Mechanism research of non-coding RNA in immune checkpoint inhibitors therapy.

Immune checkpoint inhibitor (ICI) therapies for tumors of different systems have attained significant achievements and have changed the current situation of tumor treatment due to their therapeutic characteristics of high specificity and low side effects. The immune checkpoint Programmed death 1/Programmed cell death-Ligand 1 (PD-1/PD-L1) axis exerts a vital role in the immune escape of tumor cells. As a result, it has become a key target for tumor immunotherapy. Therefore, to perfect research into potential regulatory factors for the PD-1/PD-L1 axis, in order to understand and illustrate tumor ICI therapy mechanisms, is a significant goal. Moreover, ncRNA has been verified to regulate the PD-1/PD-L1 axis in the tumor immune microenvironment to regulate tumor genesis and development. ncRNAs can improve or decrease the efficacy of ICI therapy by modulating PD-L1 expression. This review aimed to investigate the mechanisms of action of ncRNA in regulating the PD-1/PD-L1 axis in ICI therapy, to provide more efficient immunotherapy for tumors of different systems.

NEDD4L mediates ITGB4 ubiquitination and degradation to suppress esophageal carcinoma progression.

The ubiquitination-mediated protein degradation exerts a vital role in the progression of multiple tumors. NEDD4L, which belongs to the E3 ubiquitin ligase NEDD4 family, is related to tumor genesis, metastasis and drug resistance. However, the anti-tumor role of NEDD4L in esophageal carcinoma, and the potential specific recognition substrate remain unclear. Based on public esophageal carcinoma database and clinical sample data, it was discovered in this study that the expression of NEDD4L in esophageal carcinoma was apparently lower than that in atypical hyperplastic esophageal tissue and esophageal squamous epithelium. Besides, patients with high expression of NEDD4L in esophageal carcinoma tissue had longer progression-free survival than those with low expression. Experiments in vivo and in vitro also verified that NEDD4L suppressed the growth and metastasis of esophageal carcinoma. Based on co-immunoprecipitation and proteome analysis, the NEDD4L ubiquitination-degraded protein ITGB4 was obtained. In terms of the mechanism, the HECT domain of NEDD4L specifically bound to the Galx-ß domain of ITGB4, which modified the K915 site of ITGB4 in an ubiquitination manner, and promoted the ubiquitination degradation of ITGB4, thus suppressing the malignant phenotype of esophageal carcinoma.

Pan-cancer analysis of SLC2A family genes as prognostic biomarkers and therapeutic targets.

Background: The major facilitator superfamily glucose transporters (GLUTs), encoded by solute carrier 2A (SLC2A) genes, mediate the transmembrane movement and uptake of glucose. To satisfy the improved energy demands, glycolysis flux is increased in cancers compared with healthy tissues. Multiple diseases, including cancer, have been associated with GLUTs. Nevertheless, not much research has been done on the functions of SLC2As in pan-cancer prognosis or their clinical treatment potential. Methods: The SLC2A family genes' level of expression and prognostic values were analyzed in relation to pan-cancer. We then examined the association among SLC2As expression and TME, Stemness score, clinical characteristics, immune subtypes, and drug sensitivity. We merged bioinformatics analysis techniques with up-to-date public databases. Additionally, SLC2As from the KOBAS database were subjected to enrichment analysis. Results: We discovered that SLC2As' gene expression differed significantly between normal tissues and many malignancies. A number of tumors from various databases demonstrate a relationship between prognosis and SLC2A family gene expression. For instance, SLC2A2 and SLC2A5 were associated with the overall survival (OS) of hepatocellular carcinoma. SLC2A1 was associated with the OS of lung adenocarcinoma and pancreatic adenocarcinoma. Moreover, the SLC2A family gene expression is significantly correlated with the pan-cancer stromal and immune scores, and the RNA and DNA stemness scores. Furthermore, we found that the majority of SLC2As had a strong correlation with the tumor stages in KIRC. The immunological subtypes and all members of the SLC2A gene family exhibited a substantial correlation. Moreover, pathways containing insulin resistance and adipocytokine signaling pathway may influence the progression of some cancers. Finally, there is a significant positive or negative connection between drug sensitivity and SLC2A1 expression. Conclusion: Our research highlights the significant promise of SLC2As as prognostic indicators and offers insightful approaches for upcoming exploration of SLC2As as putative therapeutic targets in malignancies.

Identification of potential biomarkers for neuromyelitis optica by quantitative proteomics.

OBJECTIVE: Neuromyelitis optica (NMO) was a serious autoimmune inflammatory condition affecting the central nervous system. Currently, there was a lack of diagnostic biomarkers for AQP4-IgG-negative NMO patients. METHODS: A comparative proteomic analysis was conducted on the CSF of 10 patients with NMO and 10 patients with non-inflammatory neurological disorders (NND) using tandem mass tagging technology. Differentially expressed proteins (DEPs) were analyzed using bioinformatic methods. The candidate proteins were then validated through ELISAs in a subsequent cohort of 160 samples, consisting of paired CSF and plasma samples from 50 NMO patients, CSF samples from 30 NND patients, and plasma samples from 30 healthy individuals. RESULTS: We identified 389 proteins via proteomics, screening 79 DEPs. NCAM1, SST and AHSG were selected as candidate molecules for further validation. Compared to NND patients, there were decreased levels of AHSG in CSF and increased levels of NCAM1 and SST in NMO patients. The ELISA results revealed significantly higher levels of AHSG, SST and NCAM1 in the CSF of the NMO group compared to the NND group. Similarly, the serum levels of these three proteins were also higher in the NMO group compared to the healthy control group. It was found that serum NCAM1 levels significantly decreased in patients with non-relapsed NMO compared to patients with relapsed NMO and CSF NCAM1 level increased in patients with bilateral NMO compared to patients with unilateral NMO. Furthermore, CSF SST levels increased in AQP4 antibody-positive NMO patients compared to AQP4 antibody-negative patients. INTERPRETATION: CSF NCAM1, serum NCAM1 and serum SST may serve as potential biomarkers for NMO patients and aid in the diagnosis of AQP4 antibody-negative NMO patients.

Impacts of inflammatory cytokines on depression: a cohort study.

BACKGROUND: Inflammatory factors are associated with depression. We seek to investigate the correlation between inflammatory cytokines and prognosis of depression or suicidal ideation and behavior at 3 months in depression patients. METHODS: Eighty-two depressed outpatients were recruited and treated as usual. Plasma cytokines were measured at baseline. Patients were followed up with Patient Health Questionnaire-9 and suicidal ideation and behavior according to the item 3 of Hamilton depression scale for 3 months. RESULTS: Compared to the depression patients with low level of interleukin-1ß, the high one had severe depressive symptoms at month 2 and 3 (B 0.92, P < 0.01; B 0.86, P = 0.02; respectively). The incidence of suicidal ideation or behavior was 18.3% at 3 months. Depression patients with high levels of tumor necrosis factor-α showed high risk of suicidal ideation and behavior than the low one (OR 2.16, 95% CI 1.00-4.65, P = 0.04). CONCLUSIONS: High levels of interleukin-1ß and tumor necrosis factor-α were predictive of middle-term severe depressive symptoms and suicidal ideation and behavior respectively.

Computational-aided analysis of the pathway and mechanism of dichloroacetonitrile formation from phenylalanine upon chloramination.

Dichloroacetonitrile (DCAN) is an emerging disinfection by-product (DBP) that is widespread in drinking water. However, the pathway for DCAN formation from aromatic amino acids remains unclear, leading to a lack of an understanding of its explicit fate during chloramination. In this study, we investigated the specific formation mechanism of DCAN during the chloramination of phenylalanine based on reaction kinetics and chemical thermodynamics. The reason for differences between aldehyde and decarboxylation pathways was explained, and kinetic parameters of the pathways were obtained through quantum chemistry calculations. The results showed that the reaction rate constant of the rate-limiting step of the aldehyde pathway with 1.9 × 10-11 s-1 was significantly higher than that of decarboxylation (3.6 × 10-16 s-1 M-1), suggesting that the aldehyde pathway is the main reaction pathway for DCAN formation during the chloramination of phenylalanine to produce DCAN. Subsequently, theoretical calculations were performed to elucidate the effect of pH on the formation mechanism, which aligned well with the experimental results. Dehydrohalogenation was found to be the rate-limiting step under acidic conditions with reaction rate constants higher than those of the rate-limiting step (expulsion of amines) under neutral conditions, increasing the rate of DCAN formation. This study highlights the differences in DCAN formation between the decarboxylation and aldehyde pathways during the chloramination of precursors at both molecular and kinetic levels, contributing to a comprehensive understanding of the reaction mechanisms by which aromatic free amino acids generate DCAN.

Hostile attribution bias's role in perceived stress among college freshman students: A latent growth modelling approach.

This study's objective was to examine the growth trajectories of freshman students' perceived stress and whether hostile attribution bias predicts the pattern of perceived stress change using latent growth analyses. A longitudinal dataset with fourth measurement points was gathered from a total of 1109 college students enrolled at a university in Guizhou Province in the first 3 months after college freshmen enrollment. The freshman students' levels of perceived stress tend to show a piecewise linear decline during the transition period, which manifests as a faster decline in the first stage (within the first month) than in the second stage (after the first month). Moreover, hostile attribution bias not only positively predicted the initial level of perceived stress but also positively predicted the slope of perceived stress in the first and second stages. In addition, there was a significant sex difference in the initial level of perceived stress where the initial level of perceived stress was higher in females than in males, but there was no significant sex difference in the rate of perceived stress decline. These results highlight the longitudinal relationship between hostile attribution bias and perceived stress and have implications for improving freshmen' college adaptation.

Serum apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) is a novel stroke biomarker.

BACKGROUND: Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) is a promising stroke biomarker. However, a large study of human serum ASC has not yet to be reported; additionally, the diagnostic value of prehospital concentration and practicality of ASC remains unknown. METHODS: We recruited 774 Chinese stroke patients, including 523 with ischemic stroke (IS) and 251 with hemorrhagic stroke (HS) within 14 days following symptom onset in the emergency department, alongside 481 healthy individuals and 64 cognitive impairment patients as controls. Serum ASC concentrations were determined using automated chemiluminescence immunoassay, exploring the relationship between serum ASC concentration and subtypes, severity, and sampling timepoints of stroke. RESULTS: ASC concentrations were significantly higher in stroke patients compared with all controls (P < 0.001). HS patients had greater ASC concentrations than IS patients (P < 0.05). With increasing ASC concentration, the proportion of severe cases increased. The area under the receiver operating characteristic curve (AUC) for differentiating between healthy individuals and stroke patients in the hyperacute phase was 0.78; this markedly improved (0.90) when considering samples from healthy individuals and patients with subarachnoid hemorrhage (SAH) ≤ 3  h from last-known-well (LKW). CONCLUSIONS: Serum ASC is a valuable biomarker for stroke differentiation and aids in the clinical diagnosis of stroke severity and subtypes.

Pan-cancer analysis reveals the characteristics and roles of tooth agenesis mutant genes.

Tooth development is regulated by numerous genes and signaling pathways. Some studies suggest that mutations in these genes may be associated with several cancer types. However, the tooth agenesis mutated genes role in the prognosis and their clinical therapeutic potentials in pan-cancer have not been elaborately explored. Moreover, the intrinsic correlation between tooth agenesis and cancers also needs to be further verified. We preliminarily analyzed expression levels and prognostic values of causative genes of tooth agenesis, and explored the correlation between the expression of tooth agenesis mutated genes and TME, Stemness score, clinical characteristic, immune subtype, and drug sensitivity in pan-cancer, which based on updated public databases and integrated some bioinformatics analysis methods. In addition, we conducted the enrichment analysis of tooth agenesis mutant genes from KOBAS database. We observed that TA mutant genes had significant gene expression differences in multiple cancer types compared with normal tissues. The expression of causative genes of TA is associated with the prognosis in several cancers from different databases. For example, AXIN2 and MSX1 were correlated to the overall survival (OS) of uterine corpus endometrial carcinoma. PAX9 and TP63 were related to OS of lung squamous cell carcinoma. And TP63 was associated with OS in breast invasive carcinoma and pancreatic adenocarcinoma. Furthermore, the expression of TA mutant genes also has a significant correlation with stromal and immune scores, and RNA stemness score and DNA stemness score in pan-cancer. Besides, we observed that all causative genes of TA were significantly correlated with immune subtypes. Moreover, KEGG pathway analysis showed that causative genes of TA were associated with the development and progression of breast cancer, basal cell carcinoma, gastric cancer, and hepatocellular carcinoma. Finally, AXIN2 expression has a significantly positive or negative correlation with drug sensitivity. Our study indicates the great potential of TA mutant genes as biomarkers for prognosis and provides valuable strategies for further investigation of TA mutant genes as potential therapeutic targets in cancers. Our study can further verify that there may be an intrinsic correlation between tooth agenesis and the occurrence of multiple cancers.

Effect of antibiotic prophylaxis in the prognosis of Post-neurosurgical meningitis patients.

AIMS: To evaluate the effect of antibiotic prophylaxis(AP) in the prognosis of Post-neurosurgical meningitis(PNM) patients. METHODS: A cohort analysis was performed using the clinical database in Beijing Tiantan Hospital and Capital Medical University. Data were collected on patients with the diagnosis of PNM (n = 3931) during 2012.01 to 2022.04. The microbial distribution, types of AP, and 42 and 90 days survival analysis of AP patients were evaluated using probable statistical methods. Independent risk factors for mortality were established by constructing a logistic regression analysis. RESULT: A total of 1,190 patients were included in this study, Klebsiella pneumoniae, Acinetobacter baumannii, and Staphylococcus aureus occupied the highest proportion. Of them, 929 cases received AP, cefuroxime and ceftriaxone are the most frequent used antibiotics. In addition, We found that PNM patients without AP significantly increased the 42 days and 90 days all-cause mortality rates. The use of different levels of AP did not improve patient outcomes, and ICU admission and assisted mechanical ventilation (AMV) were identified as independent mortality risk factors for PNM patient received AP. CONCLUSIONS: AP plays an important role in the prognosis of PNM patients and has a significant function in improving prognosis. The prevention of PNM with antibiotics prior to neurosurgery should be emphasized in clinical practice, and appropriate selection of antibiotics is necessary to prevent the occurrence of infection and inhibit the emergence of antibiotic-resistant bacteria.

Effect of Follow-Up Cerebrospinal Fluid Cultures in Post-Neurosurgical Patients' Outcome with Gram-Negative Bacterial Meningitis/Encephalitis.

Background: To investigate the factors associated with follow-up CSF cultures (FUCCs) in post-neurosurgical patients with gram-negative bacterial meningitis/encephalitis and the effect of FUCCs on treatment management and patient outcomes. Methods: This single-centered retrospective cohort study enrolled post-neurosurgical patients with gram-negative bacterial meningitis/encephalitis at a tertiary-care university hospital between 2012 and 2022. The risk factors for 28-day mortality were evaluated using multivariate Cox analysis. FUCC-related risk factors were also analyzed. Results: Among the 844 enrolled patients, 504 (59.7%) underwent FUCC, and FUCC was found to be associated with lower rates of both all-cause (hazard ratio (HR) 0.391; 95% confidence interval (CI), 0.235-0.651; p<0.001) and attributable mortality (HR 0.463; 95% CI, 0.239-0.897; p=0.023) in Post-neurosurgical patients diagnosed with Gram-negative bacterial meningitis/encephalitis. Moreover, the results of the study underscored that patients with persistent gram-negative bacterial meningitis/encephalitis had a lower all-cause/attributable short-term survival rate according to 28-day mortality Kaplan-Meier analysis (P=0.001/0.006). Conclusion: Performing FUCC has been demonstrated to lower mortality rates in Post-neurosurgical patients suffering from Gram-negative bacterial meningitis/encephalitis. The higher mortality rate observed in patients with persistent gram-negative bacterial meningitis/encephalitis suggests that performing FUCC is a crucial component of proper patient care and management, and is therefore recommended for use by clinicians as a standard practice. This finding underscores the significance of consistent implementation of FUCC in the management and prognosis of patients with Post-neurosurgical infections.

The Influence of Special Environments on SiC MOSFETs.

In this work, the influences of special environments (hydrogen gas and high temperature, high humidity environments) on the performance of three types of SiC MOSFETs are investigated. The results reveal several noteworthy observations. Firstly, after 500 h in a hydrogen gas environment, all the SiC MOSFETs exhibited a negative drift in threshold voltage, accompanied by an increase in maximum transconductance and drain current (@ VGS/VDS = 13 V/3 V). This phenomenon can be attributed to that the hydrogen atoms can increase the positive fixed charges in the oxide and increase the electron mobility in the channel. In addition, high temperature did not intensify the impact of hydrogen on the devices and electron mobility. Instead, prolonged exposure to high temperatures may induce stress on the SiO2/SiC interface, leading to a decrease in electron mobility, subsequently reducing the transconductance and drain current (@ VGS/VDS = 13 V/3 V). The high temperature, high humidity environment can cause a certain negative drift in the devices' threshold voltage. With the increasing duration of the experiment, the maximum transconductance and drain current (@ VGS/VDS = 18V (20 V)/3 V) gradually decreased. This may be because the presence of moisture can lead to corrosion of the devices' metal contacts and interconnects, which can increase the devices' resistance and lead to a decrease in the devices' maximum transconductance and drain current.

Establishment and evaluation of a multiplex real-time RT-PCR for quantitative and differential detection of wild-type canine distemper virus from vaccine strains.

This study sought to establish a real-time reverse transcription (RT)-PCR method to differentially detect canine distemper virus (CDV) wild-type and vaccine strains. To this end, a pair of CDV universal primers and two specific minor groove binder (MGB) probes, harboring a T/C substitution in the hemagglutinin (H) gene, were designed. Using a recombinant plasmid expressing the H gene of the CDV wild-type or vaccine strain as standards, a sensitive and specific multiplex real-time RT-PCR was established for quantitative and differential detection of CDV wild-type and vaccine strains. The limit of detection for this multiplex assay was 22.5 copies/µL and 2.98 copies/µL of viral RNA for wild-type and vaccine strains, respectively. Importantly, the wild-type and vaccine MGB probes specifically hybridized different genotypes of wild-type CDV circulating in China as well as globally administered vaccine viruses, respectively, with no cross-reactivity observed with non-CDV viruses. Moreover, this method was successfully applied for the quantitative detection of CDV RNA in tissue samples of experimentally infected breeding foxes, raccoon dogs, and minks. Additionally, the multiplex real-time RT-PCR was able to detect the viral RNA in the whole blood samples as early as 3 days post-infection, 3 to 4 days prior to the onset of clinical signs in these CDV infection animals. Hence, the established multiplex real-time RT-PCR method is useful for differentiating wild-type CDV and vaccine strains in China, and for conducting canine distemper early diagnosis as well as dynamic mechanism of CDV replication studies in vivo.

DNA Vaccine Co-Expressing Hemagglutinin and IFN-γ Provides Partial Protection to Ferrets against Lethal Challenge with Canine Distemper Virus.

Canine distemper (CD), caused by canine distemper virus (CDV), is a highly contagious and lethal disease in domestic and wild carnivores. Although CDV live-attenuated vaccines have reduced the incidence of CD worldwide, low levels of protection are achieved in the presence of maternal antibodies in juvenile animals. Moreover, live-attenuated CDV vaccines may retain residual virulence in highly susceptible species and cause disease. Here, we generated several CDV DNA vaccine candidates based on the biscistronic vector (pIRES) co-expressing virus wild-type or codon-optimized hemagglutinin (H) and nucleocapsid (N) or ferret interferon (IFN)-γ, as a molecular adjuvant, respectively. Apparently, ferret (Mustela putorius furo)-specific codon optimization increased the expression of CDV H and N proteins. A ferret model of CDV was used to evaluate the protective immune response of the DNA vaccines. The results of the vaccinated ferrets showed that the DNA vaccine co-expressing the genes of codon-optimized H and ferret IFN-γ (poptiH-IRES-IFN) elicited the highest anti-CDV serum-neutralizing antibodies titer (1:14) and cytokine responses (upregulated TNF-α, IL-4, IL-2, and IFN-γ expression) after the third immunization. Following vaccination, the animals were challenged with a lethal CDV 5804Pe/H strain with a dose of 105.0 TCID50. Protective immune responses induced by the DNA vaccine alleviated clinical symptoms and pathological changes in CDV-infected ferrets. However, it cannot completely prevent virus replication and viremia in vivo as well as virus shedding due to the limited neutralizing antibody level, which eventually contributed to a survival rate of 75% (3/4) against CDV infection. Therefore, the improved strategies for the present DNA vaccines should be taken into consideration to develop more protective immunity, which includes increasing antigen expression or alternative delivery routes, such as gene gun injection.

Establishment of a comprehensive diagnostic model for neuromyelitis optica spectrum disorders based on the analysis of laboratory indicators and clinical data.

BACKGROUND: To establish a comprehensive diagnostic model for neuromyelitis optica spectrum disorders (NMOSDs) based on laboratory indicators and clinical data. METHODS: A retrospective method was used to query the medical records of patients with NMOSD from January 2019 to December 2021. At the same time, clinical data of other neurological diseases were also collected for comparison. Clinical data of the NMOSD group and non-NMOSD group were analyzed, and the diagnostic model was established based on these data. In addition, the model was evaluated and verified by the receiver operating curve. RESULTS: A total of 73 patients with NMOSD were included, and the ratio of males to females was 1:3.06. The indicators that showed differences between the NMOSD group and non NMOSD group included neutrophils (P = 0.0438), PT (P = 0.0028), APTT (P < 0.0001), CK (P = 0.002), IBIL (P = 0.0181), DBIL (P < 0.0001), TG (P = 0.0078), TC (P = 0.0117), LDL-C (P = 0.0054), ApoA1 (P = 0.0123), ApoB (P = 0.0217), TPO antibody (P = 0.012), T3 (P = 0.0446), B lymphocyte subsets (P = 0.0437), urine sg (P = 0.0123), urine pH (P = 0.0462), anti-SS-A antibody (P = 0.0036), RO-52 (P = 0.0138), CSF simplex virus antibody I-IGG (P = 0.0103), anti-AQP4 antibody (P < 0.0001), and anti-MOG antibody (P = 0.0036). Logistic regression analysis showed that changes in ocular symptoms, anti-SSA antibody, anti-TPO antibody, B lymphocyte subsets, anti-AQP4 antibody, anti-MOG antibody, TG, LDL, ApoB, and APTT had a significant impact on diagnosis. The AUC of the combined analysis was 0.959. The AUC of the new ROC for AQP4- and MOG- antibody negative NMOSD was 0.862. CONCLUSIONS: A diagnostic model was successfully established, which can play an important role in differential diagnosis of NMOSD.

Diagnostic Potential of Two Novel Biomarkers for Neuromyelitis Optica Spectrum Disorder and Multiple Sclerosis.

BACKGROUND: Currently, no tests can definitively diagnose and distinguish neuromyelitis optica spectrum disorder (NMOSD) from multiple sclerosis (MS). METHODS: Initially, cerebrospinal fluid (CSF) proteomics were employed to uncover the novel biomarkers that differentiate NMOSD from MS into cohorts of 10 MS and 10 NMOSD patients. Subsequently, screening biomarkers were validated using an enzyme-linked immunosorbent assay method and CSF and serum samples from 20 MS patients, 20 NMOSD patients, 20 non-inflammatory neurological controls, and 20 healthy controls. RESULTS: In study cohort, insulin-like growth factor-binding protein 7 (IGFBP7) and lysosome-associated membrane glycoprotein 2 (LAMP2) were screened. In validation cohort, serum and CSF IGFBP7 not only exhibited higher levels in MS and NMOSD patients than controls, but also had greatest area under the curve (AUC, above or equal to 0.8) in MS and NMOSD diagnoses. Serum IGFBP7 (0.945) and CSF IGFBP7 (0.890) also had the greatest AUCs for predicting MS progression, while serum LAMP2 had a moderate curve (0.720). CONCLUSIONS: IGFBP7 was superior in diagnosing MS and NMOSD, and IGFBP7 and serum LAMP2 performed exceptionally well in predicting the MS progression. These results offered reasons for further investigations into the functions of IGFBP7 and LAMP2 in MS and NMOSD.

Effect of Electro-Thermo-Mechanical Coupling Stress on Top-Cooled E-Mode AlGaN/GaN HEMT.

This work investigated the effects of single stress and electro-thermo-mechanical coupling stress on the electrical properties of top-cooled enhancement mode (E-mode) Aluminium Gallium Nitride/Gallium Nitride (AlGaN/GaN) high electron mobility transistor (HEMT) (GS66508T). Planar pressure, linear deformation, punctate deformation, environmental temperature, electro-thermal coupling, thermo-mechanical coupling, and electro-thermo-mechanical coupling stresses were applied to the device. It was found that different kinds of stress had different influence mechanisms on the device. Namely, excessive mechanical pressure/deformation stress caused serious, irrecoverable degradation of the device's leakage current, with the gate leakage current (Ig) increasing by ~107 times and the drain-to-source leakage current (Idss) increasing by ~106 times after mechanical punctate deformation of 0.5 mm. The device characteristics were not restored after the mechanical stress was removed. Compared with three mechanical stresses, environmental thermal stress had a greater influence on the device's transfer characteristic and on-resistance (Ron) but far less influence on Ig and Idss. As was expected, multiple stress coupled to the device promoted invalidation of the device. For more in-depth investigation, finite element simulation carried out with COMSOL was used to analyze the effect of electro-thermo-mechanical coupling stress on top-cooled E-mode AlGaN/GaN HEMT. The results of the experiments and simulation demonstrated that single and coupled stresses, especially mechanical stress coupled with other stresses, degraded the electrical properties or even caused irreversible damage to top-cooled E-mode AlGaN/GaN HEMT. Mechanical stress should be reduced as much as possible in the packaging design, transportation, storage, and application of top-cooled E-mode AlGaN/GaN HEMT.

Inactivation mechanism of E. coli in water by enhanced photocatalysis under visible light irradiation.

Developing efficient and economical technologies for drinking water disinfection remains a challenge. We synthesized Ag/AgBr/LDH doped with various silver mass concentrations and explored its ability to inactivate E. coli under visible light irradiation (λ ≥ 400 nm). Our results indicated a total inactivation of E. coli (107 CFU·mL-1) within 80 min using 2 % Ag/AgBr/LDH in a laboratory-scale test. The method was evaluated for disinfecting three effluent samples collected from one drinking water treatment plant, covering representative water treatment processes. After five consecutive runs, the inactivation efficiency decreased slightly to 89 % in CFU·mL-1, indicating that the photocatalysts had excellent stability and reusability. The mechanisms were analyzed by combining chemical and biological methods. It was verified that singlet oxygen (1O2), hydrogen peroxide (H2O2), and photo-generated electrons (e-) were significant contributors to the inactivation process. Scanning electron microscopy images analysis showed the disruption of the membrane integrity of E. coli by photocatalytic oxidation. Internal component leakage and reduced enzyme activity were also observed in terms of K+ leakage, ß-galactosidase activity, and antioxidant enzyme activity. The results by the transcriptomic analysis implied that Ag/AgBr/LDH regulating the oxidative stress response and cell membrane damage related genes was the main inactivation mechanism.

Persistent and Severe Viral Replication in PBMCs with Moderate Immunosuppression Served an Alternative Novel Pathogenic Mechanism for Canine Morbillivirus.

Measles virus and canine distemper virus (CDV) cause lethal infections in their respective hosts characterized by severe immunosuppression. To furtherly acknowledge the attenuated mechanisms of the regionally ongoing epidemic CDV isolates and provide novel perspectives for designing new vaccines and therapeutic drugs, a recombinant CDV rHBF-vacH was employed with a vaccine hemagglutinin (H) gene replacement by reverse genetics based on an infectious cDNA clone for the CDV wild-type HBF-1 strain. Interestingly, unlike previously published reports that a vaccine H protein completely changed a pathogenic wild-type CDV variant to be avirulent, rHBF-vacH was only partially attenuated by alleviating the degree of viral immunosuppression, and still caused 66.7% lethality in ferrets with a prolonged period of disease. Further comparisons of pathogenic mechanisms proved that the weaker but necessary invasions into peripheral blood mononuclear cells (PBMCs) of rHBF-vacH, and subsequently persistent viral replications in PBMCs and multiple organs, together contributed to its 66.7% mortality. In addition, despite significantly higher titers than the parent viruses, rHBF-vacH would not be a suitable candidate for a live vaccine, with great invasion and infection potentials of PBMCs from 16 tested kinds of host species. Altogether, sustained and severe viral replication in PBMCs with moderate immunosuppression was first proven to be an alternative novel pathogenic mechanism for CDV, which might help us to understand possible reasons for CDV fatal infections among domestic dogs and the highly susceptible wild species during natural transmission. IMPORTANCE Despite widespread vaccine campaigns for domestic dogs, CDV remained an important infectious disease in vaccinated carnivores and wild species. In recent years, the regionally ongoing epidemic CDV isolates have emphasized conservation threats to, and potentially disastrous epidemics in, endangered species worldwide. However, little is known about how to deal with the CDV variants constantly regional epidemic. In this study, we employed a recombinant CDV rHBF-vacH with a vaccine H gene replacement in a CDV wild-type HBF-1 context to attenuate the epidemic CDV variant to design a new vaccine candidate. Interestingly, rHBF-vacH was only partially attenuated by alleviating the degree of viral immunosuppression, and still caused 66.7% lethality in ferrets by weaker but necessary invasions into PBMCs, and subsequently persistent and severe viral replications in PBMCs. Significantly higher virus titers of rHBF-vacH in vitro might indicate the rapid cell-to-cell spreads in vivo that indirectly contribute to fatal infections of rHBF-vacH in ferrets.