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Abstract Understanding the sex determination pathway and its disruptions in mosquitoes is critical for the effective control of disease vectors through genetic manipulations based on sex separation. When male hybrids of Aedes aegypti females and Ae. mascarensis males are backcrossed to Ae. aegypti females, a portion of the backcross progeny manifests as males with abnormal sexual differentiation. We discovered a significant correlation between pupal abnormalities and the feminization of subsequent adults exemplified by the relative abundance of ovarian and testicular tissues. All intersex individuals were genetic males as they expressed a male determining factor, Nix. Further, our analysis of the sex-specific splicing of doublesex and fruitless transcripts demonstrated the presence of both male and female splice variants indicating that sex determination is disrupted. A comparative transcriptomic analysis revealed similar expression levels of most female-associated genes in reproductive organs and carcasses between intersexual males and normal females. Moreover, intersexes had largely normal gene expression in testes but significant gene downregulation in male accessory glands when compared with normal males. We conclude that evolving hybrid incompatibilities between Ae. aegypti and Ae. mascarensis involve disruption of sex determination and are accompanied by changes in gene expression associated with sexual differentiation.

Abstract Efficiently fabricating a cavity that can achieve strong interactions between terahertz waves and matter would allow researchers to exploit the intrinsic properties due to the long wavelength in the terahertz waveband. Here we show a terahertz detector embedded in a Tamm cavity with a record Q value of 1017 and a bandwidth of only 469 MHz for direct detection. The Tamm-cavity detector is formed by embedding a substrate with an Nb5N6 microbolometer detector between an Si/air distributed Bragg reflector (DBR) and a metal reflector. The resonant frequency can be controlled by adjusting the thickness of the substrate layer. The detector and DBR are fabricated separately, and a large pixel-array detector can be realized by a very simple assembly process. This versatile cavity structure can be used as a platform for preparing high-performance terahertz devices and opening up the study of the strong interactions between terahertz waves and matter.

Abstract Frequency combs, specialized laser sources emitting multiple equidistant frequency lines, have revolutionized science and technology with unprecedented precision and versatility. Recently, integrated frequency combs are emerging as scalable solutions for on-chip photonics. Here, we demonstrate a fully integrated superconducting microcomb that is easy to manufacture, simple to operate, and consumes ultra-low power. Our turnkey apparatus comprises a basic nonlinear superconducting device, a Josephson junction, directly coupled to a superconducting microstrip resonator. We showcase coherent comb generation through self-started mode-locking. Therefore, comb emission is initiated solely by activating a DC bias source, with power consumption as low as tens of picowatts. The resulting comb spectrum resides in the microwave domain and spans multiple octaves. The linewidths of all comb lines can be narrowed down to 1 Hz through a unique coherent injection-locking technique. Our work represents a critical step towards fully integrated microwave photonics and offers the potential for integrated quantum processors.

Abstract Background Inappropriate eating behaviors, particularly a lack of food diversity and poor diet quality, have a significant impact on the prognosis of certain chronic conditions and exacerbate these conditions in the community-dwelling elderly population. Current dietary interventions for the elderly have not adequately considered the nutritional needs associated with multiple chronic conditions and personal dietary preferences of elderly individuals. A personalized recommendation system has been recognized as a promising approach to address this gap. However, its effectiveness as a component of an elderly-targeted dietary intervention in real-world settings remains unknown. Additionally, it is unclear whether this intervention approach will be user-friendly for the elderly. Therefore, this study aims to examine the effectiveness of a personalized meal recommendation system designed to improve dietary behavior in community-dwelling elders. The implementation process in terms of System usability and satisfaction will also be assessed. Methods The trial has been designed as a 6-month, non-blinded, parallel two-arm trial. One hundred fifty community-dwelling elders who meet the eligibility criteria will be enrolled. Subjects will be allocated to either the intervention group, receiving personalized meal recommendations and access to corresponding food provided as one component of the intervention, as well as health education on elder nutrition topics, or the control group, which will receive nutritional health education lectures. Outcomes will be measured at three time points: baseline at 0 months, 3 months, and 6 months. The primary outcomes will include dietary diversity (DDS) and diet quality (CDGI-E) of enrolled community-dwelling elders, representing their dietary behavior improvement, along with dietary behavior adherence to recommended meals. Secondary outcomes will measure the perceived acceptability and usability of the personalized meal recommendation system for the intervention group. Exploratory outcomes will include changes in the nutritional status and anthropometric measurements of the community-dwelling elders. Discussion This study aims to examine the effectiveness, acceptability, and usability of a personalized meal recommendation system as a data-driven dietary intervention to benefit community-dwelling elders. The successful implementation will inform the future development and integration of digital health strategies in daily nutrition support for the elderly. Trial registration Chinese Clinical Trial Registry ChiCTR2300074912. Registered on August 20, 2023, https://www.chictr.org.cn/showproj.html?proj=127583

Microring resonators have been widely used in passive optical devices such as wavelength division multiplexers, differentiators, and integrators. Research on terahertz (THz) components has been accelerated by these photonics technologies. Compact and integrated time-domain differentiators that enable low-loss, high-speed THz signal processing are necessary for THz applications. In this study, an on-chip THz temporal differentiator based on all-silicon photonic technology was developed. This device primarily consisted of a microring waveguide resonator and was packaged with standard waveguide compatibility. It performed time-domain differentiation on input signals at a frequency of 405.45 GHz with an insertion loss of 2.5 dB and a working bandwidth of 0.36 GHz. Various periodic waveforms could be handled by this differentiator. This device could work as an edge detector, which detected step-like edges in high-speed input signals through differential effects. This development holds significant promise for future THz data processing technologies and THz communication systems.

Intestinal obstruction, a rare manifestation of immunotherapy-related gastrointestinal adverse events, can be severe and even life-threatening with intestinal perforation. We present a 64-year-old man with HCC and currently under the therapy with Pembrolizumab, who was admitted in our hospital with abdominal distension. Radiologic findings were consistent with small bowel ileus. After conservative treatment, the patient underwent colonoscopy where no cause of ileus was discovered. The patient received high-dose prednisone due to the side effects of immune checkpoint inhibitor therapy. This resulted in a gradual improvement of symptoms.

Abstract The metasurface platform with time-varying characteristics has emerged as a promising avenue for exploring exotic physics associated with Floquet materials and for designing photonic devices like linear frequency converters. However, the limited availability of materials with ultrafast responses hinders their applications in the terahertz range. Here we present a time-varying metasurface comprising an array of superconductor-metal hybrid meta-molecules. Each meta-molecule consists of two meta-atoms that are “bonded” together by double superconducting microbridges. Through experimental investigations, we demonstrate high-efficiency linear terahertz frequency conversion by rapidly breaking the bond using a coherent ultrashort terahertz pump pulse. The frequency and relative phase of the converted wave exhibit strong dependence on the pump-probe delay, indicating phase controllable wave conversion. The dynamics of the meta-molecules during the frequency conversion process are comprehensively understood using a time-varying coupled mode model. This research not only opens up new possibilities for developing innovative terahertz sources but also provides opportunities for exploring topological dynamics and Floquet physics within metasurfaces.

$p,q,r-$ spherical fuzzy ( $p,q,r-$ SF) sets are a significant advancement in fuzzy set (FS) theory, providing an effective way to describe hesitation inside a set. This development goes beyond membership degrees (MDs) by incorporating three parameters (p, q and r) that shape and define the spread of FS. The presence of these parameters makes $p,q,r-$ SF sets ideal for dealing with complicated decision-making (DM) scenarios in a wide range of applications. In this paper, we proposed a new reliable method for smart DM in logo design projects that uses $p,q,r-$ SF Einstein aggregation operators (AOs). First, we present the $p,q,r-$ SF Einstein operators, which are accomplished of capturing the relationship and interrelationship of numerous criteria while making decisions on logo design, including originality, relevance, beauty, and usability. Next, we use the proposed framework, a multi-criteria decision analysis tool, to rank the choices. We demonstrate the practical application and efficiency of our method in a scenario in which a team of three designers is entrusted with developing five different logo styles for diverse enterprises. Moreover, we compare proposed procedure with some existing methods, demonstrating its advantages in terms of precision and reliability.

Abstract Classical and quantum space-to-ground communications necessitate highly sensitive receivers capable of extracting information from modulated photons to extend the communication distance from near-earth orbits to deep space explorations. To achieve gigabit data rates while mitigating strong background noise photons and beam drift in a highly attenuated free-space channel, a comprehensive design of a multi-functional detector is indispensable. In this study, we present an innovative compact multi-pixel superconducting nanowire single-photon detector array that integrates near-unity detection efficiency (91.6%), high photon counting rate (1.61 Gcps), large dynamic range for resolving different photon numbers (1–24), and four-quadrant position sensing function all within one device. Furthermore, we have constructed a communication testbed to validate the advantages offered by such an architecture. Through 8-PPM (pulse position modulation) format communication experiments, we have achieved an impressive maximum data rate of 1.5 Gbps, demonstrating sensitivities surpassing previous benchmarks at respective speeds. By incorporating photon number information into error correction codes, the receiver can tolerate maximum background noise levels equivalent to 0.8 photons/slot at a data rate of 120 Mbps—showcasing a great potential for daylight operation scenarios. Additionally, preliminary beam tracking tests were conducted through open-loop scanning techniques, which revealed clear quantitative dependence indicating sensitivity variations based on beam location. Based on the device characterizations and communication results, we anticipate that this device architecture, along with its corresponding signal processing and coding techniques, will be applicable in future space-to-ground communication tasks.

Abstract Background The relationship between leukocyte telomere length (LTL) and mortality risk in individuals with metabolic syndrome (MetS) remains poorly understood. This study aimed to investigate the association between telomere length and long-term all-cause mortality, and cardiovascular disease (CVD) mortality, in individuals with MetS in the United States. Methods A total of 1980 participants with MetS aged 18 years or older from the National Health and Nutrition Examination Survey (NHANES) prospective cohort study (1999–2002) were included in this cohort study. Medical records review was used to identify the cause of deaths as of December 2018. We employed Kaplan-Meier curves, fitted curves, and Cox proportional hazards regression models to estimate hazard ratios (HRs) for all-cause and CVD mortality, stratified by tertiles of LTL. Results Over a median follow-up of 17.75 years of participants with metabolic syndrome, 819 deaths occurred, including 231 cardiovascular deaths. After adjusting for multiple covariates, participants with shorter telomere length had a significantly higher risk of all-cause mortality (HR, 1.33; 95% CI, 1.11–1.6) and CVD mortality (HR, 1.36; 95% CI, 0.96–1.93) compared with those in the highest tertile of telomere length. All-cause mortality (P

Abstract Background Exercise mimetics is a proposed class of therapeutics that specifically mimics or enhances the therapeutic effects of exercise. Muscle glycogen and lactate extrusion are critical for physical performance. The mechanism by which glycogen and lactate metabolism are manipulated during exercise remains unclear. This study aimed to assess the effect of miR‐92b on the upregulation of exercise training‐induced physical performance. Methods Adeno‐associated virus (AAV)‐mediated skeletal muscle miR‐92b overexpression in C57BLKS/J mice, and global knockout of miR‐92b mice were used to explore the function of miR‐92b in glycogen and lactate metabolism in skeletal muscle. AAV‐mediated UGP2 or MCT4 knockdown in WT or miR‐92 knockout mice was used to confirm whether miR‐92b regulates glycogen and lactate metabolism in skeletal muscle through UGP2 and MCT4. Body weight, muscle weight, grip strength, running time and distance to exhaustion, and muscle histology were assessed. The expression levels of muscle mass‐related and function‐related proteins were analysed by immunoblotting or immunostaining. Results Global knockout of miR‐92b resulted in normal body weight and insulin sensitivity, but higher glycogen content before exercise exhaustion (0.8538 ± 0.0417 vs. 1.043 ± 0.040, **P = 0.0087), lower lactate levels after exercise exhaustion (4.133 ± 0.2589 vs. 3.207 ± 0.2511, *P = 0.0279), and better exercise capacity (running distance to exhaustion, 3616 ± 86.71 vs. 4231 ± 90.29, ***P = 0.0006; running time to exhaustion, 186.8 ± 8.027 vs. 220.8 ± 3.156, **P = 0.0028), as compared with those observed in the control mice. Mice skeletal muscle overexpressing miR‐92b (both miR‐92b‐3p and miR‐92b‐5p) displayed lower glycogen content before exercise exhaustion (0.6318 ± 0.0231 vs. 0.535 ± 0.0194, **P = 0.0094), and higher lactate accumulation after exercise exhaustion (4.5 ± 0.2394 vs. 5.467 ± 0.1892, *P = 0.01), and poorer exercise capacity (running distance to exhaustion, 4005 ± 81.65 vs. 3228 ± 149.8, ***P

Abstract Metabolic reprogramming to glycolysis is closely associated with the development of chronic kidney disease (CKD). Although it has been reported that phosphofructokinase 1 (PFK) is a rate-limiting enzyme in glycolysis, the role of the platelet isoform of PFK (PFKP) in kidney fibrosis initiation and progression is as yet poorly understood. Here, we investigated whether PFKP could mediate the progression of kidney interstitial fibrosis by regulating glycolysis in proximal tubular epithelial cells (PTECs). We induced PFKP overexpression or knockdown in renal tubules via an adeno-associated virus (AAV) vector in the kidneys of mice following unilateral ureteral occlusion. Our results show that the dilated tubules, the area of interstitial fibrosis, and renal glycolysis were promoted by proximal tubule-specific overexpression of PFKP, and repressed by knockdown of PFKP. Furthermore, knockdown of PFKP expression restrained, while PFKP overexpression promoted TGF-β1-induced glycolysis in the human PTECs line. Mechanistically, Chip-qPCR revealed that TGF-β1 recruited the small mothers against decapentaplegic (SMAD) family member 3-SP1 complex to the PFKP promoter to enhance its expression. Treatment of mice with isorhamnetin notably ameliorated PTEC-elevated glycolysis and kidney fibrosis. Hence, our results suggest that PFKP mediates the progression of kidney interstitial fibrosis by regulating glycolysis in PTECs.

Ovarian cancer is the leading cause of death among gynecological cancers in most developed countries, with many patients developing chemotherapy resistance leaving them with a 5-year survival rate of

Objective: The COVID-19 pandemic has had an enormous impact on society and the medical environment in Taiwan in 2022. As pregnant women with COVID-19 are at higher risk for multiple complications, Taiwan needs a COVID-19 specialized maternity unit to improve the quality of maternal and neonatal care. Materials and methods: We share our experience with specialized maternity unit for pregnant women with COVID-19 at the National Cheng Kung University Hospital, where we can have careful evaluation, safe birth, and comprehensive postpartum care. Results: Our COVID-19 specialized maternity unit enrolled 253 pregnant women with COVID-19, 90 (35.6%) pregnant women were admitted to the specialized maternity unit, and 71 (28.1%) pregnant women gave birth during hospitalization in two months. All pregnant women recovery well and real-time polymerase chain reaction tests on all infants were negative for COVID-19. Conclusion: A specialized maternity unit can provide pregnant women with a safe birth environment, immediate maternity care, and high medical quality. It can also help health workers in non-specialized maternity units deal with COVID-19-related psychological stress. Therefore, setting up one specialized maternity unit in the city during the pandemic should be guardedly considered.

Abstract Chronic diseases often lead to metabolic disorders, causing anabolic resistance and increased energy consumption, which result in cachexia. Cachexia, in turn, can lead to major clinical consequences such as impaired quality of life, shortened life expectancy, and increased healthcare expenditure. Existing international diagnostic criteria for cachexia employ thresholds derived from Western populations, which may not apply to Asians due to differing body compositions. To address this issue, the Asian Working Group for Cachexia (AWGC) was initiated. The AWGC comprises experts in cachexia research and clinical practice from various Asian countries and aims to develop a consensus on diagnostic criteria and significant clinical outcomes for cachexia in Asia. The AWGC, composed of experts in cachexia research and clinical practice from several Asian countries, undertook three‐round Delphi surveys and five meetings to reach a consensus. Discussions were held on etiological diseases, essential diagnostic items for cachexia, including subjective and objective symptoms and biomarkers, and significant clinical outcomes. The consensus highlighted the importance of multiple diagnostic factors for cachexia, including chronic diseases, either or both weight loss or low body mass index, and at least one of the following: anorexia, decreased grip strength (5 mg/L [0.5 mg/dL]). The AWGC proposed a significant weight change of 2% or more over a 3–6 month period and suggested a tentative cut‐off value of 21 kg/m2 for low body mass index in diagnosing cachexia. Critical clinical outcomes were determined to be mortality, quality of life as assessed by tools such as EQ‐5D or the Functional Assessment of Anorexia/Cachexia Therapy, and functional status as measured by the Clinical Frailty Scale or Barthel Index, with significant emphasis on patient‐reported outcomes. The AWGC consensus offers a comprehensive definition and user‐friendly diagnostic criteria for cachexia, tailored specifically for Asian populations. This consensus is set to stimulate future research and enhance the multidisciplinary approach to managing cachexia. With plans to develop further guidelines for the optimal treatment, prevention, and care of cachexia in Asians, the AWGC criteria are expected to drive research across chronic co‐morbidities and cancer in Asia, leading to future refinement of diagnostic criteria.

Abstract Transforming growth factor-β (TGF-β) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease. In kidneys that are obstructed, specific deletion of Sirt2 in renal tubule epithelial cells (TEC) has been shown to aggravate renal fibrosis, while renal tubule specific overexpression of Sirt2 has been shown to ameliorate renal fibrosis. Similarly, specific deletion of Sirt2 in hepatocyte aggravated CCl4-induced hepatic fibrosis. In addition, we have demonstrated that SIRT2 overexpression and knockdown restrain and enhance TGF-β-induced fibrotic gene expression, respectively, in TEC. Mechanistically, SIRT2 reduced the phosphorylation, acetylation, and nuclear localization levels of SMAD2 and SMAD3, leading to inhibition of the TGF-β signaling pathway. Further studies have revealed that that SIRT2 was able to directly interact with and deacetylate SMAD2 at lysine 451, promoting its ubiquitination and degradation. Notably, loss of SMAD specific E3 ubiquitin protein ligase 2 abolishes the ubiquitination and degradation of SMAD2 induced by SIRT2 in SMAD2. Regarding SMAD3, we have found that SIRT2 interact with and deacetylates SMAD3 at lysine 341 and 378 only in the presence of TGF-β, thereby reducing its activation. This study provides initial indication of the anti-fibrotic role of SIRT2 in renal tubules and hepatocytes, suggesting its therapeutic potential for fibrosis.

Abstract Photoacid generators (PAGs) are compounds capable of producing hydrogen protons (H+) upon irradiation, including irreversible and reversible PAGs, which have been widely studied in photoinduced polymerization and degradation for a long time. In recent years, the applications of PAGs in the biomedical field have attracted more attention due to their promising clinical value. So, an increasing number of novel PAGs have been reported. In this review, the recent progresses of PAGs for biomedical applications is systematically summarized, including tumor treatment, antibacterial treatment, regulation of protein folding and unfolding, control of drug release and so on. Furthermore, a concept of water‐dependent reversible photoacid (W‐RPA) and its antitumor effect are highlighted. Eventually, the challenges of PAGs for clinical applications are discussed.

In this study, the loess hill site of an elevated bridge section in Tongwei-Qin’an of the Baolan high-speed railroad was selected as the research object, and the vibration acceleration of the loess hill site under the elevated bridge was tested in the field under the train operating load. The results show that under the same intensity of train load, the time range of vibration acceleration observed by field test and numerical simulation decays linearly with increasing distance from the source, while the amplification effect appears in the loess hill site at a greater distance, and the vibration duration also appears to increase. The vibration acceleration waveforms at each observation point observed by field tests and numerical simulations are similar, and the peak vertical acceleration at each observation point obtained from numerical simulations is overall greater than the peak acceleration at each point obtained from field tests, with aSimulated− max/aObservated− max values ranging from 1.04 to 1.63. The Fourier spectrum frequencies recorded by numerical simulation and field test are mainly concentrated in the range of 1∼40 Hz, but the difference between the main frequencies recorded by the two is large. The main frequency of the energy spectrum recorded by the numerical simulation is around 15 Hz, which is the same as the main frequency of the energy spectrum vibration of the input vibration wave, and the main frequency of the energy spectrum vibration recorded by the field test is around 25 Hz.

Abstract Electrochemical carbon monoxide (CO) reduction to high-energy-density fuels provides a potential way for chemical production and intermittent energy storage. As a valuable C3 species, n-propanol still suffers from a relatively low Faradaic efficiency (FE), sluggish conversion rate and poor stability. Herein, we introduce an “atomic size misfit” strategy to modulate active sites, and report a facile synthesis of a Pb-doped Cu catalyst with numerous atomic Pb-concentrated grain boundaries. Operando spectroscopy studies demonstrate that these Pb-rich Cu-grain boundary sites exhibit stable low coordination and can achieve a stronger CO adsorption for a higher surface CO coverage. Using this Pb-Cu catalyst, we achieve a CO-to-n-propanol FE (FEpropanol) of 47 ± 3% and a half-cell energy conversion efficiency (EE) of 25% in a flow cell. When applied in a membrane electrode assembly (MEA) device, a stable FEpropanol above 30% and the corresponding full-cell EE of over 16% are maintained for over 100 h with the n-propanol partial current above 300 mA (5 cm2 electrode). Furthermore, operando X-ray absorption spectroscopy and theoretical studies reveal that the structurally-flexible Pb-Cu surface can adaptively stabilize the key intermediates, which strengthens the *CO binding while maintaining the C–C coupling ability, thus promoting the CO-to-n-propanol conversion.

Abstract Superconducting nanocircuits, which are usually fabricated from superconductor films, are the core of superconducting electronic devices. While emerging transition-metal dichalcogenide superconductors (TMDSCs) with exotic properties show promise for exploiting new superconducting mechanisms and applications, their environmental instability leads to a substantial challenge for the nondestructive preparation of TMDSC nanocircuits. Here, we report a universal strategy to fabricate TMDSC nanopatterns via a topotactic conversion method using prepatterned metals as precursors. Typically, robust NbSe2 meandering nanowires can be controllably manufactured on a wafer scale, by which a superconducting nanowire circuit is principally demonstrated toward potential single photon detection. Moreover, versatile superconducting nanocircuits, e.g., periodical circle/triangle hole arrays and spiral nanowires, can be prepared with selected TMD materials (NbS2, TiSe2, or MoTe2). This work provides a generic approach for fabricating nondestructive TMDSC nanocircuits with precise control, which paves the way for the application of TMDSCs in future electronics.

Protective hard coatings can significantly improve the bottleneck problem of low hardness and poor wear resistance on titanium alloy surface. However, hardness and adhesive strength usually exhibit an inverse relationship, which greatly limits its widespread use. In this work, TiC–Fe gradient coating with high hardness and adhesion was successfully fabricated by in-situ solid-phase diffusion method (ISDM) on pure titanium at 1000 °C for 2 h. The average thickness of the coating was approximately 5 μm, and the volume fraction of TiC in the coating was greater than 95 vol%. The grain size of TiC gradually increased from 200 nm at the coating surface to 2 μm towards the substrate. The phase interface and the coating/substrate interface exhibited excellent interfacial bonding at the atomic scale. The novel TiC–Fe gradient coating can simultaneously achieve superior hardness (42.9 ± 2.6 GPa) and elastic modulus (557.4 ± 10.3 GPa) that is mainly dominated by in situ synthesised high volume fraction TiC, as well as high adhesion strength (>225 ± 10 MPa). The increased adhesion strength was attributed to the excellent macro/micro interfaces and gradient transition of the microstructure. The use of ISDM to fabricate TiC–Fe gradient coating on titanium alloy may provide a new strategy to improve the comprehensive properties including hardness, elastic modulus, interfacial adhesion strength, and wear resistance for wider applications.

Clostridium perfringens alpha toxin (CPA), which causes yellow lamb disease in sheep and gas gangrene and food poisoning in humans, is produced by all types of C. perfringens and is the major virulence determinant of C. perfringens type A. CPA induces hemolysis in many species, including humans, murines, sheep and rabbits, through its enzymatic activity, which dissolves the cell membrane. Recent studies have shown that some pore-forming toxins cause hemolysis, which is achieved by the activation of purinergic receptors (P2). However, the relationship between P2 receptors and non-pore-forming toxin hemolysis has not been investigated. In the present study, we examined the function of P2 receptors in CPA toxin hemolysis and found that CPA-induced hemolysis was dependent on P2 receptor activation, and this was also true for Staphylococcus aureus β-Hemolysin, another non-pore-forming toxin. Furthermore, we use selective P2 receptor antagonists to demonstrate that P2X1 and P2X7 play important roles in the hemolysis of human and murine erythrocytes. In addition, we found that redox metabolism was mainly involved in CPA-induced hemolysis using metabolomic analysis. We further demonstrate that CPA activates P2 receptors and then activates NADPH oxidase through the PI3K/Akt and MEK1/ERK1 pathways, followed by the production of active oxygen to induce hemolysis. These findings contribute to our understanding of the pathological effects of CPA, clarify the relationship between P2 activation and non-pore-forming toxin-induced hemolysis, and provide new insights into CPA-induced hemolysis.

Food poisoning caused by Staphylococcal enterotoxins (SEs) is prevalent globally, making efficient detection of these toxins very important. Traditionally, liquid chromatography–mass spectrometry required immunosorbent enrichment by magnetic bead-coupled antibodies obtained by animal-specific immunization. However, this method is time-consuming and costly. In this study, two recombinant protein capture molecules were designed based on the principle of toxins binding to Major Histocompatibility Complex (MHCII) and T cell receptor (TCR) molecules. The two capture molecules are called MHCII and MHCII-D10. The design of the MHCII and TCR-D10 was achieved through searching for the binding site protein sequence of Staphylococcal enterotoxins in the relevant literature, and MHCII-D10 was to link MHCII sequence with TCR-D10 sequence using linker (G4S)3 linking peptide. These capture molecules were shown to effectively bind to seven types of toxins and to capture SEs in various matrices. The digestion time, ratio, and temperature were further optimized, reducing the overall digestion time to just 2 h. The specificity, linearity, sensitivity, precision (RSD%), and recovery of the two methods were verified by liquid chromatography–mass spectrometry. When the MHCII and MHCII-D10 captured the toxins, the limit of quantification (LOD) in the 1 × PBS, plasma, and milk matrices ranged from 1.5625 to 100 fmol/µL, with the recovery rate ranging from 18.4% to 96%. The design of these capture molecules eliminates the need for animal-specific immunization, simplifying the pre-detection process and avoiding ethical concerns. This development holds significant promise for clinical diagnosis and reference.

Abstract Background The pathogenesis of schizophrenia is still unknown. Nearly a half of schizophrenic patients have depressive symptoms and even some impulsive behaviors. The definite diagnosis of schizophrenia is an immense challenge. Molecular biology plays an essential role in the research on the pathogenesis of schizophrenia. Objective This study aims to analyze the correlations of serum protein factor levels with depressive emotion and impulsive behaviors in drug-naïve patients with first-episode schizophrenia. Methods Seventy drug-naïve patients with first-episode schizophrenia and sixty-nine healthy volunteers from the health check center in the same period participated in this study. In both the patient group and control group, brain-derived neurotrophic factor (BDNF), phosphatidylin-ositol-3-kinase (PI3K), protein kinase B (AKT), and cAMP-response element binding protein (CREB) levels in the peripheral blood were tested by enzyme-linked immunosorbent assay (ELISA). The depressive emotion and impulsive behaviors were evaluated with Chinese versions of the Calgary Depression Scale for Schizophrenia (CDSS) and Short UPPS-P Impulsive Behavior Scale (S-UPPS-P), respectively. Results The serum levels of BDNF, PI3K, and CREB in the patient group were lower than those in the control group, while AKT level, total CDSS score and total S-UPPS-P score were all higher. In the patient group, total CDSS score, and total S-UPPS-P score were both correlated negatively with BDNF, PI3K, and CREB levels but positively with AKT level, and the lack-of-premeditation (PR) sub-scale score was not significantly correlated with BDNF, PI3K, AKT, and CREB levels. Conclusion Our study results showed that the peripheral blood levels of BDNF, PI3K, AKT, and CREB in drug-naïve patients with first-episode schizophrenia were significantly different from those in the control group. The levels of these serum protein factors are promising biomarkers to predict schizophrenic depression and impulsive behaviors.

Abstract Clostridium perfringens ε-toxin (ETX) is the main toxin leading to enterotoxemia of sheep and goats and is classified as a potential biological weapon. In addition, no effective treatment drug is currently available in clinical practice for this toxin. We developed membrane-camouflaged nanoparticles (MNPs) with different membrane origins to neutralize ETX and protect the host from fatal ETX intoxication. We evaluated the safety and therapeutic efficacy of these MNPs in vitro and in vivo. Compared with membranes from karyocytes, such as Madin-Darby canine kidney (MDCK) cells and mouse neuroblastoma N2a cells (N2a cells), membrane from erythrocytes, which do not induce any immune response, are superior in safety. The protective ability of MNPs was evaluated by intravenous injection and lung delivery. We demonstrate that nebulized inhalation is as safe as intravenous injection and that both modalities can effectively protect mice against ETX. In particular, pulmonary delivery of nanoparticles more effectively treated the challenge of inhaled toxins than intravenously injected nanoparticles. Moreover, MNPs can alter the biological distribution of ETX among different organs in the body, and ETX was captured, neutralized and slowly delivered to the liver and spleen, where nanoparticles with ETX could be phagocytized and metabolized. This demonstrates how MNPs treat toxin infections in vivo. Finally, we injected the MNPs into mice in advance to find out whether MNPs can provide preventive protection, and the results showed that the long-cycle MNPs could provide at least a 3-day protection in mice. These findings demonstrate that MNPs provide safe and effective protection against ETX intoxication, provide new insights into membrane choices and delivery routes of nanoparticles, and new evidence of the ability of nanoparticles to provide preventive protection against infections. Graphical Abstract

Summary: Transforming growth factor β1 (TGFβ1) has been identified as a major pathogenic factor underlying the development of chronic kidney disease (CKD). This study investigated the role of miR-92b-3p in the progression of renal fibrosis in unilateral ureteral occlusion (UUO) and unilateral ischemia-reperfusion injury (uIRI) mouse models, as well as explored its underlying mechanisms in human proximal tubular epithelial (HK2) cells. We found that renal fibrosis increased in UUO mice after miR-92b knockout, while it reduced in miR-92b overexpressing mice. MiR-92b knockout aggravated renal fibrosis in uIRI mice. RNA-sequencing analysis, the luciferase reporter assay, qPCR analysis, and western blotting confirmed that miR-92b-3p directly targeted TGF-β receptor 1, thereby ameliorating renal fibrosis by suppressing the TGF-β signaling pathway. Furthermore, we found that TGF-β suppressed miR-92b transcription through Snail family transcriptional repressors 1 and 2. Our results suggest that miR-92b-3p may serve as a novel therapeutic for mitigating fibrosis in CKD.

BackgroundSarcopenia has been linked to adverse health outcomes, including an increased risk of mortality. This study aimed to assess the 7-year mortality risk of sarcopenia in a community-based population in China and explore the causal relationship between components of sarcopenia and any death.MethodsData were sourced from the China Health and Retirement Longitudinal Study (CHARLS) conducted between 2011 and 2018. Sarcopenia was diagnosed using the Asian Working Group for Sarcopenia (AWGS) 2019 criteria. Logistic regression, Kaplan–Meier (KM) survival analysis, and propensity score matching with inverse probability of treatment weighting were used. Mendelian randomization (MR) analyses, conducted using European population data, were utilized to assess causality between sarcopenia and any death.ResultsThe study included 9,006 participants: 3,892 had no sarcopenia, 3,570 had possible sarcopenia, 1,125 had sarcopenia, and 419 had severe sarcopenia. Over 7 years of follow-up, there were 871 deaths, including 196 with sarcopenia and 133 with severe sarcopenia. The KM curves showed that sarcopenia had a higher risk of mortality. Compared to those of no sarcopenia, the odds ratios (ORs) of sarcopenia for 7-year mortality were 1.41 (95% CI, 1.06–1.87) after adjusting for confounding variables (p < 0.05). The ORs of severe sarcopenia were 2.11 (95% CI, 1.51–2.95). Propensity score matching analysis and inverse probability of treatment weighting analysis confirmed these findings. The adjusted ORs of sarcopenia and 7-year mortality were 2.94 (95% CI, 1.6–5.39) in the 45–60 age group, 1.72 (95% CI, 1.11–2.68) in the 60–80 age group, and 5.03 (95% CI, 0.48–52.65) in the ≥80 age group. The ORs of severe sarcopenia and 7-year mortality were 6.92 (95% CI, 1.95–24.5) in the 45–60 age group, 2.59 (95% CI, 1.61–4.17) in the 60–80 age group, and 12.52 (95% CI, 1.18–133.18) in the ≥80 age group. The MR analyses, leveraging the inverse variance weighted (IVW) method, unveiled substantial causal links between low hand grip strength in individuals aged 60 and older, the usual walking pace, and mortality risk.ConclusionThis study underscores the significant impact of sarcopenia and its components on mortality risk within the Chinese population. Particularly, low hand grip strength and usual walking pace emerged as noteworthy contributors to mortality risk.

ObjectiveTo investigate the association between handgrip strength (HGS) with all-cause and cardiovascular disease (CVD) mortality in US adults.MethodWe analyzed data from the National Health and Nutrition Examination Survey (NHANES) prospective cohort study (2011–2014) with 10,470 participants. The cox regression analysis, Kaplan–Meier survival curves, fitted curves, ROC curves, and propensity score-matched analysis (PSM) with inverse probability of treatment weighting (IPTW), SMRW (PSM with repeated weights), PA (pairwise algorithm), and OW (overlap weighting) regression analysis were performed to assess the relationship between HGS and all-cause and CVD mortality.ResultsThe low HGSs (men

Abstract Fiber components form the standard not only in modern telecommunication but also for future quantum information technology. For high-performance single-photon detection, superconducting nanowire single-photon detectors (SPDs) are typically fabricated on a silicon chip and fiber-coupled for easy handling and usage. The fiber-to-chip interface hinders the SPD from being an all-fiber device for full utilization of its excellent performance. Here, we report a scheme of SPD that is directly fabricated on the fiber tip. A bury-and-planar fabrication technique is developed to improve the roughness of the substrate for all-fiber detectors’ performance for single-photon detection with amorphous molybdenum silicide (MoSi) nanowires. The low material selectivity and universal planar process enable fabrication and packaging on a large scale. Such a detector responds to a broad wavelength range from 405 nm to 1550 nm at a dark count rate of 100 cps. The relaxation time of the response pulse is ~ 15 ns, which is comparable to that of on-chip SPDs. Therefore, this device is free from fiber-to-chip coupling and easy packaging for all-fiber quantum information systems.

Vibrio vulnificus, a foodborne pathogen, has a high mortality rate. Despite its relevance to public health, the identification of virulence genes associated with the pathogenicity of currently known clinical isolates of V. vulnificus is incomplete and its synergistic pathogenesis remains unclear. Here, we integrate whole genome sequencing (WGS), genome-wide association studies (GWAS), and genome-wide epistasis studies (GWES), along with phenotype characterization to investigate the pathogenesis and survival strategies of V. vulnificus. GWAS and GWES identified a total of six genes (purH, gmr, yiaV, dsbD, ramA, and wbpA) associated with the pathogenicity of clinical isolates related to nucleotide/amino acid transport and metabolism, cell membrane biogenesis, signal transduction mechanisms, and protein turnover. Of these, five were newly discovered potential specific virulence genes of V. vulnificus in this study. Furthermore, GWES combined with phenotype experiments indicated that V. vulnificus isolates were clustered into two ecological groups (EGs) that shared distinct biotic and abiotic factors, and ecological strategies. Our study reveals pathogenic mechanisms and their evolution in V. vulnificus to provide a solid foundation for designing new vaccines and therapeutic targets.

Background and PurposeNonproliferative diabetic retinopathy (NPDR) occurs in the early stages of Diabetic retinopathy (DR), and the study of its metabolic markers will help to prevent DR. Hence, we aimed to establish a risk score based on multiple metabolites through untargeted metabolomic analysis of venous blood from NPDR patients and diabetic non-DR patients.Experimental ApproachUntargeted metabolomics of venous blood samples from patients with NPDR, diabetes melitus without DR were performed using high-performance liquid chromatography-mass spectrometry.ResultsDetailed metabolomic evaluation showed distinct clusters of metabolites in plasma samples from patients with NPDR and diabetic non-DR patients. NPDR patients had significantly higher levels of phenylacetylglycine, L-aspartic acid, tiglylglycine, and 3-sulfinato-L-alaninate, and lower level of indolelactic acid, threonic acid, L-arginine (Arg), and 4-dodecylbenzenesulfonic acid compared to control. The expression profiles of these eight NPDR risk-related characteristic metabolites were analyzed using Cox regression to establish a risk score model. Subsequently, univariate and multivariate Cox regression analyses were used to determine that this risk score model was a predictor of independent prognosis for NPDR.ConclusionsUntargeted metabolome analysis of blood metabolites revealed unreported metabolic alterations in NPDR patients compared with those in diabetic non-DR patients or MH. In the venous blood, we identified depleted metabolites thA and Arg, indicating that they might play a role in NPDR development.

With the ability to produce components with complex and precise structures, additive manufacturing or 3D printing techniques are now widely applied in both industry and consumer markets. The emergence of tissue engineering has facilitated the application of 3D printing in the field of biomedical implants. 3D printed implants with proper structural design can not only eliminate the stress shielding effect but also improve in vivo biocompatibility and functionality. By combining medical images derived from technologies such as X-ray scanning, CT, MRI, or ultrasonic scanning, 3D printing can be used to create patient-specific implants with almost the same anatomical structures as the injured tissues. Numerous clinical trials have already been conducted with customized implants. However, the limited availability of raw materials for printing and a lack of guidance from related regulations or laws may impede the development of 3D printing in medical implants. This review provides information on the current state of 3D printing techniques in orthopedic implant applications. The current challenges and future perspectives are also included.

Extracellular vesicles (EVs)-based cell-free therapy, particularly stem cell-derived extracellular vesicles (SC-EVs), offers new insights into treating a series of neurological disorders and becomes a promising candidate for alternative stem cell regenerative therapy. Currently, SC-EVs are considered direct therapeutic agents by themselves and/or dynamic delivery systems as they have a similar regenerative capacity of stem cells to promote neurogenesis and can easily load many functional small molecules to recipient cells in the central nervous system. Meanwhile, as non-living entities, SC-EVs avoid the uncontrollability and manufacturability limitations of live stem cell products in vivo (e.g., low survival rate, immune response, and tumorigenicity) and in vitro (e.g., restricted sources, complex preparation processes, poor quality control, low storage, shipping instability, and ethical controversy) by strict quality control system. Moreover, SC-EVs can be engineered or designed to enhance further overall yield, increase bioactivity, improve targeting, and extend their half-life. Here, this review provides an overview on the biological properties of SC-EVs, and the current progress in the strategies of native or bioengineered SC-EVs for nerve injury repairing is presented. Then we further summarize the challenges of recent research and perspectives for successful clinical application to advance SC-EVs from bench to bedside in neurological diseases.

Abstract Background Esophageal cancer (EC), one highly malignant gastrointestinal cancer, is the 6th leading cause of cancer-related deaths worldwide. Necroptosis and long non-coding RNA (lncRNA) play important roles in the occurrence and development of EC, but the research on the role of necroptosis-related lncRNA in EC is not conclusive. This study aims to use bioinformatics to investigate the prognostic value of necroptosis-related lncRNA in EC. Methods Transcriptome data containing EC and normal samples, and clinical information were obtained from the Cancer Genome Atlas database. 102 necroptosis-related genes were obtained from Kanehisa Laboratories. Necroptosis-related lncRNAs were screened out via univariate, multivariate Cox and the least absolute shrinkage and selection operator regression analyses to construct the risk predictive model. The reliability of the risk model was evaluated mainly through quantitative real-time PCR (qRT-PCR), the receiver operating characteristic (ROC) curves and the constructed nomogram. KEGG pathways were explored in the high- and low-risk groups of EC patients via gene set enrichment analyses (GSEA) software. Immune microenvironment and potential therapeutic agents in risk groups were also analyzed. Results A 6 necroptosis-related lncRNAs risk model composed of AC022211.2, Z94721.1, AC007991.2, SAMD12-AS1, AL035461.2 and AC051619.4 was established to predict the prognosis level of EC patients. qRT-PCR analysis showed upregulated Z94721.1 and AL035461.2 mRNA levels and downregulated AC051619.4 mRNA level in EC tissues compared with normal tissues. According to clinical characteristics, the patients in the high-risk group had a shorter overall survival than the low-risk group. The ROC curve and nomogram confirmed this model as one independent and predominant predictor. GSEA analysis showed metabolic and immune-related pathways enriched in the risk model. Most of the immune cells and immune checkpoints were positively correlated with the risk model, mainly active in the high-risk group. For the prediction of potential therapeutic drugs, 16 compounds in the high-risk group and 2 compounds in the low-risk group exhibited higher sensitivity. Conclusions Our results supported the necroptosis-related lncRNA signature could independently predict prognosis of EC patients, and provided theoretical basis for improving the clinical treatment of EC.

Abstract A simple method for preparing superconducting NbN thin films on flexible dielectric substrates with controllable thickness was developed. The structure and surface characteristics and superconducting properties of the flexible film were studied by X-ray diffraction (XRD), atomic force microscopy (AFM) and physical property measurement system (PPMS). We found that NbN films on the flexible substrate show certain preferred orientations through the self-buffering effect of the amorphous NbN layer. The zero resistance superconducting transition temperature (TC0) for 10 nm thick NbN films is 8.3 K, and the TC0 for 30 nm thick NbN films in a magnetic field of 9 T remains above 7 K. This flexible film can be transferred to any substrate and adapted to different shape applications. It can also be further processed into single-layer or multilayer flexible superconducting devices.

Countries must have strong early warning, detection, and response capabilities in the face of the risks and challenges posed by major infectious diseases and bioterrorism threats. Vaccination is one of the most effective means for countries to maintain biosecurity and respond to bioterrorism attacks. Microneedles are emerging as a potential vaccine delivery method with minimal pain, no bleeding, and the ability to be self-administered, doing away with the need for professional health care workers. This last advantage, particularly if combined with room temperature preservation, could have an important role in improving national biosecurity through large-scale, rapid deployment of a biological vaccine. In this review, we summarized the research status of microneedles, including the types, materials, and production technologies of microneedles. Recent progress regarding microneedles in the field of biosecurity is introduced and challenges in its future application are discussed.

Summary: Transforming growth factor β (TGF-β) is the primary factor that drives fibrosis in most forms of chronic kidney disease. The aim of this study was to identify endogenous regulators of TGF-β signaling and fibrosis. Here, we show that tubulointerstitial fibrosis is aggravated by global deletion of KLF13 and attenuated by adeno-associated virus-mediated KLF13 overexpression in renal tubular epithelial cells. KLF13 recruits a repressor complex comprising SIN3A and histone deacetylase 1 (HDAC1) to the TGF-β target genes, limiting the profibrotic effects of TGF-β. Temporary upregulation of TGF-β induces KLF13 expression, creating a negative feedback loop that triggers the anti-fibrotic effect of KLF13. However, persistent activation of TGF-β signaling reduces KLF13 levels through FBXW7-mediated ubiquitination degradation and HDAC-dependent mechanisms to inhibit KLF13 transcription and offset the anti-fibrotic effect of KLF13. Collectively, our data demonstrate a role of KLF13 in regulating TGF-β signaling and fibrosis.

Abstract Adult skeletal muscle stem cells, also known satellite cells (SCs), are a highly heterogeneous population and reside between the basal lamina and the muscle fiber sarcolemma. Myofibers function as an immediate niche to support SC self-renewal and activation during muscle growth and regeneration. Herein, we demonstrate that microRNA 378 (miR-378) regulates glycolytic metabolism in skeletal muscle fibers, as evidenced by analysis of myofiber-specific miR-378 transgenic mice (TG). Subsequently, we evaluate SC function and muscle regeneration using miR-378 TG mice. We demonstrate that miR-378 TG mice significantly attenuate muscle regeneration because of the delayed activation and differentiation of SCs. Furthermore, we show that the miR-378-mediated metabolic switch enriches Pax7Hi SCs, accounting for impaired muscle regeneration in miR-378 TG mice. Mechanistically, our data suggest that miR-378 targets the Akt1/FoxO1 pathway, which contributes the enrichment of Pax7Hi SCs in miR-378 TG mice. Together, our findings indicate that miR-378 is a target that links fiber metabolism to muscle stem cell heterogeneity and provide a genetic model to approve the metabolic niche role of myofibers in regulating muscle stem cell behavior and function.

Vibrio parahaemolyticus is a common foodborne pathogen in seafood, which often causes seafood borne bacterial gastroenteritis or food poisoning. Thermostable direct hemolysin (TDH) is considered to be one of the main virulence factors involved in this pathogen. The most clinical V. parahaemolyticus isolates produce TDH. Therefore, high sensitivity and specificity detection of TDH are of great significance for food safety and early diagnosis of diseases caused by V. parahaemolyticus. In this study, we developed a rapid, sensitive immunochromatographic test paper assay for the quantitative detection of TDH in seafood samples using time-resolved fluorescence techniques. First, we completed the preparation of fluorescent detection antibodies by coupling lanthanide fluorescent nanospheres with homemade high-affinity polyclonal antibodies based on the principle of the double-antibody sandwich. The lanthanide fluorescent nanospheres used in this study are characterized by a large stokes shift and a long fluorescence lifetime, which effectively reduces background noise and improves detection sensitivity. In addition, the method can be completed within 15 min for the detection of TDH, has a detection limit below 50 ng/mL and good linearity in the range of 50–5000 ng/mL. Moreover, it has good specificity and no cross-reactivity with Vibrio vulnificus hemolysin (VVH), Clostridium perfringens α toxin (CPA) or C. perfringens ε toxin (ETX). Finally, the sensitivity of this method was unchanged when the three simulated samples of Patinopecten yessoensis, Ruditapes philippinarum, and Scapharca broughtonii tested, indicating that the method is not affected by samples in a complex matrix. In conclusion, this study establishes a practical new method for on-site rapid detection of TDH, which is easy to operate, fast response, easy to carry and can be implemented under the field conditions without expensive equipment and professional person.

Psoriasis is a chronic autoimmune inflammatory skin disorder characterized by epidermal hyperplasia and aberrant immune response. In addition to aberrant cytokine production, psoriasis is associated with activation of the Akt/mTOR pathway. mTOR/S6K1 regulates T-lymphocyte activation and migration, keratinocytes proliferation and is upregulated in psoriatic lesions. Several drugs that target Th1/Th17 cytokines or their receptors have been approved for treating psoriasis in humans with variable results necessitating improved therapies. Fisetin, a natural dietary polyphenol with anti-oxidant and anti-proliferative properties, covalently binds mTOR/S6K1. The effects of fisetin on psoriasis and its underlying mechanisms have not been clearly defined. Here, we evaluated the immunomodulatory effects of fisetin on Th1/Th17-cytokine-activated adult human epidermal keratinocytes (HEKa) and anti-CD3/CD28-stimulated inflammatory CD4+ T cells and compared these activities with those of rapamycin (an mTOR inhibitor). Transcriptomic analysis of HEKa revealed 12,713 differentially expressed genes (DEGs) in the fisetin-treated group compared to 7,374 DEGs in the rapamycin-treated group, both individually compared to a cytokine treated group. Gene ontology analysis revealed enriched functional groups related to PI3K/Akt/mTOR signaling pathways, psoriasis, and epidermal development. Using in silico molecular modeling, we observed a high binding affinity of fisetin to IL-17A. In vitro, fisetin significantly inhibited mTOR activity, increased the expression of autophagy markers LC3A/B and Atg5 in HEKa cells and suppressed the secretion of IL-17A by activated CD4+ T lymphocytes or T lymphocytes co-cultured with HEKa. Topical administration of fisetin in an imiquimod (IMQ)-induced mouse psoriasis model exhibited a better effect than rapamycin in reducing psoriasis-like inflammation and Akt/mTOR phosphorylation and promoting keratinocyte differentiation and autophagy in mice skin lesions. Fisetin also significantly inhibited T-lymphocytes and F4/80+ macrophage infiltration into skin. We conclude that fisetin potently inhibits IL-17A and the Akt/mTOR pathway and promotes keratinocyte differentiation and autophagy to alleviate IMQ-induced psoriasis-like disease in mice. Altogether, our findings suggest fisetin as a potential treatment for psoriasis and possibly other inflammatory skin diseases.

Epsilon toxin (ETX) is an exotoxin produced by type B and D Clostridium perfringens that causes enterotoxemia or necrotic enteritis in animals such as goats, sheep, and cattle. Vaccination is a key method in preventing such diseases. In this study, we developed a new type of dissolving microneedle patch (dMN) with a nanoparticle adjuvant for enhanced immune response to deliver the rETXY196E-C protein vaccine. We chose FDA-approved poly(lactic-co-glycolic acid) (PLGA) to prepare nanospheres as the vaccine adjuvant and introduced dimethyldioctadecylammonium bromide (DDAB) to make the surface of PLGA nanoparticles (PLGA NPs) positively charged for antigen adsorption. PLGA NPs with a diameter of 100~200 nm, a surface ZETA potential of approximately +40 mV, and good safety were successfully prepared and could effectively adsorb rETXY196E-C protein. Using non-toxic and antibacterial fish gelatin as the microneedle (MN) matrix, we prepared a PLGA-DDAB dMN vaccine with good mechanical properties that successfully penetrated the skin. After immunization of subcutaneous (SC) and dMN, antibody titers of the PLGA and Al adjuvant groups were similar in both two immune ways. However, in vivo neutralization experiments showed that the dMN vaccines had a better protective effect. When challenged with 100 × LD50 GST-ETX, the survival rate of the MN group was 100%, while that of the SC Al group was 80%. However, a 100% protective effect was achieved in both immunization methods using PLGA NPs. In vitro neutralization experiments showed that the serum antibodies from the dMN and SC PLGA NPs groups both protect naive mice from 10 × LD50 GST-ETX attack after being diluted 20 times and could also protect MDCK cells from 20 × CT50 GST-ETX attack. In conclusion, the PLGA-DDAB dMN vaccine we prepared has good mechanical properties, immunogenicity, and protection, and can effectively prevent ETX poisoning. This provides a better way of delivering protein vaccines.

Influenza A virus (IAV) infections are associated with a high healthcare burden around the world and there is an urgent need to develop more effective therapies. Natural killer (NK) cells have been shown to play a pivotal role in reducing IAV-induced pulmonary infections in preclinical models; however, little is known about the therapeutic potential of adoptively transferred NK cells for IAV infections. Here, we investigated the effects of CYNK-001, human placental hematopoietic stem cell derived NK cells that exhibited strong cytolytic activity against a range of malignant cells and expressed high levels of activating receptors, against IAV infections. In a severe IAV-induced acute lung injury model, mice treated with CYNK-001 showed a milder body weight loss and clinical symptoms, which led to a delayed onset of mortality, thus demonstrating their antiviral protection in vivo. Analysis of bronchoalveolar lavage fluid (BALF) revealed that CYNK-001 reduced proinflammatory cytokines and chemokines highlighting CYNK-001’s anti-inflammatory actions in viral induced-lung injury. Furthermore, CYNK-001-treated mice had altered immune responses to IAV with reduced number of neutrophils in BALF yet increased number of CD8+ T cells in the BALF and lung compared to vehicle-treated mice. Our results demonstrate that CYNK-001 displays protective functions against IAV via its anti-inflammatory and immunomodulating activities, which leads to alleviation of disease burden and progression in a severe IAV-infected mice model. The potential of adoptive NK therapy for IAV infections warrants clinical investigation.

Esophageal cancer (EC) is recognized as one of the most common malignant tumors in the word. Based on the biological process of EC occurrence and development, exploring molecular biomarkers can provide a good guidance for predicting the risk, prognosis and treatment response of EC. Proteomics has been widely used as a technology that identifies, analyzes and quantitatively acquires the composition of all proteins in the target tissues. Proteomics characterization applied to construct a prognostic signature will help to explore effective biomarkers and discover new therapeutic targets for EC. This study showed that we established a 8 proteins risk model composed of ASNS, b-Catenin_pT41_S45, ARAF_pS299, SFRP1, Vinculin, MERIT40, BAK and Atg4B via multivariate Cox regression analysis of the proteome data in the Cancer Genome Atlas (TCGA) to predict the prognosis power of EC patients. The risk model had the best discrimination ability and could distinguish patients in the high- and low-risk groups by principal component analysis (PCA) analysis, and the high-risk patients had a poor survival status compared with the low-risk patients. It was confirmed as one independent and superior prognostic predictor by the receiver operating characteristic (ROC) curve and nomogram. K-M survival analysis was performed to investigate the relationship between the 8 proteins expressions and the overall survival. GSEA analysis showed KEGG and GO pathways enriched in the risk model, such as metabolic and cancer-related pathways. The high-risk group presented upregulation of dendritic cells resting, macrophages M2 and NK cells activated, downregulation of plasma cells, and multiple activated immune checkpoints. Most of the potential therapeutic drugs were more appropriate treatment for the low-risk patients. Through adequate analysis and verification, this 8 proteins risk model could act as a great prognostic evaluation for EC patients and provide new insight into the diagnosis and treatment of EC.

Aims: Osteoarthritis (OA) is prevalent among the elderly and incurable. Intra-articular parathyroid hormone (PTH) ameliorated OA in papain-induced and anterior cruciate ligament transection-induced OA models; therefore, we hypothesized that PTH improved OA in a preclinical age-related OA model. Methods: Guinea pigs aged between six and seven months of age were randomized into control or treatment groups. Three- or four-month-old guinea pigs served as the young control group. The knees were administered 40 μl intra-articular injections of 10 nM PTH or vehicle once a week for three months. Their endurance as determined from time on the treadmill was evaluated before kill. Their tibial plateaus were analyzed using microcalculated tomography (μCT) and histological studies. Results: PTH increased the endurance on the treadmill test, preserved glycosaminoglycans, and reduced Osteoarthritis Research Society International score and chondrocyte apoptosis rate. No difference was observed in the subchondral plate bone density or metaphyseal trabecular bone volume and bone morphogenetic 2 protein staining. Conclusion: Subchondral bone is crucial in the initiation and progression of OA. Although previous studies have shown that subcutaneous PTH alleviates knee OA by improving subchondral and metaphyseal bone mass, we demonstrated that intra-articular PTH injections improved spontaneous OA by directly affecting the cartilage rather than the subchondral or metaphyseal bone in a preclinical age-related OA model.

Abstract Background The therapeutic potential of exosomes derived from stem cells has attracted increasing interest recently, because they can exert similar paracrine functions of stem cells and overcome the limitations of stem cells transplantation. Exosomes derived from bone mesenchymal stem cells (BMSC-Exos) have been confirmed to promote osteogenesis and angiogenesis. The magnetic nanoparticles (eg. Fe3O4, γ-Fe2O3) combined with a static magnetic field (SMF) has been commonly used to increase wound healing and bone regeneration. Hence, this study aims to evaluate whether exosomes derived from BMSCs preconditioned with a low dose of Fe3O4 nanoparticles with or without the SMF, exert superior pro-osteogenic and pro-angiogenic activities in bone regeneration and the underlying mechanisms involved. Methods Two novel types of exosomes derived from preconditioned BMSCs that fabricated by regulating the contents with the stimulation of magnetic nanoparticles and/or a SMF. Then, the new exosomes were isolated by ultracentrifugation and characterized. Afterwards, we conducted in vitro experiments in which we measured osteogenic differentiation, cell proliferation, cell migration, and tube formation, then established an in vivo critical-sized calvarial defect rat model. The miRNA expression profiles were compared among the exosomes to detect the potential mechanism of improving osteogenesis and angiogenesis. At last, the function of exosomal miRNA during bone regeneration was confirmed by utilizing a series of gain- and loss-of-function experiments in vitro. Results 50 µg/mL Fe3O4 nanoparticles and a 100 mT SMF were chosen as the optimum magnetic conditions to fabricate two new exosomes, named BMSC-Fe3O4-Exos and BMSC-Fe3O4-SMF-Exos. They were both confirmed to enhance osteogenesis and angiogenesis in vitro and in vivo compared with BMSC-Exos, and BMSC-Fe3O4-SMF-Exos had the most marked effect. The promotion effect was found to be related to the highly riched miR-1260a in BMSC-Fe3O4-SMF-Exos. Furthermore, miR-1260a was verified to enhance osteogenesis and angiogenesis through inhibition of HDAC7 and COL4A2, respectively. Conclusion These results suggest that low doses of Fe3O4 nanoparticles combined with a SMF trigger exosomes to exert enhanced osteogenesis and angiogenesis and that targeting of HDAC7 and COL4A2 by exosomal miR-1260a plays a crucial role in this process. This work could provide a new protocol to promote bone regeneration for tissue engineering in the future. Graphical abstract

Francisella tularensis is a dangerous pathogen that causes an extremely contagious zoonosis in humans named tularemia. Given its low-dose morbidity, the potential to be fatal, and aerosol spread, it is regarded as a severe threat to public health. The US Centers for Disease Control and Prevention (CDC) has classified it as a category A potential agent for bioterrorism and a Tier 1 Select Agent. Herein, we combined recombinase polymerase amplification (RPA) with CRISPR/Cas12a system to select the F. tularensis target gene (TUL4), creating a two-pronged rapid and ultrasensitive diagnostic method for detecting F. tularensis. The real-time RPA (RT-RPA) assay detected F. tularensis within 10 min at a sensitivity of 5 copies/reaction, F. tularensis genomic DNA of 5 fg, and F. tularensis of 2 × 102 CFU/ml; the RPA-CRISPR/Cas12a assay detects F. tularensis within 40 min at a sensitivity of 0.5 copies/reaction, F. tularensis genomic DNA of 1 fg, and F. tularensis of 2 CFU/ml. Furthermore, the evaluation of specificity showed that both assays were highly specific to F. tularensis. More importantly, in a test of prepared simulated blood and sewage samples, the RT-RPA assay results were consistent with RT-PCR assay results, and the RPA-CRISPR/Cas12a assay could detect a minute amount of F. tularensis genomic DNA (2.5 fg). There was no nonspecific detection with blood samples and sewage samples, giving the tests a high practical application value. For example, in on-site and epidemic areas, the RT-RPA was used for rapid screening and the RPA-CRISPR/Cas12a assay was used for more accurate diagnosis.