Clinical presentation, antimicrobial resistance, and treatment outcomes of Aeromonas human infections: A 14-year retrospective study and comparative genomics of two isolates from fatal cases.

BACKGROUND: Aeromonas virulence may not be entirely dependent on the host immune status. Pathophysiologic determinants of disease progression and severity remain unclear. METHODS: One hundred five patients with Aeromonas infections and 112 isolates were identified, their clinical presentations and outcomes analyzed, and their antimicrobial resistance (AMR) patterns assessed. Two isolates (A and B) from fatal cases of Aeromonas dhakensis bacteremia were characterized using whole genome sequence analysis. Virulence factor- and AMR-encoding genes from these isolates were compared with a well-characterized diarrheal isolate A. dhakensis SSU, and environmental isolate A. hydrophila ATCC_7966T. RESULTS: Skin and soft tissue infections, traumatic wound infections, sepsis, burns, and intraabdominal infections were common. Diabetes, malignancy, and cirrhosis were frequent comorbidities. Male sex, age ≥ 65 years, hospitalization, burns, and intensive care were associated with complicated disease. High rates of AMR to carbapenems and piperacillin-tazobactam were found. Treatment failure was observed in 25.7% of cases. Septic shock and hospital-acquired infections were predictors of treatment failure. All four isolates harbored assorted broad-spectrum AMR genes including blaOXA, ampC, cphA, and efflux pumps. Only clinical isolates possessed both polar and lateral flagellar genes, genes for various surface adhesion proteins, type 3- and -6 secretion systems and their effectors, and toxin genes, including exotoxin A. Both isolates A and B were resistant to colistin and harbored the mobile colistin resistance-3 (mcr-3) gene. CONCLUSIONS: Empirical therapy tailored to local Aeromonas antibiograms may facilitate more favorable outcomes, while advanced diagnostic methods may aid in identifying correct Aeromonas spp. of significant clinical importance.

Antimicrobial resistance in aeromonads and new therapies targeting quorum sensing.

Aeromonas species (spp.) are well-known fish pathogens, several of which have been recognized as emerging human pathogens. The organism is capable of causing a wide spectrum of diseases in humans, ranging from gastroenteritis, wound infections, and septicemia to devastating necrotizing fasciitis. The systemic form of infection is often fatal, particularly in patients with underlying chronic diseases. Indeed, recent trends demonstrate rising numbers of hospital-acquired Aeromonas infections, especially in immuno-compromised individuals. Additionally, Aeromonas-associated antibiotic resistance is an increasing challenge in combating both fish and human infections. The acquisition of antibiotic resistance is related to Aeromonas' innate transformative properties including its ability to share plasmids and integron-related gene cassettes between species and with the environment. As a result, alternatives to antibiotic treatments are desperately needed. In that vein, many treatments have been proposed and studied extensively in the fish-farming industry, including treatments that target Aeromonas quorum sensing. In this review, we discuss current strategies targeting quorum sensing inhibition and propose that such studies empower the development of novel chemotherapeutic approaches to combat drug-resistant Aeromonas spp. infections in humans. KEY POINTS: • Aeromonas notoriously acquires and maintains antimicrobial resistance, making treatment options limited. • Quorum sensing is an essential virulence mechanism in Aeromonas infections. • Inhibiting quorum sensing can be an effective strategy in combating Aeromonas infections in animals and humans.

A Bacteriophage Cocktail Targeting Yersinia pestis Provides Strong Post-Exposure Protection in a Rat Pneumonic Plague Model.

Yersinia pestis , one of the deadliest bacterial pathogens ever known, is responsible for three plague pandemics and several epidemics, with over 200 million deaths during recorded history. Due to high genomic plasticity, Y. pestis is amenable to genetic mutations as well as genetic engineering that can lead to the emergence or intentional development of pan-drug resistant strains. The dissemination of such Y. pestis strains could be catastrophic, with public health consequences far more daunting than those caused by the recent COVID-19 pandemic. Thus, there is an urgent need to develop novel, safe, and effective treatment approaches for managing Y. pestis infections. This includes infections by antigenically distinct strains for which vaccines, none FDA approved yet, may not be effective, and those that cannot be controlled by approved antibiotics. Lytic bacteriophages provide one such alternative approach. In this study, we examined post-exposure efficacy of a bacteriophage cocktail, YPP-401, to combat pneumonic plague caused by Y. pestis CO92. YPP-401 is a four-phage preparation with a 100% lytic activity against a panel of 68 genetically diverse Y. pestis strains. Using a pneumonic plague aerosol challenge model in gender-balanced Brown Norway rats, YPP-401 demonstrated ∼88% protection when delivered 18 hours post-exposure for each of two administration routes (i.e., intraperitoneal and intranasal) in a dose-dependent manner. Our studies suggest that YPP-401 could provide an innovative, safe, and effective approach for managing Y. pestis infections, including those caused by naturally occurring or intentionally developed strains that cannot be managed by vaccines in development and antibiotics.

A two-step downscaling method for high-scale super-resolution of daily temperature - a case study of Wei River Basin, China.

Climate data with high spatial and temporal resolution were of great significance for regional environmental management, such as for early response to possible predicted local climate changes and extreme weather. However, the current downscaling targets for CMIP6 climate simulations were mostly medium-resolution (MR) reanalysis data, which were still coarse for local analysis. A two-step downscaling method was proposed for 100 × resolution enhancements of general circulation model (GCM) daily temperature data in this study. First, the historical GCM outputs were 10 × downscaled to a set of dynamically predictable MR data using a deep convolutional neural network (CNN), which included both encode-decode structure and long-short skip connections. Then, using high-resolution (HR) topographic data and MR climate data as auxiliary data, the GCM data were super-resolved to a series of images with spatial resolution of 1 km. A one-step downscaling analysis combined only with HR topographic data was performed as comparison. Seven evaluation metrics were selected to evaluate the prediction accuracy, and the results showed that the overall performance of two-step downscaling method was better than one-step downscaling method. Higher Nash-Sutcliffe efficiency (NSE) and lower mean absolute relative error (MARE) indicated that the two-step method performed better prediction of peak and low values. It was further confirmed by accuracy evaluation on the 10% max and 10% min values of the testing dataset. The introduction of dynamically predictable MR data could provide effective detailed information during the downscaling process and improve the prediction accuracies. Finally, the projected data of four scenarios (SSP1-2.6, SSP2-4.5, SSP3-7.0, and SSP5-8.5) during 2015-2050 were downscaled to the study area. The complex temporal and spatial variations indicated that there were great differences in temperature changes in a basin, and differentiated management measures should be proposed in advance.

FDA-Approved Amoxapine Effectively Promotes Macrophage Control of Mycobacteria by Inducing Autophagy.

Antibiotic resistance poses a significant hurdle in combating global public health crises, prompting the development of novel therapeutics. Strategies to enhance the intracellular killing of mycobacteria by targeting host defense mechanisms offer numerous beneficial effects, which include reducing cytotoxicity caused by current lengthy anti-tubercular treatment regimens and slowing or circumventing the development of multidrug-resistant strains. The intracellular pathogen Mycobacterium tuberculosis infects macrophages and exploits host machinery to survive and multiply. Using a cell-based screen of FDA-approved drugs, we identified an antidepressant, Amoxapine, capable of inhibiting macrophage cytotoxicity during mycobacterial infection. Notably, this reduced cytotoxicity was related to the enhanced intracellular killing of Mycobacterium bovis BCG and M. tuberculosis within human and murine macrophages. Interestingly, we discovered that postinfection treatment with Amoxapine inhibited mTOR (mammalian target of rapamycin) activation, resulting in the induction of autophagy without affecting autophagic flux in macrophages. Also, inhibition of autophagy by chemical inhibitor 3-MA or knockdown of an essential component of the autophagic pathway, ATG16L1, significantly diminished Amoxapine's intracellular killing effects against mycobacteria in the host cells. Finally, we demonstrated that Amoxapine treatment enhanced host defense against M. tuberculosis in mice. In conclusion, our study identified Amoxapine as a novel host-directed drug that enhances the intracellular killing of mycobacteria by induction of autophagy, with concomitant protection of macrophages against death. IMPORTANCE The emergence and spread of multidrug-resistant (MDR) and extensive drug-resistant (XDR) TB urges the development of new therapeutics. One promising approach to combat drug resistance is targeting host factors necessary for the bacteria to survive or replicate while simultaneously minimizing the dosage of traditional agents. Moreover, repurposing FDA-approved drugs presents an attractive avenue for reducing the cost and time associated with new drug development. Using a cell-based screen of FDA-approved host-directed therapies (HDTs), we showed that Amoxapine inhibits macrophage cytotoxicity during mycobacterial infection and enhances the intracellular killing of mycobacteria within macrophages by activating the autophagy pathway, both in vitro and in vivo. These findings confirm targeted autophagy as an effective strategy for developing new HDT against mycobacteria.

A Bacteriophage-Based, Highly Efficacious, Needle- and Adjuvant-Free, Mucosal COVID-19 Vaccine.

The U.S. Food and Drug Administration-authorized mRNA- and adenovirus-based SARS-CoV-2 vaccines are intramuscularly injected in two doses and effective in preventing COVID-19, but they do not induce efficient mucosal immunity or prevent viral transmission. Here, we report the first noninfectious, bacteriophage T4-based, multicomponent, needle- and adjuvant-free, mucosal vaccine harboring engineered Spike trimers on capsid exterior and nucleocapsid protein in the interior. Intranasal administration of two doses of this T4 SARS-CoV-2 vaccine 21 days apart induced robust mucosal immunity, in addition to strong systemic humoral and cellular immune responses. The intranasal vaccine induced broad virus neutralization antibody titers against multiple variants, Th1-biased cytokine responses, strong CD4+ and CD8+ T cell immunity, and high secretory IgA titers in sera and bronchoalveolar lavage specimens from vaccinated mice. All of these responses were much stronger in intranasally vaccinated mice than those induced by the injected vaccine. Furthermore, the nasal vaccine provided complete protection and sterilizing immunity against the mouse-adapted SARS-CoV-2 MA10 strain, the ancestral WA-1/2020 strain, and the most lethal Delta variant in both BALB/c and human angiotensin converting enzyme (hACE2) knock-in transgenic mouse models. In addition, the vaccine elicited virus-neutralizing antibodies against SARS-CoV-2 variants in bronchoalveolar lavage specimens, did not affect the gut microbiota, exhibited minimal lung lesions in vaccinated and challenged mice, and is completely stable at ambient temperature. This modular, needle-free, phage T4 mucosal vaccine delivery platform is therefore an excellent candidate for designing efficacious mucosal vaccines against other respiratory infections and for emergency preparedness against emerging epidemic and pandemic pathogens. IMPORTANCE According to the World Health Organization, COVID-19 may have caused ~15-million deaths across the globe and is still ravaging the world. Another wave of ~100 million infections is predicted in the United States due to the emergence of highly transmissible immune-escaped Omicron variants. The authorized vaccines would not prevent these transmissions since they do not trigger mucosal immunity. We circumvented this limitation by developing a needle-free, bacteriophage T4-based, mucosal vaccine. This intranasally administered vaccine generates superior mucosal immunity in mice, in addition to inducing robust humoral and cell-mediated immune responses, and provides complete protection and sterilizing immunity against SARS-CoV-2 variants. The vaccine is stable, adjuvant-free, and cost-effectively manufactured and distributed, making it a strategically important next-generation COVID vaccine for ending this pandemic.

Combinatorial Viral Vector-Based and Live Attenuated Vaccines without an Adjuvant to Generate Broader Immune Responses to Effectively Combat Pneumonic Plague.

Mice immunized with a combination of an adenovirus vector (Ad5-YFV) and live-attenuated (LMA)-based vaccines were evaluated for protective efficacy against pneumonic plague. While the Ad5-YFV vaccine harbors a fusion cassette of three genes encoding YscF, F1, and LcrV, LMA represents a mutant of parental Yersinia pestis CO92 deleted for genes encoding Lpp, MsbB, and Ail. Ad5-YFV and LMA were either administered simultaneously (1-dose regimen) or 21 days apart in various orders and route of administration combinations (2-dose regimen). The 2-dose regimen induced robust immune responses to provide full protection to animals against parental CO92 and its isogenic F1 deletion mutant (CAF-) challenges during both short- and long-term studies. Mice intranasally (i.n.) immunized with Ad5-YFV first followed by LMA (i.n. or intramuscularly [i.m.]) had higher T- and B-cell proliferative responses and LcrV antibody titers than those in mice vaccinated with LMA (i.n. or i.m.) first ahead of Ad5-YFV (i.n.) during the long-term study. Specifically, the needle- and adjuvant-free vaccine combination (i.n.) is ideal for use in plague regions of endemicity. Conversely, with a 1-dose regimen, mice vaccinated with Ad5-YFV i.n. and LMA by the i.m. route provided complete protection to animals against CO92 and its CAF- mutant challenges and elicited Th1/Th2, as well as Th17 responses, making it suitable for emergency vaccination during a plague outbreak or bioterrorist attack. This is a first study in which a viral vector-based and live-attenuated vaccines were effectively used in combination, representing adjuvant- and/or needle-free immunization, with each vaccine triggering a distinct cellular immune response. IMPORTANCE Yersinia pestis, the causative agent of plague, is a Tier-1 select agent and a reemerging human pathogen. A 2017 outbreak in Madagascar with >75% of cases being pneumonic and 8.6% causalities emphasized the importance of the disease. The World Health Organization has indicated an urgent need to develop new-generation subunit and live-attenuated plague vaccines. We have developed a subunit vaccine, including three components (YscF, F1, and LcrV) using an adenovirus platform (Ad5-YFV). In addition, we have deleted virulence genes of Y. pestis (e.g., lpp, msbB, and ail) to develop a live-attenuated vaccine (LMA). Both of these vaccines generated robust humoral and cellular immunity and were highly efficacious in several animal models. We hypothesized the use of a heterologous prime-boost strategy or administrating both vaccines simultaneously could provide an adjuvant- and/or a needle-free vaccine(s) that has attributes of both vaccines for use in regions of endemicity and during an emergency situation.

A universal bacteriophage T4 nanoparticle platform to design multiplex SARS-CoV-2 vaccine candidates by CRISPR engineering.

A "universal" platform that can rapidly generate multiplex vaccine candidates is critically needed to control pandemics. Using the severe acute respiratory syndrome coronavirus 2 as a model, we have developed such a platform by CRISPR engineering of bacteriophage T4. A pipeline of vaccine candidates was engineered by incorporating various viral components into appropriate compartments of phage nanoparticle structure. These include expressible spike genes in genome, spike and envelope epitopes as surface decorations, and nucleocapsid proteins in packaged core. Phage decorated with spike trimers was found to be the most potent vaccine candidate in animal models. Without any adjuvant, this vaccine stimulated robust immune responses, both T helper cell 1 (TH1) and TH2 immunoglobulin G subclasses, blocked virus-receptor interactions, neutralized viral infection, and conferred complete protection against viral challenge. This new nanovaccine design framework might allow the rapid deployment of effective adjuvant-free phage-based vaccines against any emerging pathogen in the future.

Curcumin inhibits prostate cancer progression by regulating the miR-30a-5p/PCLAF axis.

Curcumin has been shown to inhibit the growth of a variety of tumor cells. However, the biological functions of curcumin in prostate cancer (PCa) have not yet fully elucidated. The objective of the present study was to investigate the role of curcumin on the proliferation, migration, invasion and apoptosis of PCa cells and the underlying mechanism. Cell Counting Kit-8 and flow cytometry were used to detect the effects of curcumin at different concentrations on the proliferation and apoptosis of PCa cell lines, PC-3 and DU145. BrdU and Transwell assays, western blotting and reverse transcription-quantitative PCR were used to determine the effect of curcumin on cell proliferation, migration and invasion, apoptosis-related protein expression, and microRNA (miR)-30a-5p and PCNA clamp associated factor (PCLAF) expression, respectively. In addition, bioinformatics analysis and Pearson's correlation test were used to verify the relationship between miR-30a-5p and PCLAF. Curcumin was observed to impede the proliferation, migration and invasion of PCa cells, and promote their apoptosis in a time- and dose-dependent manner. Curcumin enhanced miR-30a-5p expression and inhibited PCLAF expression; furthermore, there was a negative correlation between miR-30a-5p and PCLAF expression in PCa tissues. In addition, transfection of miR-30a-5p inhibitors partially reversed the function of curcumin on cell proliferation, migration, invasion and apoptosis. Overall, curcumin suppressed the malignant biological behaviors of PCa cells by regulating the miR-30a-5p/PCLAF axis.

Low power consumption photoelectric coupling perovskite memristor with adjustable threshold voltage.

Organic-inorganic halide perovskites (OHPs) have been proven to possess unique optical and electrical properties, and achieved more extensive application as excellent materials for memristors in recent years. Based on the traditional OHP-based memristors, the intermediate layer of the memristor was prepared using yttrium oxide (Y2O3)/OHP stacking structure in this manuscript. The potential barrier between Y2O3and perovskite is relatively high (ΔEC = 2.13 eV) which leads to comparatively low current of the memristor, thus the power consumption can be reduced. Besides, by changing the external light conditions, one can realize sharp or slow switch between high resistance state (HRS) and low resistance state (LRS), so as to meet the requirement of multilevel data storage, which indicates its promising application prospect in information storage and biological simulation. In addition, based on characteristics of photoelectric coupling, the Y2O3/OHP memristor can also achieve the advantage of adjustable threshold voltage. The transition of HRS and LRS can be realized by changing the illumination condition at any voltage, which means the set and reset voltage are not fixed, so that the memristor with adjustable threshold voltage can adapt to various working conditions.

Influence of the Three Gorges Reservoir on climate drought in the Yangtze River Basin.

Although El Niño-Southern Oscillation (ENSO) has been widely confirmed to have significant impacts on climate change in Asia, it is unknown whether the climate change in the Yangtze River Basin (YTR basin) is related to the operation of the Three Gorges Reservoir, which is the world's largest hydropower station. In this study, we used the Standardized Precipitation Evapotranspiration Index (SPEI) as an indicator of climate change and found that the mutation period of the YTR basin was 2003-2006 based on three mutation tests. By analyzing the trends of the SPEI and five related meteorological factors before and after 2003, it was found that the construction of the Three Gorges Reservoir increased the relative humidity and provided a more humid climate for the downstream basin. The relationships between drought events and ENSO and the water level of the reservoir indicated that the basin was more prone to drought in El Niño years and the Three Gorges Reservoir could alleviate agricultural drought in the downstream basin. The spatial impacts of the Three Gorges Reservoir on regional climate change were more pronounced, while the impact of ENSO could not be reflected at the station scale.

Self-powered and high responsivity photodetector based on a n-Si/p-GaTe heterojunction.

Heterojunction integrated by two-dimensional/three-dimensional materials has shown great potential applications in optoelectronic devices because of its fast response speed, high specific detectivity and broad spectral response. In this work, the vertical n-Si/p-GaTe heterojunction has been designed and fabricated, which shows a high responsivity up to 5.73 A W-1and a fast response time of 20µs at zero bias benifitting from the high efficiency of light absorption, internal photocurrent gain and strong built-in electrical field. A specific detectivity of 1012Jones and a broad spectral response ranging from 300 to 1100 nm can also be achieved. This work provides an alternative strategy for high-performance self-powered optoelectronic devices.

A Universal Bacteriophage T4 Nanoparticle Platform to Design Multiplex SARS-CoV-2 Vaccine Candidates by CRISPR Engineering.

A "universal" vaccine design platform that can rapidly generate multiplex vaccine candidates is critically needed to control future pandemics. Here, using SARS-CoV-2 pandemic virus as a model, we have developed such a platform by CRISPR engineering of bacteriophage T4. A pipeline of vaccine candidates were engineered by incorporating various viral components into appropriate compartments of phage nanoparticle structure. These include: expressible spike genes in genome, spike and envelope epitopes as surface decorations, and nucleocapsid proteins in packaged core. Phage decorated with spike trimers is found to be the most potent vaccine candidate in mouse and rabbit models. Without any adjuvant, this vaccine stimulated robust immune responses, both T H 1 and T H 2 IgG subclasses, blocked virus-receptor interactions, neutralized viral infection, and conferred complete protection against viral challenge. This new type of nanovaccine design framework might allow rapid deployment of effective phage-based vaccines against any emerging pathogen in the future.

A new generation needle- and adjuvant-free trivalent plague vaccine utilizing adenovirus-5 nanoparticle platform.

A plague vaccine with a fusion cassette of YscF, F1, and LcrV encoding genes in an adenovirus-5 vector (rAd5-YFV) is evaluated for efficacy and immune responses in mice. Two doses of the vaccine provides 100% protection when administered intranasally against challenge with Yersinia pestis CO92 or its isogenic F1 mutant in short- or long- term immunization in pneumonic/bubonic plague models. The corresponding protection rates drop in rAd5-LcrV monovalent vaccinated mice in plague models. The rAd5-YFV vaccine induces superior humoral, mucosal and cell-mediated immunity, with clearance of the pathogen. Immunization of mice with rAd5-YFV followed by CO92 infection dampens proinflammatory cytokines and neutrophil chemoattractant production, while increasing Th1- and Th2-cytokine responses as well as macrophage/monocyte chemo-attractants when compared to the challenge control animals. This is a first study showing complete protection of mice from pneumonic/bubonic plague with a viral vector-based vaccine without the use of needles and the adjuvant.

N-type doping of black phosphorus single crystal by tellurium.

Black phosphorus has many potential applications in optoelectronic devices because of its unique properties. Adjusting its performance by doping is an important issue of research. In this paper, we synthesized high-quality Te-doped crystals by the chemical vapor transport method. Tellurium doping with an atomic ratio of 0.1% was confirmed by X-ray photoelectron spectroscopy, X-ray diffraction, and energy dispersive X-ray analysis. The performance of field effect transistors devices shows that the hole mobility of Te-doped black phosphorous (BP) is significantly improved compared with that of undoped-BP. The highest hole mobility at room temperature is 719 cm2 V-1 s-1, and the electron mobility is 63 cm2 V-1 s-1. Te-doped BP field effect transistors show an obvious bipolar behavior.

Mutational and transcriptomic landscapes of a rare human prostate basal cell carcinoma.

BACKGROUND: As a rare subtype of prostate carcinoma, basal cell carcinoma (BCC) has not been studied extensively and thus lacks systematic molecular characterization. METHODS: Here, we applied single-cell genomic amplification and RNA-Seq to a specimen of human prostate BCC (CK34ßE12+ /P63+ /PAP- /PSA- ). The mutational landscape was obtained via whole exome sequencing of the amplification mixture of 49 single cells, and the transcriptomes of 69 single cells were also obtained. RESULTS: The five putative driver genes mutated in BCC are CASC5, NUTM1, PTPRC, KMT2C, and TBX3, and the top three nucleotide substitutions are C>T, T>C, and C>A, similar to common prostate cancer. The distribution of the variant allele frequency values indicated that these single cells are from the same tumor clone. The 69 single cells were clustered into tumor, stromal, and immune cells based on their global transcriptomic profiles. The tumor cells specifically express basal cell markers like KRT5, KRT14, and KRT23 and epithelial markers EPCAM, CDH1, and CD24. The transcription factor covariance network analysis showed that the BCC tumor cells have distinct regulatory networks. By comparison with current prostate cancer datasets, we found that some of the bulk samples exhibit basal cell signatures. Interestingly, at single-cell resolution the gene expression patterns of prostate BCC tumor cells show uniqueness compared with that of common prostate cancer-derived circulating tumor cells. CONCLUSIONS: This study, for the first time, discloses the comprehensive mutational and transcriptomic landscapes of prostate BCC, which lays a foundation for the understanding of its tumorigenesis mechanism and provides new insights into prostate cancers in general.

New Host-Directed Therapeutics for the Treatment of Clostridioides difficile Infection.

Frequent and excessive use of antibiotics primes patients to Clostridioides difficile infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier reports, we used a drug repurposing strategy and identified amoxapine (an antidepressant), doxapram (a breathing stimulant), and trifluoperazine (an antipsychotic), which provided significant protection to mice against lethal infections with several pathogens, including C. difficile However, the mechanisms of action of these drugs were not known. Here, we provide evidence that all three drugs offered protection against experimental CDI by reducing bacterial burden and toxin levels, although the drugs were neither bacteriostatic nor bactericidal in nature and had minimal impact on the composition of the microbiota. Drug-mediated protection was dependent on the presence of the microbiota, implicating its role in evoking host defenses that promoted protective immunity. By utilizing transcriptome sequencing (RNA-seq), we identified that each drug increased expression of several innate immune response-related genes, including those involved in the recruitment of neutrophils, the production of interleukin 33 (IL-33), and the IL-22 signaling pathway. The RNA-seq data on selected genes were confirmed by quantitative real-time PCR (qRT-PCR) and protein assays. Focusing on amoxapine, which had the best anti-CDI outcome, we demonstrated that neutralization of IL-33 or depletion of neutrophils resulted in loss of drug efficacy. Overall, our lead drugs promote disease alleviation and survival in the murine model through activation of IL-33 and by clearing the pathogen through host defense mechanisms that critically include an early influx of neutrophils.IMPORTANCEClostridioides difficile is a spore-forming anaerobic bacterium and the leading cause of antibiotic-associated colitis. With few therapeutic options and high rates of disease recurrence, the need to develop new treatment options is urgent. Prior studies utilizing a repurposing approach identified three nonantibiotic Food and Drug Administration-approved drugs, amoxapine, doxapram, and trifluoperazine, with efficacy against a broad range of human pathogens; however, the protective mechanisms remained unknown. Here, we identified mechanisms leading to drug efficacy in a murine model of lethal C. difficile infection (CDI), advancing our understanding of the role of these drugs in infectious disease pathogenesis that center on host immune responses to C. difficile Overall, these studies highlight the crucial involvement of innate immune responses, as well as the importance of immunomodulation as a potential therapeutic option to combat CDI.

[Effects of potassium levels on translocation of 13C-photoassimilates to fruit in 'Fuji' apple during fruit expanding period].

A field experiment was carried out in a six-year old 'Fuji'3/M26/Malus hupehensis Rehd. apple with the 13C tracer method to examine the changes of chlorophyll fluorescence parameters, photosynthetic characteristics of leaf, sugar transporter gene expression, 13C assimilation capability and the characteristics of translocation and distribution of 13C-photoassimilates to fruit under different levels of potassium addition (K2O 0, 0.5%, 1.0%, 1.5%, 2.0%, expressed by CK, K1, K2, K3, K4, respectively). Potassium aqueous solution smear the leaves within 20 cm around the fruit at fruit enlargement stage. Compared with other treatments, K3 treatment significantly increased Rubisco enzyme activity, net photosynthetic rate, maximal photochemical efficiency of PSII, actual photochemical efficiency of PSII, coefficient of photochemical quenching, sorbitol and sucrose content, sorbitol 6-phosphate dehydrogenase (S6PDH) and sucrose phosphate synthase (SPS) enzyme activities and 13C assimilation capability of leaves. Furthermore, K3 treatment increased gene expression of sorbitol transporter MdSOT1 and MdSOT2 and sucrose transporter MdSUT4, and promoted the unloading of sugar in fruit. The 13C of self retention (self leaves and self branches) was the highest in CK (82.6%) and the lowest in K3 treatment (60.5%). With increasing potassium concentration, the 13C absorption of fruit first increased and then decreased, which was the highest in K3 treatment (1.31 mg·g-1) and the lowest in CK (0.57 mg·g-1). Our results indicated that foliage application of potassium solution improved PSII photochemical efficiency, activities of key enzymes related with carbon assimilation, synthesis ability, and outward transport ability of photosynthates in leaves, and consequently promoted the directional transportation of sugar to fruit. The amount of photoassimilates transported to fruit was the most under 1.5% K2O treatment (K3).

Design of a two-layer structure to significantly improve the performance of zinc oxide resistive memory.

Resistive random access memory (RRAM) is considered to be one of the important candidates for the next generation of memory devices. Zinc oxide resistive memory has also been studied for many years, but there are still some controversial topics and problems. Herein, an unusual resistance state has been observed in devices following the measurement and analysis of ZnO resistive memories with different thicknesses, a middle resistance state was speculated to explain the instability of ZnO RRAM. According to this speculation, a two-layer structure ZnO RRAM has been designed to significantly increase the device performance with the introduction of an HfO2 layer and the enhancement has also been explained based on the results of first-principles calculations.

T6SS and ExoA of flesh-eating Aeromonas hydrophila in peritonitis and necrotizing fasciitis during mono- and polymicrobial infections.

An earlier report described a human case of necrotizing fasciitis (NF) caused by mixed infection with 4 Aeromonas hydrophila strains (NF1-NF4). While the NF2, NF3, and NF4 strains were clonal and possessed exotoxin A (ExoA), the NF1 strain was determined to be phylogenetically distinct, harboring a unique type 6 secretion system (T6SS) effector (TseC). During NF1 and NF2 mixed infection, only NF1 disseminated, while NF2 was rapidly killed by a contact-dependent mechanism and macrophage phagocytosis, as was demonstrated by using in vitro models. To confirm these findings, we developed 2 NF1 mutants (NF1ΔtseC and NF1ΔvasK); vasK encodes an essential T6SS structural component. NF1 VasK and TseC were proven to be involved in contact-dependent killing of NF2 in vitro, as well as in its elimination at the intramuscular injection site in vivo during mixed infection, with overall reduced mouse mortality. ExoA was shown to have an important role in NF by both NF1-exoA (with cis exoA) and NF2 during monomicrobial infection. However, the contribution of ExoA was more important for NF2 than NF1 in the murine peritonitis model. The NF2∆exoA mutant did not significantly alter animal mortality or NF1 dissemination during mixed infection in the NF model, suggesting that the ExoA activity was significant at the injection site. Immunization of mice to ExoA protected animals from NF2 monomicrobial challenge, but not from polymicrobial infection because of NF2 clearance. This study clarified the roles of T6SS and ExoA in pathogenesis caused by A. hydrophila NF strains in both mouse peritonitis and NF models in monomicrobial and polymicrobial infections.