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Prions are infectious protein particles known to cause prion diseases. The biochemical entity of the pathogen is the misfolded prion protein (PrPSc) that forms insoluble amyloids to impair brain function. PrPSc interacts with the non-pathogenic, cellular prion protein (PrPC) and facilitates conversion into a nascent misfolded isoform. Several small molecules have been reported to inhibit the aggregation of PrPSc but no pharmacological intervention was well established thus far. We, here, report that acylthiosemicarbazides inhibit the prion aggregation. Compounds 7x and 7y showed almost perfect inhibition (EC50 = 5 µM) in prion aggregation formation assay. The activity was further confirmed by atomic force microscopy, semi-denaturing detergent agarose gel electrophoresis and real-time quaking induced conversion assay (EC50 = 0.9 and 2.8 µM, respectively). These compounds also disaggregated pre-existing aggregates in vitro and one of them decreased the level of PrPSc in cultured cells with permanent prion infection, suggesting their potential as a treatment platform. In conclusion, hydroxy-2-naphthoylthiosemicarbazides can be an excellent scaffold for the discovery of anti-prion therapeutics.

The Pearl River Delta (PRD) is a highly urbanized region in China that faces significant challenges in land use management. These challenges include the decrease in agricultural and ecological land resulting from rapid urbanization, the effectiveness of government governance, and the trajectory of development, all of which warrant careful research examination. Moreover, existing studies on land use in the PRD predominantly rely on static historical analysis, lacking a multi-scenario simulation approach. This study examines land use in PRD using a Patch-Generating Simulation (PLUS), from 1985 to 2020 to address this gap. Three scenarios were established to simulate potential land use outcomes in the PRD by 2030: spontaneous change, cropland protection, and ecological protection. The findings reveal that cropland, forest, and impervious surfaces are the dominant land use types in the PRD. From 1985 to 2020, the proportion of cropland decreased from 37.63% to 27.40%, with most conversions occurring to impervious surfaces and forest land. The proportion of impervious surfaces increased from 1.81% to 12.57%, primarily from conversions of cropland, forest, and water bodies. Economic development, population growth, accessibility, climatic factors, and topographic conditions were shown to be the primary determinants of land use in the PRD. Modelling results suggest that under the spontaneous change scenario, cropland and ecological land decrease, while impervious surfaces expand significantly, threatening cropland preservation and ecological construction. However, under the cropland protection scenario, the conversion rate of cropland to other land types can be effectively controlled, contributing to efficient preservation. Under the ecological protection scenario, impervious infrastructure encroachment on ecological land can be mitigated, but cropland protection is limited. The study proposes cropland protection and ecological priority policies to optimize the structure of land use, enhance efficiency, and offer policy guidance for the efficient utilization of land resources and the preservation of the ecological environment in the PRD.

Broadband and high efficiency are the two core indexes of absorption research, which usually requires a balance between them. Therefore, how to take into account both and achieve broadband and efficient absorption is a hot topic in current research. In this paper, by the compound design of multiple mechanisms, a kind of wideband hybrid metamaterial absorber (HMA) is proposed. The overall structure consists of a layer of patterned resistive film and a layer of magnetic absorbing material (MAM) separated by the air. The resistive layer is designed as square ring type to regulate the local magnetic field, which results in significant magnetic field enhancement within the MAM layer, and this mechanism provides a prerequisite for wideband and high-efficiency absorption in the low frequency band. Furthermore, due to the electrical losses of the resistive film, another absorption band is additionally excited in the high frequency band. Thanks to the multiple mechanisms, the absorption efficiency above 90% in the 3.2–22.0 GHz frequency band can be realized, and the thickness of the overall structure is 7.0 mm that is 0.07 of the wavelengths at the lowest frequency point. To demonstrate this method, a prototype is designed, fabricated and measured. Both the simulation and experiment results verify the effectiveness of the proposed method. This work provides a new method to design wideband and high-efficiency electromagnetic absorption structures and may find potential applications in multi-functional planar or conformal structures.

The accuracy of carbon emission data is essential for various disciplines to maintain reasonable expectations and certainty regarding the carbon emission rights trading market. However, the management of carbon emission data quality faces many challenges, especially due to the harmful behavior of enterprises that falsify such data, which seriously disrupts the order and credibility of the carbon market. Currently, few studies focus on the behavior and mechanism of corporate carbon emission data fraud, which requires an in-depth stakeholder analysis to obtain theoretical and empirical support for the formulation of effective regulatory policies. To investigate the influence of government regulation and media monitoring on addressing enterprise carbon emission data falsification, as well as to analyze the game behaviors and equilibrium outcomes among the government, media, and enterprises under different policy combinations and market environments, this study develops an evolutionary game model incorporating the government, media, and enterprises as three key stakeholders. Furthermore, numerical simulations are conducted for empirical validation. The key findings of this research highlight the significant impact of government regulation and media monitoring on deterring enterprise carbon emission data falsification, thus effectively reducing falsification motives and behaviors and enhancing the quality of carbon emission data. Additionally, the game between the government, media, and enterprises reveals the existence of multiple evolutionary stable strategies. Of these, the optimal strategy is the comprehensive implementation of all three elements: government regulation, media monitoring, and corporate integrity disclosure. This paper comprehensively examines the influence of government regulation and media monitoring on enterprise carbon emission data falsification and addresses the gaps in existing research. Moreover, it provides theoretical guidance and policy recommendations for establishing a high-quality carbon market.

With increasing awareness of environmental protection, food safety has become an increasingly important concern for people. The excessive use of pesticides and fertilizers by agricultural enterprises poses a threat to food safety. However, effective promotion of their reduction faces many difficulties. To analyze how to promote the reduction of pesticide and fertilizer use and the path of decision-making evolution of different stakeholders under the changes of different influencing factors, this paper considers the interests of the government, agricultural enterprises and consumers, and constructs an evolutionary game model between the government and agricultural enterprises. The study found that: (1) the governance evolutionary game of reducing the use of pesticides and fertilizers can achieve four stable evolutionary strategies, among which the ideal stable state from a multi-centre governance perspective is the government choosing the regulatory strategy and agricultural enterprises choosing pesticide and fertilizer use reduction strategy. (2) The reward measures taken by the government have a more significant impact on both parties, and in the actual regulatory process, reward measures should be used cautiously, and regulatory mechanisms should be strengthened. (3) The green preferences of consumers are a key exogenous variable that significantly affects the decisions of agricultural enterprises and government. This study improves the policy analysis of pesticide and fertilizer use reduction in the Chinese context and provides innovative ideas for building a policy system to reduce the use of pesticides and fertilizers. The research conclusions provide guidance for promoting the reduction of pesticides and fertilizers use by agricultural enterprises.

V-ATPase, which comprises 13-14 subunits, is essential for pH homeostasis in all eukaryotes, but its proper function requires a regulator to assemble its subunits. While RAVE (regulator of H+-ATPase of vacuolar and endosomal membranes) and Raboconnectin-3 complexes assemble V-ATPase subunits in Saccharomyces cerevisiae and humans, respectively, the function of the RAVE complex in fungal pathogens remains largely unknown. In this study, we identified two RAVE complex components, Rav1 and Wdr1, in the fungal meningitis pathogen Cryptococcus neoformans, and analyzed their roles. Rav1 and Wdr1 are orthologous to yeast RAVE and human Rabconnectin-3 counterparts, respectively, forming the hybrid RAVE (hRAVE) complex. Deletion of RAV1 caused severe defects in growth, cell cycle control, morphogenesis, sexual development, stress responses, and virulence factor production, while the deletion of WDR1 resulted in similar but modest changes, suggesting that Rav1 and Wdr1 play central and accessary roles, respectively. Proteomics analysis confirmed that Wdr1 was one of the Rav1-interacting proteins. Although the hRAVE complex generally has V-ATPase-dependent functions, it also has some V-ATPase-independent roles, suggesting a unique role beyond conventional intracellular pH regulation in C. neoformans. The hRAVE complex played a critical role in the pathogenicity of C. neoformans, and RAV1 deletion attenuated virulence and impaired blood-brain barrier crossing ability. This study provides comprehensive insights into the pathobiological roles of the fungal RAVE complex and suggests a novel therapeutic strategy for controlling cryptococcosis.

ABSTRACT The emergence of multidrug-resistant fungal pathogens is a significant concern for global public health. Candida auris poses a considerable threat as a multidrug-resistant fungal pathogen. Our recent study revealed that the adenylyl cyclase Cyr1 and protein kinase A (PKA) pathways play distinct and redundant roles in drug resistance and pathogenicity of C. auris. However, the upstream and negative feedback regulatory mechanisms of C. auris are not yet fully understood. In this study, we discovered that the small GTPase Ras1, along with its nucleotide exchange factor Cdc25 and GTPase-activating protein Ira2, plays a major role in regulating cAMP/PKA-dependent traits, while G-protein-coupled receptor Gpr1 and heterotrimeric G-protein α subunit Gpa2 play a minor role. Pde2 plays a major role in negative feedback regulation of the cAMP/PKA pathway, while Pde1 plays a minor role. Hyperactivation of the Ras/cAMP/PKA pathway by deleting PDE2 or BCY1 renders C. auris cells thermosensitive and susceptible to nutrient deficiency, which leads to attenuated virulence. Our study demonstrates the distinct contributions of hyperactivation of the Ras/cAMP/PKA signaling pathway to C. auris pathogenesis and suggests potential therapeutic targets for C. auris-mediated candidiasis. IMPORTANCE Candida auris is a major concern as a multidrug-resistant fungal pathogen. While our previous studies highlighted the crucial roles of the cAMP/protein kinase A (PKA) pathway in regulating drug resistance, stress responses, morphogenesis, ploidy change, biofilm formation, and pathogenicity in this pathogen, their regulatory mechanism remains unclear. In our study, we provided evidence that the cAMP/PKA signaling pathway in C. auris is primarily governed by the small GTPase RAS rather than a G-protein-coupled receptor. Additionally, we discovered that the negative feedback regulation of cAMP, controlled by phosphodiesterases, is vital for C. auris virulence by promoting resistance to high temperatures and nutrient deficiencies. These findings underscore the diverse pathobiological significance of the Ras/cAMP/PKA signaling pathway in C. auris, shedding light on potential therapeutic targets and strategies for combating this multidrug-resistant fungal pathogen.

BackgroundIron is an essential element for organismal health but excessive iron is potentially toxic. However, few observational studies link plasma iron (PI) concentrations and cancer risk, and the results are inconsistent.ObjectiveThis study aimed to explore the associations of PI concentrations with cancer risk in Chinese adults with hypertension.MethodsWe conducted a nested, case-control study, including 223 pairs of incident cancer cases and matched controls from the China Stroke Primary Prevention Trial. The median time between blood sample collection and subsequent cancer event occurrence was 2.13 years. The odds ratio (OR) and 95% confidence interval (CI) for the risk of cancer by PI were estimated from multivariable conditional logistic regression models.ResultsThere was a nonlinear association between PI concentrations and total cancer risk. When compared with participants in tertile 2 of PI, the ORs of total cancer were 2.17 (95%CI: 1.25-3.85) and 1.29 (95%CI: 0.77-2.19) in participants in PI tertiles 3 and 1, respectively. Furthermore, higher PI was associated with increased digestive system cancer risk (OR=3.25, 95%CI:1.29-8.90), while lower PI was associated with increased risk of non-digestive system cancer (OR=3.32, 95%CI: 1.39-8.71). In a sensitivity analysis, the increases in total cancer risk or digestive system cancer risk were still observed with higher PI after excluding cancer cases occurring within the first year.ConclusionOur results showed an increased risk of cancer related to higher PI or lower PI in Chinese adults with hypertension. Higher iron levels were linked to an increased risk of digestive system cancers, whereas lower iron levels were linked to an increased risk of non-digestive system cancers.

This paper studies the problem of scheduling $ n $ jobs on a single machine to minimize total completion time and maximum cost, simultaneously. Each job is associated with a positional deadline that indicates the largest ordinal number of this job in any feasible schedule. The jobs have agreeable release and processing times, meaning that jobs with larger release times also have larger processing times. The agreeability assumption is reasonable since both the single-criterion problems (without positional deadline constraints) of minimizing total completion time and maximum lateness on a single machine with arbitrary release and processing times are strongly NP-hard. An $ O(n^3) $-time Pareto optimal algorithm is presented. The previously known algorithms only solve two special cases of the agreeability assumption: either the case of equal release times in $ O(n^4) $ time, or the case of equal processing times (without positional deadline constraints) in $ O(n^3) $ time.

To explore the effects of different drying methods on lipid oxidation and volatile flavor components of fishery products, the corresponding experimental groups were prepared by hot-air drying, cold-air drying and traditional natural drying using fresh Spanish mackerel (Scomberomorus niphonius) as raw material. The moisture content, pH value, lipid content, acid value (AV), peroxide value (POV), malondialdehyde (MDA), fatty acid composition and volatile flavor components of raw materials and different dried samples were measured. The results showed that the moisture content of dried samples prepared by three drying methods was about 30% with the pH value above 6. The AV, POV and the contents of MDA in the cold-air drying group were lower than the other groups (P

Abstract Although 2020 was the fourth warmest year on record in northern Asia, the cold condition in April 2020 caused severe damage to the agricultural and marine ecosystems in northeastern Asia. Previous studies have indicated that the dipole atmospheric circulation over Siberia and the East Sea (Japan Sea) produced this cold environment with strong northwesterly wind. However, the potential causes of the dipole circulation over northeastern Asia remain unclear. In this study, we found that the East Atlantic/Western Russia (EAWR) pattern and blocking combined to produce the atmospheric structure. The wave train originated from the vorticity forcing of northwestern/central Russia and propagated from Western Europe to the East Sea via the background westerly and northerly winds. In addition, the Siberian blocking days increased eleven times in April 2020 relative to the climatological average, and an easterly (westerly) anomaly was observed over Mongolia–northeastern China (northern Russia). The strong blocking and EAWR pattern led to the robust atmospheric dipole structure with a prevailing northerly flow in April 2020, thereby causing the extreme cold condition over northeastern Asia. Our results provide novel insights into the cause of extreme cold condition in April over northeastern Asia.

With low density, high porosity, and outstanding physicochemical stability, ceramic nanowire aerogels and sponges exhibit various interesting properties. Herein, an ultrathin silica nanowire aerogel (SiO2 NWs-A) was achieved via a facile chemical vapor deposition route. In addition to good mechanical and thermal performances, properties resulting from active water-aerogel interactions are revealed, i.e., outstanding transparency, strong capillary effect, enhanced compressive strength (a reversible strain of ∼62%), switchable wettability and robust shape retention ability when filled with water. The physical mechanism related to these interesting properties is demonstrated basically according to its unique features (distinctly reduced nanowire diameter, enriched nanoscopic gap channels, and reinforced network). To demonstrate the superiority, an advantageous solar vapor generation system (hydrophilic NWs-A/reduced graphene oxide (rGO)/ hydrophobic NWs-A) was obtained by integrating these favorable characteristics, giving rise to remarkably promoted vapor evaporation rate and energy efficiency compared to the rGO hydrophobic NWs-A device. These results contribute to the structural design and functional exploration of nanowire aerogels.

Abstract Supramolecular peptides exhibit obvious similarities with collagen fibers in terms of self-assembly characteristics, nanofibrous structure, and responsiveness to external stimuli. Here, a series of supramolecular peptides were developed by altering the amino acid sequence, enabling the self-assembly of three types of 4-biphenylacetic acid (BPAA)-tripeptides into fibrous hydrogel through hydrogen bonding and π–π stacking under the influence of ion induction. Transmission electron and scanning electron microscopies revealed that the diameter of the fiber within nanofibrous hydrogels was ~ 10 and ~ 40 nm, respectively, which was similar with the self-assembled collagen fibers. For this reason, these hydrogels could be considered as a biomimetic extracellular substitute. Meanwhile, the gelation concentration induced by ions was even lower than 0.66 wt%, with an elastic modulus of ~ 0.27 kPa, corresponding to a water content of 99.34 wt%. In addition, the three supramolecular hydrogels were found to be good substrates for L929 cell adhesion and MC-3T3 cell proliferation. The overall results implied that BPAA-based hydrogels have a lucrative application potential as cell carriers. Graphical Abstract

Introduction: Considerable evidence has linked periodontitis (PD) to hypertension (HTN), but the nature behind this connection is unclear. Dysbiosis of oral microbiota leading to PD is known to aggravate different systematic diseases, but the alteration of oral microbiota in HTN and their impacts on blood pressure (BP) remains to be discovered. Objectives: To characterize the alterations of oral and gut microbiota and their roles in HTN. Methods: We performed a cross-sectional (95 HTN participants and 39 controls) and a 6-month follow-up study (52 HTN participants and 26 controls) to analyze the roles of oral and gut microbiota in HTN. Saliva, subgingival plaques, and feces were collected for 16S rRNA gene sequencing or metagenomic analysis. C57BL/6J mice were pretreated with antibiotics to deplete gut microbiota, and then transplanted with human saliva by gavage to test the impacts of abnormal oral-gut microbial transmission on HTN. Results: BP in participants with PD was higher than no PD in both cross-sectional and follow-up cohort. Relative abundances of 14 salivary genera, 15 subgingival genera and 10 gut genera significantly altered in HTN and those of 7 salivary genera, 12 subgingival genera and 6 gut genera significantly correlated with BP. Sixteen species under 5 genera were identified as oral-gut transmitters, illustrating the presence of oral-gut microbial transmission in HTN. Veillonella was a frequent oral-gut transmitter stably enriched in HTN participants of both cross-sectional and follow-up cohorts. Saliva from HTN participants increased BP in hypertensive mice. Human saliva-derived Veillonella successfully colonized in mouse gut, more abundantly under HTN condition. Conclusions: PD and oral microbiota are strongly associated with HTN, likely through oral-gut transmission of microbes. Ectopic colonization of saliva-derived Veillonella in the gut may aggravate HTN. Therefore, precise manipulations of oral microbiota and/or oral-gut microbial transmission may be useful strategies for better prevention and treatment of HTN.

Abstract Metastasis constitutes one of the major causes of tumor-related death in gastric cancer (GC), and understanding key events in the initiation of this phenotypic switch may provide therapeutic opportunities. Long noncoding RNAs (lncRNAs) are emerging as molecules that play vital roles in tumorigenesis and metastasis. In this study, we aimed to identify metastasis-related lncRNAs in the context of GC. The lncRNAs overexpressed in tumor tissues and positively associated with overall survival were screened out using the TCGA database. qPCR assays in clinical samples showed that LINC00858 was significantly upregulated in GC tissues compared with normal counterparts. Functional analysis suggested that LINC00858 depletion attenuated the migration, and invasion of cancer cells in vitro and suppressed the metastasis of xenografted tumors in vivo. Mechanistically, LINC00858 could interact with the metastasis-associated RAN and stabilize its protein expression by decreasing posttranslational ubiquitination. The transcription factor YY1 could bind to the promoter of LINC00858 to upregulate its expression in GC cells. Moreover, overexpression of YY1 and RAN was positively associated with upregulation of LINC00858 in GC tissues. Our results suggest that LINC00858 might play a role in GC metastasis, and be a diagnostic biomarker and potential therapeutic target.

Abstract Background Nonalcoholic Fatty Liver Disease (NAFLD) is a chronic Liver Disease prevalent all over the world. It has become more and more common in Japan, China and most western developed countries. The global prevalence rate is 25.24%, and the trend is increasing year by year. Related studies have shown that Cynarine has certain liver protection, lipid lowering and immune intervention effects. So, this study to systematically predict and analyze the mechanism of Cynarine in the treatment of non-alcoholic fatty liver disease (NAFLD) based on the integration of network pharmacology, molecular docking, and cell experiment. Methods We performed Heatmap and Venn diagram analyses to identify genes and targets in Cynarine treat NAFLD. The network of Cynarine-therapeutic targets and the protein-protein interaction network (PPI) was constructed. We used gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to visualize associated functional pathways. The Sybyl tool was used to dock the Cynarine with key therapeutic targets molecularly. Finally, cell experiments were applied to validate the role of Cynarine in the treatment of NAFLD. Results The Cynarine could act on 48 targets of NAFLD, and the role of CASP3, TP53, MMP9, ELANE, NOTCH1 were more important. The PPI network showed that immune and inflammation-related targets played a pivotal role. The KEGG analysis found that the PI3K-Akt signaling pathway, cell cycle and MAPK signaling pathway may be the main pathways for Cynarine to prevent and treat NAFLD. Molecular docking studies confirmed that Cynarine has good binding activity with therapeutic targets. Cynarine reduced the fat deposition ability of NAFLD model cells, and effectively reduced the levels of ALT and AST released by liver cells due to excessive lipid accumulation. We also found that Cynarine inhibited the expression of AKT1 and MAPK1. Conclusions This study revealed that Cynarine could significantly reduce the fat deposition ability of NAFLD model cells, which may be closely related to the effective regulation of AKT1 and MAPK1 expression by Cynarine.

Abiotic stresses lead to excessive crop yield losses and are a major threat to agriculture. It is essential to equip crops with multi-stress tolerance to mitigate the adverse effects of abiotic stressors and meet the demands of the increasing global population. The association between plants and symbiotic microorganisms is involved in key functions at the ecosystem and plant levels, and the application of microbial plant biostimulants (MPBs) is a sustainable strategy to augment plant growth and productivity, even under abiotic stress conditions. Several different microorganisms can be used as MPBs to enhance plant growth and produce progressive and reproducible effects on crops. In the present review, we assessed the current knowledge on the use of MPBs, discuss the diversity and characteristics of MPBs, and provide a meticulous assessment of the possible applications of MPBs in abiotic stress relief in crops.

Photodynamic therapy (PDT) has been applied in cancer treatment by utilizing reactive oxygen species (ROS) to kill cancer cells. However, the effectiveness of PDT is greatly reduced due to local hypoxia. Hypoxic activated chemotherapy combined with PDT is expected to be a novel strategy to enhance anti-cancer therapy. Herein, a novel liposome (LCT) incorporated with photosensitizer (PS) and bioreductive prodrugs was developed for PDT-activated chemotherapy. In the design, CyI, an iodinated cyanine dye, which could simultaneously generate enhanced ROS and heat than other commonly used cyanine dyes, was loaded into the lipid bilayer; while tirapazamine (TPZ), a hypoxia-activated prodrug was encapsulated in the hydrophilic nucleus. Upon appropriate near-infrared (NIR) irradiation, CyI could simultaneously produce ROS and heat for synergistic PDT and photothermal therapy (PTT), as well as provide fluorescence signals for precise real-time imaging. Meanwhile, the continuous consumption of oxygen would result in a hypoxia microenvironment, further activating TPZ free radicals for chemotherapy, which could induce DNA double-strand breakage and chromosome aberration. Moreover, the prepared LCT could stimulate acute immune response through PDT activation, leading to synergistic PDT/PTT/chemo/immunotherapy to kill cancer cells and reduce tumor metastasis. Both in vitro and in vivo results demonstrated improved anticancer efficacy of LCT compared with traditional PDT or chemotherapy. It is expected that these iodinated cyanine dyes-based liposomes will provide a powerful and versatile theranostic strategy for tumor target phototherapy and PDT-induced chemotherapy.

A Tesla valve is a kind of micro-valve without moving parts. Due to the great difference between the reverse and forward flow, the Tesla valve is often used in passive fluid control devices. However, most of the current Tesla valve components are optimized and designed based on asymmetric structures. In this study, a Tesla valve pipe system model with symmetric structure is proposed. The characteristics of fluid flow and pressure drop were studied by finite element method and dimensional analysis. First, the pressure drop characteristics of symmetric and asymmetric Tesla valves with different Reynolds number are considered. The results show that the better the symmetry, the better the one-direction flow characteristics of Tesla valve system. Afterwards, through parametric analysis, computational fluid dynamics was used to verify flow characteristics of completely symmetrical Tesla valve system. The shunt angle, shunt pipe diameter and number of valves have significant effects on the pressure drop characteristics of the system. Eventually, based on numerical simulation results, by using the dimensional analysis method, the modification parameter $ \alpha ( {\alpha = \alpha ( {\theta,d,N} )} ) $ was introduced to obtain the scaling law $ \Delta p \sim ({1 + \ln (1 + {N^{3/5R{e^{1/3}}}})})\rho {V^2}L{D^{ - 1}}Re^{ - 1/4} $ between the pressure drop and other parameters of the completely symmetrical Tesla valve piping system.

Chemotherapy for tumors occasionally results in drug resistance, which is the major reason for the treatment failure. Higher drug doses could improve the therapeutic effect, but higher toxicity limits the further treatment. For overcoming drug resistance, functional nano-drug delivery system (NDDS) has been explored to sensitize the anticancer drugs and decrease its side effects, which are applied in combating multidrug resistance (MDR) via a variety of mechanisms including bypassing drug efflux, controlling drug release, and disturbing metabolism. This review starts with a brief report on the major MDR causes. Furthermore, we searched the papers from NDDS and introduced the recent advances in sensitizing the chemotherapeutic drugs against MDR tumors. Finally, we concluded that the NDDS was based on several mechanisms, and we looked forward to the future in this field.

Shigella sonnei is a major contributor to the global burden of dysenteric diarrhoea in developed countries. In this work, authors report a S. sonnei clone which has caused numerous waterborne shigellosis outbreaks in China from 2015 to 2020.

Abstract In tissue engineering, bioactive materials play an important role, providing structural support, cell regulation and establishing a suitable microenvironment to promote tissue regeneration. As the main component of extracellular matrix, collagen is an important natural bioactive material and it has been widely used in scientific research and clinical applications. Collagen is available from a wide range of animal origin, it can be produced by synthesis or through recombinant protein production systems. The use of pure collagen has inherent disadvantages in terms of physico-chemical properties. For this reason, a processed collagen in different ways can better match the specific requirements as biomaterial for tissue repair. Here, collagen may be used in bone/cartilage regeneration, skin regeneration, cardiovascular repair and other fields, by following different processing methods, including cross-linked collagen, complex, structured collagen, mineralized collagen, carrier and other forms, promoting the development of tissue engineering. This review summarizes a wide range of applications of collagen-based biomaterials and their recent progress in several tissue regeneration fields. Furthermore, the application prospect of bioactive materials based on collagen was outlooked, aiming at inspiring more new progress and advancements in tissue engineering research. Graphical Abstract

Abstract Multidrug resistance (MDR) has been restricting the efficacy of chemotherapy, which mainly include pump resistance and non-pump resistance. In order to fight overall MDR, a novel targeted gene/drug co-deliver nano system is developed, which can suppress the drug efflux pumps and modulate autophagy to overcoming both pump and non-pump resistance. Here, small interfere RNA (siRNA) is incorporated into polymer-drug conjugates (PEI-PTX, PP) which are composed of polyethyleneimine (PEI) and paclitaxel (PTX) via covalent bonds, and hyaluronic acid (HA) is coated on the surface of PP/siRNA to achieve long blood cycle and CD44-targeted delivery. The RNA interference to mdr1 gene is combined with autophagy inhibition by PP, which efficiently facilitate apoptosis of Taxol-resistant lung cancer cells (A549/T). Further study indicates that PEI in PP may play a significant role to block the autophagosome–lysosome fusion process by means of alkalizing lysosomes. Both in vitro and in vivo studies confirm that the nanoassemblies can successfully deliver PTX and siRNA into tumor cells and significantly inhibited A549/T tumor growth. In summary, the polymeric nanoassemblies provide a potential strategy for combating both pump and non-pump resistance via the synergism of RNAi and autophagy modulation.

The selective oxidation of 5-hydroxymethylfurfural (HMF), a versatile bio-based platform molecule, leads to the formation of several intriguing and useful downstream chemicals, such as 2,5-diformylfuran (DFF), 5-hydroxymethyl-2-furancarboxylic acid (HMFCA), formyl 2-furancarboxylic acid (FFCA), 2,5-furandicarboxylic acid (FDCA) and furan-2,5-dimethylcarboxylate (FDMC). These products have been extensively employed to fabricate novel polymers, pharmaceuticals, sustainable dyes and many other value-added fine chemicals. The heart of the developed HMF oxidation processes is always the catalyst. In this regard, this review comprehensively summarized the established heterogeneous catalyst design strategy for the selective oxidation of HMF via thermo-catalysis. Particular attention has been focused on the reaction mechanism of HMF oxidation over different catalysts as well as enhancing the catalytic performance of the catalyst through manipulating the properties of the support and fabricating of multi-component metal nano-particles and oxides. The current challenges and possible research directions for the catalytic oxidation of HMF in the future are also discussed.

Abstract With the emergence of DNA nanotechnology in the 1980s, self-assembled DNA nanostructures have attracted considerable attention worldwide due to their inherent biocompatibility, unsurpassed programmability, and versatile functions. Especially promising nanostructures are tetrahedral framework nucleic acids (tFNAs), first proposed by Turberfield with the use of a one-step annealing approach. Benefiting from their various merits, such as simple synthesis, high reproducibility, structural stability, cellular internalization, tissue permeability, and editable functionality, tFNAs have been widely applied in the biomedical field as three-dimensional DNA nanomaterials. Surprisingly, tFNAs exhibit positive effects on cellular biological behaviors and tissue regeneration, which may be used to treat inflammatory and degenerative diseases. According to their intended application and carrying capacity, tFNAs could carry functional nucleic acids or therapeutic molecules through extended sequences, sticky-end hybridization, intercalation, and encapsulation based on the Watson and Crick principle. Additionally, dynamic tFNAs also have potential applications in controlled and targeted therapies. This review summarized the latest progress in pure/modified/dynamic tFNAs and demonstrated their regenerative medicine applications. These applications include promoting the regeneration of the bone, cartilage, nerve, skin, vasculature, or muscle and treating diseases such as bone defects, neurological disorders, joint-related inflammatory diseases, periodontitis, and immune diseases.

Purpose: To assess the safety and effect of the multifocal low-intensity extracorporeal shockwave therapy (MESWT) in the treatment of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Materials and Methods: We randomly separated 30 patients with CP/CPPS into a MESWT and placebo group of same number using prospective-randomized, double-blind design. The participants’ National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) total and subdomain scores, International Prostate Symptom Score (IPSS), International Index of Erectile Function-5 (IIEF-5), and visual analogue scale (VAS) were assessed and compared at baseline and at finishing immediately and 4 weeks after procedure and also were compared between MESWT and placebo group. Results: A total of 30 participants were randomized a MESWT or placebo group. Twenty of thirty participants completed this trial. NIH-CPSI total and subdomain scores, IPSS, IIEF-5, and VAS had significantly ameliorated compared with baseline in the MESWT group at 4 weeks assessment. Furthermore, comparison of the results from MESWT and placebo groups represented statistically significant differences in NIH-CPSI total and subdomain scores, IPSS, IIEF-5, and VAS. No side effects or events were occurred in both groups of the participants during study periods. Conclusions: MESWT can be an effective treatment modality in patients with CP/CPPS as it improves pain and QoL.

We conducted a study on the confinement properties of non-neutral proton plasma in an asymmetric magnetic mirror using the three-dimensional (3D) particle-in-cell simulation method. Our findings indicate a close relationship between the ability of the magnetic mirror to confine protons and the incidence orientation of the proton beam. This relationship can only be accurately assessed through 3D simulation, as opposed to two-dimensional simulation. In addition, we observed that a higher velocity parallel to the magnetic field direction results in a shorter confinement time. The electric field at and near the central point of the mirror exhibits quasi-periodic vibrations, attributed to the electrostatic oscillation of the proton and the cyclotron motion. Furthermore, we discovered a drift motion of the confined proton plasma in the direction of the magnetic field gradient. These findings hold implications for the design of magnetic mirrors capable of effectively confining charged particle beams.

Abstract Biologically inspired neuromorphic sensory memory systems based on memristor have received a lot of attention in the booming artificial intelligence industry due to significant potential to effectively process multi‐sensory signals from complex external environments. However, many memristors have significant switching parameters disperse, which is a great challenge for using memristors in bionic neuromorphic sensory memory systems. Herein, a stable ferroelectric memristor based on the Pd/BaTiO3:Eu2O3/La0.67Sr0.33MnO3 grown on Silicon structure with SrTiO3 as buffer layer is presented. The device possesses low coercive field voltage (−1.3–2.1 V) and robust endurance characteristic (~1010 cycles) through optimizing the growth temperature. More importantly, an ultra‐stable artificial multimodal sensory memory system with visual and tactile functions was reported for the first time by combining a pressure sensor, a photosensitive sensor, and a robotic arm. Utilizing the above system, the sensitivity value of the system is expressed by the conductance of the memristor to realize the gradual change of external stimulus, and multi signals inputs at the same time to this system have faithfully achieved sensory adaptation to multimodal sensors. This work paves the way for future development of memristor‐based perception systems in efficient multisensory neural robots.

The surge of multidrug-resistant fungal pathogens, especially Candida auris, poses significant threats to global public health. Candida auris exhibits resistance to multiple antifungal drugs, leading to major outbreaks and a high mortality rate. With an urgent call for innovative therapeutic strategies, this study focused on the regulation and pathobiological significance of secreted aspartyl proteinases (SAPs) in C. auris, as these enzymes play pivotal roles in the virulence of some fungal species. We delved into the Ras/cAMP/PKA signaling pathway’s influence on SAP activity in C. auris. Our findings underscored that the Ras/cAMP/PKA pathway significantly modulates SAP activity, with PKA catalytic subunits, Tpk1 and Tpk2, playing a key role. We identified a divergence in the SAPs of C. auris compared to Candida albicans, emphasizing the variation between Candida species. Among seven identified secreted aspartyl proteases in C. auris (Sapa1 to Sapa7), Sapa3 emerged as the primary SAP in the pathogen. Deletion of Sapa3 led to a significant decline in SAP activity. Furthermore, we have established the involvement of Sapa3 in the biofilm formation of C. auris. Notably, Sapa3 was primarily regulated by Tpk1 and Tpk2. Deletion of SAPA3 significantly reduced C. auris virulence, underscoring its pivotal role in C. auris pathogenicity. The outcomes of this study provide valuable insights into potential therapeutic targets, laying the groundwork for future interventions against C. auris infection.

BackgroundSpontaneous lens absorption is rare and usually occurs in eyes with certain syndromes, hyper-mature cataracts, and ocular trauma. The application of an implantable collamer lens (ICL) is widely performed in patients with high myopia for refractive correction. This study reports a case of spontaneous lens absorption after ICL implantation.Case summaryA 23-year-old man was referred with complaints of poor vision in his left eye. The patient had undergone binocular ICL implantation for refractive correction of high myopia 1.5 years prior. Approximately 10 months later, he experienced a sudden loss of vision and pain in his left eye, which resolved spontaneously the next day without any treatment. Since then, the visual acuity in his left eye gradually decreased. At presentation, slit-lamp examination revealed an ICL in the posterior chamber of both eyes, with anterior capsular fibrotic proliferation and posterior capsular opacity, and the residual lens cortex sandwiched between the anterior fibrotic membrane and opacified posterior lens capsule in his left eye. The number of corneal endothelial cells in his left eye was 1,337, which was lower than before ICL implantation (2,902). The patient then underwent ICL extraction, anterior capsular capsulotomy, residual cortex aspiration, posterior capsular polishing, and intraocular lens implantation.ConclusionsSpontaneous lens absorption may occur in patients with ICL implantation. Patients should undergo routine follow-ups after ICL implantation.

The successful treatment of patients with advanced non–small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) with ALK tyrosine kinase inhibitors (ALK-TKIs) represents a promising targeted therapy. As a result, various ALK-TKIs have been rapidly developed, some of which are approved while some are being tested in clinical trials. Death receptor 4 (DR4; also called TNFRSF10A or TRAIL-R1) is a cell surface protein, which functions as a pro-apoptotic protein that transduces TRAIL death signaling to trigger apoptosis. DR4 expression is positively regulated by MEK/ERK signaling and thus can be downregulated by MEK/ERK inhibition. This study thus focused on determining the effects of AKL-TKIs on DR4 expression and the underlying mechanisms. Three tested ALK-TKIs including APG-2449, brigatinib and alectinib effectively and preferentially inhibited Akt/mTOR as well as MEK/ERK signaling and decreased cell survival in ALK-mutant (ALKm) NSCLC cells with induction of apoptosis. This was also true for DR4 downregulation, which occurred even at 2 h post treatment. These ALK-TKIs did not affect DR4 protein stability, rather decreased DR4 mRNA expression. In parallel, they promoted degradation and reduced the levels of Fra-1 and c-Jun, two critical components of AP-1, and suppressed AP-1 (Fra-1/c-Jun)-dependent transcription/expression of DR4. Hence, it appears that ALK-TKIs downregulate DR4 expression in ALKm NSCLC cells via facilitating Fra-1 and c-Jun degradation and subsequent AP-1 suppression. Our findings thus warrant further investigation of the biological significance of DR4 downregulation in ALK-targeted cancer therapy.

Purpose: Chemokine ligand 5 (CCL5), a vital member of the CC chemokine family, plays diverse roles in tumorigenesis, metastasis, and prognosis in various human tumors. However, no pan-cancer analysis has been conducted to illustrate its distinctive effects on clinical prognosis via underlying mechanisms and biological characteristics. Methods: Herein, we exploited the existed public bioinformatics database, primarily TCGA database and GTEx data, to comprehensively analyze the value of CCL5 involved in patient prognosis. Results: This study found that CCL5 was excessively expressed in most tumors and significantly associated with clinical prognosis in 10 out of 33 types of tumors. Notably, CCL5 might be an independent predictive biomarker of clinical outcome in SKCM patients, confirmed by univariate and multivariate Cox regression analysis. Furthermore, we acquired the genetic alteration status of CCL5 in multiple types of tumor tissues from TCGA cohorts. We revealed a potential correlation between the expression level of CCL5 and tumor mutational burden in 33 types of tumors. In addition, data showed that DNA methylation was associated with CCL5 gene expression in THCA, PRAD, LUSC, and BRCA cancers. Immune infiltration and immune checkpoints are fine indexes for evaluating immunotherapy. We uncovered that CCL5 was negatively correlated with the immune infiltration of CD8+ T cell, CD4+ T cell, macrophages, and gamma delta T cells in BRCA-basal and CESC tumors, while a significant positive correlation was observed in BLCA, COAD and other 7 types of tumors. Besides, CCL5 was closely associated with the immune checkpoint molecules in 8 types of tumors. The TIDE score was less in the CCL5 high-expressed group than in the CCL5 low-expressed group in SKCM patients, which indicated that CCL5 might be a fine monitor of immune response for immunotherapy. GO enrichment analysis data uncovered that cytokine-cytokine receptor interaction and chemokine signaling might be involved in the role of CCL5 in regulating tumor pathogenesis and prognosis. Conclusion: In conclusion, CCL5 was preliminarly identified as a biomarker of immune response and prognosis for tumors patients via our first comprehensive pan-cancer analysis.

Vascular calcification is accelerated in patients with diabetes mellitus and increases risk of cardiovascular events and mortality. Vascular smooth muscle cells (VSMC) play a key role in regulating vascular tone and contribute significantly to the development of diabetic vasculopathy. In this study, the function of stromal interaction molecule 1 (STIM1), an important regulator for intracellular calcium homeostasis, in diabetic vascular calcification was investigated, and the underlying molecular mechanisms were uncovered.A SMC-specific STIM1 deletion mouse model (STIM1Δ/Δ) was generated by breeding the STIM1 floxed mice (STIM1f/f) with SM22α-Cre transgenic mice. Using aortic arteries from the STIM1Δ/Δ mice and their STIM1f/f littermates, we found that SMC-specific STIM1 deletion induced calcification of aortic arteries cultured in osteogenic media ex vivo. Furthermore, STIM1 deficiency promoted osteogenic differentiation and calcification of VSMC from the STIM1Δ/Δ mice. In the low-dose streptozotocin (STZ)-induced mouse model of diabetes, SMC-specific STIM1 deletion markedly enhanced STZ-induced vascular calcification and stiffness in the STIM1Δ/Δ mice. The diabetic mice with SMC-specific STIM1 ablation also exhibited increased aortic expression of the key osteogenic transcription factor, Runx2, and protein O-GlcNAcylation, an important post-translational modulation that we have reported to promote vascular calcification and stiffness in diabetes. Consistently, elevation of O-GlcNAcylation was demonstrated in aortic arteries and VSMC from the STIM1Δ/Δ mice. Inhibition of O-GlcNAcylation with a pharmacological inhibitor abolished STIM1 deficiency-induced VSMC calcification, supporting a critical role of O-GlcNAcylation in mediating STIM1 deficiency-induced VSMC calcification. Mechanistically, we identified that STIM1 deficiency resulted in impaired calcium homeostasis, which activated calcium signaling and increased endoplasmic reticulum (ER) stress in VSMC, while inhibition of ER stress attenuated STIM1-induced elevation of protein O-GlcNAcylation.In conclusion, the study has demonstrated a causative role of SMC-expressed STIM1 in regulating vascular calcification and stiffness in diabetes. We have further identified a novel mechanisms underlying STIM1 deficiency-induced impairment of calcium homeostasis and ER stress in upregulation of protein O-GlcNAcylation in VSMC, which promotes VSMC osteogenic differentiation and calcification in diabetes.