the greater the cumulative expansion of salt crystals was, and the larger the porosity was, whose results were in good agreement with the experimental results. This research provides a significant theoretical basis for the application of TRC in engineering.

Background: Sepsis still remains a major challenge in intensive care medicine with unacceptably high mortality among patients with septic shock. Due to current limitations of human CD19 + CD24 hi CD38 hi Breg cells (Bregs) studies among sepsis, here, we tried to evaluate Bregs in severity and prognostic value in patients with sepsis., Methods: Peripheral blood from 58 patients with sepsis and 22 healthy controls was analyzed using flow cytometry to evaluate the frequency and number of Bregs. All cases were divided into non-survived or survived group after 28 days followed up. Spearman's correlation analysis was performed on Bregs frequency and clinical indices. The area under the curve was acquired using the receiver operating characteristic analysis to assess the sensitivity and specificity of Bregs for outcome of sepsis. Survival curve analysis and binary logistic regression were applied to estimate the value of Bregs in prognosis among cases with sepsis., Results: Sepsis patients had decreased proportions and number of Bregs. Sepsis patients with low frequency of Bregs were associated with an increased risk of septic shock. Bregs frequency is inversely associated with lactate, SOFA, and APACHE II and positively correlated with Tregs frequency. Low levels of Bregs closely correlated with septic outcomes. Numbers of Bregs were prediction factors for poor prognosis., Conclusions: Frequency and number of Bregs decreased, and Bregs deficiency revealed poor prognosis in patients with sepsis., (© 2022. The Author(s).)

The molecular mechanism of the Ca 2+ -mediated formation of competent cells in Escherichia coli remains unclear. In this study, transcriptome and proteomics techniques were used to screen genes in response to Ca 2+ treatment. A total of 333 differentially expressed genes (317 upregulated and 16 downregulated) and 145 differentially expressed proteins (54 upregulated and 91 downregulated) were obtained. These genes and proteins are mainly enriched in cell membrane components, transmembrane transport, and stress response-related functional terms. Fifteen genes with these functions, including yiaW , ygiZ , and osmB , are speculated to play a key role in the cellular response to Ca 2+ . Three single-gene deletion strains were constructed with the Red homologous recombination method to verify its function in genetic transformation. The transformation efficiencies of yiaW , ygiZ , and osmB deletion strains for different-size plasmids were significantly increased. None of the three gene deletion strains changed in size, which is one of the main elements of microscopic morphology, but they exhibited different membrane permeabilities and transformation efficiencies. This study demonstrates that Ca 2+ -mediated competence formation in E. coli is not a simple physicochemical process and may involve the regulation of genes in response to Ca 2+ . This study lays the foundation for further in-depth analyses of the molecular mechanism of Ca 2+ -mediated transformation. IMPORTANCE Using transcriptome and proteome techniques and association analysis, we identified several key genes involved in the formation of Ca 2+ -mediated E. coli DH5α competent cells. We used Red homologous recombination technology to construct three single-gene deletion strains and found that the transformation efficiencies of yiaW , ygiZ , and osmB deletion strains for different-size plasmids were significantly increased. These results proved that the genetic transformation process is not only a physicochemical process but also a reaction process involving multiple genes. These results suggest ways to improve the horizontal gene transfer mechanism of foodborne microorganisms and provide new ideas for ensuring the safety of food preservation and processing.

Introduction: In China, the increasing number of people with Alzheimer's disease (AD) poses a great challenge to families and the country. Economic and cultural differences cause a urban-rural gap in medical resources. This multicenter survey aimed to investigate the real-world practice of disease treatment among people with AD., Methods: People with AD and their caregivers from 30 provincial regions in mainland China were enrolled from October 2020 to December 2020 to be surveyed for their treatment experience. Logistic regression was used to explore the factors that influence medication adherence in all areas, urban areas, and rural areas., Results: In this survey, 1,427 participants came from urban areas, and 539 participants came from rural areas. Patients in urban areas were older (mean age 74 vs. 70, p = 0.001), less frequently had mild AD (36.0 vs. 52.1%, p < 0.001), and more often were cared for at professional institutions (8.8 vs. 3.2%, p < 0.001). In terms of pharmacotherapy, 77.8% of people accepted taking lifelong medication, whereas 61.3% of patients insisted on taking medications. Although 72.0% of rural people believed in taking lifelong medication, only 30.0% adhered to drug use. The major factors that influenced medication adherence for all patients with AD were regional distribution ( p < 0.001, OR = 6.18, 95% CI: 4.93-7.74) and family earnings ( p = 0.003, OR = 1.22, 95% CI: 1.07-1.38). In rural areas, family earnings ( p = 0.008, OR = 1.44, 95% CI: 1.10-1.89) and severity of AD ( p = 0.033, OR = 1.31, 95% CI: 1.02-1.68) were the main factors. Family earnings ( p = 0.038, OR = 1.16, 95% CI: 1.01-1.34) was the only factor among urban areas. Among all non-pharmaceutical activities except for cognitive intervention, the participation rates of rural patients were significantly higher than those of urban patients ( p < 0.05)., Conclusion: Although national progress has been made in the public awareness of disease treatment, adequate diagnosis and medication adherence need to be prompted, especially in rural areas. Furthermore, lifelong treatment should be improved based on regional characteristics through the joint efforts of the government, health workers, and social volunteers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Liu, Wan, Sheng, Wang, Leng, Peng, Wang, Du, Zhu, Mima, Wang, Xie, Wang, Jin and Sun.)

Combining different drugs into a single crystal form is one of the current challenges in crystal engineering, with the number of reported multi-drug solid forms remaining limited. This paper builds upon an efficient approach to combining Active Pharmaceutical Ingredients (APIs) containing carboxylic groups in their structure with APIs containing pyridine moieties. By transforming the former into their zinc salts, they can be successfully combined with the pyridine-containing APIs. This work highlights the successfulness of this approach, as well as the improvement in the physical properties of the obtained solid forms.

Bacterial DNA gyrase, a type IIA DNA topoisomerase that plays an essential role in bacterial DNA replication and transcription, is a clinically validated target for discovering and developing new antibiotics. In this article, based on a supercoiling-dependent fluorescence quenching (SDFQ) method, we developed a high-throughput screening (HTS) assay to identify inhibitors targeting bacterial DNA gyrase and screened the National Institutes of Health's Molecular Libraries Small Molecule Repository library containing 370,620 compounds in which 2891 potential gyrase inhibitors have been identified. According to these screening results, we acquired 235 compounds to analyze their inhibition activities against bacterial DNA gyrase using gel- and SDFQ-based DNA gyrase inhibition assays and discovered 155 new bacterial DNA gyrase inhibitors with a wide structural diversity. Several of them have potent antibacterial activities. These newly discovered gyrase inhibitors include several DNA gyrase poisons that stabilize the gyrase-DNA cleavage complexes and provide new chemical scaffolds for the design and synthesis of bacterial DNA gyrase inhibitors that may be used to combat multidrug-resistant bacterial pathogens. Additionally, this HTS assay can be applied to screen inhibitors against other DNA topoisomerases., Competing Interests: The authors declare the following competing financial interest(s): A provisional patent application has been filed for the newly identified gyrase inhibitors. L.H.S. is an employee of Fate Therapeutics. S.V. and B.S.H. are employees of Alchem Laboratories., (© 2022 American Chemical Society.)

Glucose oxidase, which uses molecular oxygen as an electron acceptor to specifically catalyze the conversion of β-d-glucose to gluconic acid and hydrogen peroxide (H 2 O 2 ), has been considered an important enzyme in increasing environmental sustainability and food security. However, achieving the high yield, low price and high activity required for commercial viability remains challenging. In this review, we first present a brief introduction, looking at the sources, characteristics, catalytic process, and applications of glucose oxidase. Then, the predictive structures of glucose oxidase from two different sources are comparatively discussed. We summarize the inhibitors of glucose oxidase. Finally, we highlight how the production of glucose oxidase can be improved by optimizing the culture conditions and microbial metabolic engineering.

FoxP3 is an essential transcription factor (TF) for immunologic homeostasis, but how it utilizes the common forkhead DNA-binding domain (DBD) to perform its unique function remains poorly understood. We here demonstrated that unlike other known forkhead TFs, FoxP3 formed a head-to-head dimer using a unique linker (Runx1-binding region [RBR]) preceding the forkhead domain. Head-to-head dimerization conferred distinct DNA-binding specificity and created a docking site for the cofactor Runx1. RBR was also important for proper folding of the forkhead domain, as truncation of RBR induced domain-swap dimerization of forkhead, which was previously considered the physiological form of FoxP3. Rather, swap-dimerization impaired FoxP3 function, as demonstrated with the disease-causing mutation R337Q, whereas a swap-suppressive mutation largely rescued R337Q-mediated functional impairment. Altogether, our findings suggest that FoxP3 can fold into two distinct dimerization states: head-to-head dimerization representing functional specialization of an ancient DBD and swap dimerization associated with impaired functions., Competing Interests: Declaration of interests L.H. is co-founder of and holds equity in Edelweiss Immune Inc. A.Y.R. is an SAB member and holds equity in Sonoma Biotherapeutics, RAPT Therapeutics, Surface Oncology, Vedanta Biosciences, and an SAB member of BioInvent. S.H. is an SAB member of IFM therapeutics and CJ CheilJedang Corporation., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Diabetic wounds have an extremely complex microenvironment of hyperglycemia, hypoxia and high reactive oxygen species (ROS). Therefore, the regulation and management of this microenvironment may provide a new and improved treatment method for chronic diabetic wound healing. Herein, a glucose/ROS cascade-responsive nanozyme (CHA@GOx) was developed for diabetic wound treatment based on Ce-driven coassembly by a special dual ligand (alendronic acid and 2-methylimidazole) and glucose oxidase (GOx). It possesses superoxide dismutase and catalase mimic activities, which effectively remove excess ROS. In particular, it can catalyze excessive hydrogen peroxide generated by the glucose oxidation reaction to produce oxygen, regulate the oxygen balance of the wound, and reduce the toxic side effects of GOx, thus achieving the purpose of synergistically repairing diabetic wounds. In vitro experiments show that CHA@GOx assists mouse fibroblast migration and promotes human umbilical vein endothelial cell tube formation. In vivo , it can induce angiogenesis, collagen deposition, and re-epithelialization during wound healing in diabetic mice. Taken together, this study indicates that the coassembly of multifunctional nanozymes has implications in diabetic wound healing., Competing Interests: 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., (© 2022 The Authors.)

This paper investigates the properties of white high-strength concrete (WHSC) prepared with ground limestone powder (GLP). Response surface methodology (RSM) was used to design the proportions of mixes and evaluate the influence of the water-binder ratio (w/b), slurry volume fraction (Vs), and the content of GLP in a binder (Cg) on the slump, whiteness and compressive strength of WHSC via Box-Behnken equations. Results indicate that quadratic polynomial regression equations can be used to predict the performance of WHSC as influenced by combined factors. Both slump and compressive strength of WHSC are found highly influenced by w/b while GLP significantly improves the whiteness of WHSC. An optimal mix proportion of WHSC is provided by the multi-objective optimization with high-accuracy predictions. This paper demonstrates the feasibility of preparing WHSC with GLP and presents the potential of using RSM in the mix proportioning of concrete.

Resorption and loss of alveolar bone leads to oral dysfunction and loss of natural or implant teeth. Biomimetic delivery of growth factors based on stem cell recruitment and osteogenic differentiation, as the key steps in natural alveolar bone regenerative process, has been an area of intense research in recent years. A mesoporous self-healing hydrogel (DFH) with basic fibroblast growth factor (bFGF) entrapment and transforming growth factor β3 (TGFβ3) - loaded chitosan microspheres (CMs) was developed. The formulation was optimized by multiple tests of self-healing, in-bottle inversion, SEM, rheological, swelling rate and in vitro degradation. In vitro tubule formation assays, cell migration assays, and osteogenic differentiation assays confirmed the ability of DFH to promote blood vessels, recruit stem cells, and promote osteogenic differentiation. The optimum DFH formula is 0.05 ml 4Arm-PEG-DF (20%) added to 1 ml CsGlu (2%) containing bFGF (80 ng) and TGFβ3-microspheres (5 mg). The results of in vitro release studied by Elisa kit, indicated an 95% release of bFGF in 7 d and long-term sustained release of TGFβ3. For alveolar defects rat models, the expression levels of CD29 and CD45, the bone volume fraction, trabecular number, and trabecular thickness of new bone monitored by Micro-CT in DFH treatment groups were significantly higher than others (* P < 0.05, vs Model). HE and Masson staining show the same results. In conclusion, DFH is a design of bionic alveolar remodelling microenvironment, that is in early time microvessels formed by bFGF provide nutritious to recruited endogenous stem cells, then TGFβ3 slowly released speed up the process of new bones formation to common facilitate rat alveolar defect repair. The DFH with higher regenerative efficiency dovetails nicely with great demand due to the requirement of complicated biological processes., Competing Interests: The authors report no conflicts of interest. The authors are responsible for the content and writing of this paper., (© 2022 Shenyang Pharmaceutical University. Published by Elsevier B.V.)

The mammalian high mobility group protein AT-hook 2 (HMGA2) houses three motifs that preferentially bind short stretches of AT-rich DNA regions. These DNA binding motifs, known as 'AT-hooks', are traditionally characterized as being unstructured. Upon binding to AT-rich DNA, they form ordered assemblies. It is this disordered-to-ordered transition that has implicated HMGA2 as a protein actively involved in many biological processes, with abnormal HMGA expression linked to a variety of health problems including diabetes, obesity, and oncogenesis. In the current work, the solution binding dynamics of the three 'AT-hook' peptides (ATHPs) with AT-rich DNA hairpin substrates were studied using DNA UV melting studies, fluorescence spectroscopy, native ion mobility spectrometry-mass spectrometry (IMS-MS), solution isothermal titration calorimetry (ITC) and molecular modeling. Results showed that the ATHPs bind to the DNA to form a single, 1:1 and 2:1, 'key-locked' conformational ensemble. The molecular models showed that 1:1 and 2:1 complex formation is driven by the capacity of the ATHPs to bind to the minor and major grooves of the AT-rich DNA oligomers. Complementary solution ITC results confirmed that the 2:1 stoichiometry of ATHP: DNA is originated under native conditions in solution., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: The increasing prevalence of Alzheimer's disease (AD) has emerged as a major challenge worldwide. China as the most populous country in the globe is amid rapid aging of its population, highlighting the need for appropriate social and medical policies to meet the challenge. The current multicenter cross-sectional observational study aims to provide understanding of the current status of caring given to AD patients in China and investigate the factors that influence the family burden as well as the choice of care given to AD patients., Methods: A total of 1,675 patients with probable AD from 30 provincial regions of mainland China were enrolled in the current study from August 2019 to December 2019. We analyzed the caregiving status and its relationship with family burden and various socio-economical and medical factors., Results: In the current study, 90.87% of the AD patients enrolled adopted family care. The choice of caregiving method was influenced by factors including age (>80 years old, OR 0.648; 95% CI, 0.427-0.983), overall family burden (high, OR 0.574; 95% CI, 0.0.373-0.884), patients' income (OR 0.511; 95% CI, 0.330-0.789) and self-care ability (OR 0.329; 95% CI, 0.183-0.588)., Conclusion: Family care is the primary method of care for AD patients in China and the institutional care system for AD patients is still underprepared in China., Competing Interests: XK was employed by The People’s Daily, China. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Leng, Xiong, Zhou, Du, Zhu, Kou, Sun, Chen, Wang, Xie, Gao, Jin and Sun.)

As the incidence of diabetes increases, its complication, diabetic foot ulcers, has become the main type of clinically chronic refractory wounds. Due to the hyperglycemic microenvironment of the diabetic wound, which leads to vascular defects and bacterial growth, the therapeutic effect of wound dressings lacking strategic design is relatively limited. In this study, we designed an injectable, "self-healing", and glucose-responsive multifunctional metal-organic drug-loaded hydrogel (DG@Gel) for diabetic wound healing. The functionalized hydrogel was prepared by phase-transfer-mediated metallo-nanodrugs, which were made by co-assembling zinc ions, organic ligands, and a small-molecule drug, deferoxamine mesylate (DFO), and the programmed loading of glucose oxidase (GOX). When injected into a diabetic wound, the GOX in DG@Gel changed the hyperglycemic wound microenvironment by decomposing excess glucose into hydrogen peroxide and glucuronic acid, which decreased the pH of the wound site. The low pH promoted the release of zinc ions and DFO, which exhibited synergistic antibacterial and angiogenesis activity for diabetic wound repair. In vitro experiments revealed the antibacterial activity and the cell proliferation, migration, and tube formation ability of DG@Gel. Moreover, in vivo experiments showed that DG@Gel can induce re-epithelialization, collagen deposition, and angiogenesis during wound healing in diabetic mice with good biocompatibility and biodegradability. The results suggest that this hydrogel is a promising innovative dressing for the treatment of diabetic wounds. STATEMENT OF SIGNIFICANCE: Diabetic ulcers, as one of the main types of chronic refractory wounds, are not treated effectively in the clinic due to a lack of strategic approach. In this study, we designed a glucose-responsive multifunctional metal-organic drug-loaded hydrogel (DG@Gel), which can change the hyperglycemic wound microenvironment by decomposing excess glucose into hydrogen peroxide and glucuronic acid. This in turn promoted the release of zinc ions and deferoxamine mesylate (DFO) in the hydrogel, which exhibited synergistic antibacterial and angiogenic activity for diabetic wound repair. Furthermore, the DG@Gel exhibited good biocompatibility and biodegradability in vivo. In general, this innovative strategy design may have great application potential in the treatment of various chronic wounds., 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 © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Root restriction (RR) has been reported to enhance grape berry quality in diverse aspects of grape life. In this study, RR-induced increases in the main primary metabolites in the grape berry and the expression of their related genes were studied at different developmental stages. Mainly the transcriptomic and metabolomic level were analyzed using 'Summer Black' grape berry as a material. The main results were as follows: A total of 11 transcripts involved in the primary metabolic pathways were significantly changed by the RR treatment. Metabolites such as sugars, organic acids, amino acids, starch, pectin, and cellulose were qualitatively and quantitatively analyzed along with their metabolic pathways. Sucrose synthase ( VIT&#95;07s0005g00750 , VIT&#95;11s0016g00470 ) and sucrose phosphate synthase ( VIT&#95;18s0089g00410 ) were inferred to play critical roles in the accumulation of starch, sucrose, glucose, and fructose, which was induced by the RR treatment. RR treatment also promoted the malic acid and tartaric acid accumulation in the young berry. In addition, the grape berries after the RR treatment tended to have lower pectin and cellulose content.