Light-triggered 2D electron gas in a GaN-based HEMT with sandwiched p-GaN layers.

In this work, a p-n junction-coupled metal-insulator-semiconductor (MIS) normally-off high-electron-mobility transistor (HEMT) UVPD is proposed. A two-dimensional electron gas (2DEG) at the AlN/U-GaN interface is entirely depleted with a dark current of 1.97 × 10-11 A because of the design of the sandwiched p-GaN layers. Under 365 nm illumination, the 2DEG is light triggered at Vds = 1 V with a high light on/off ratio of over 107 at a light power density of 286.39 mW·cm-2. Meanwhile, it exhibits fast rise and decay times of 248.39 and 584.79 µs, respectively. Moreover, a maximum responsivity (R) of 2.33 A/W, a maximum EQE of 793%, and a D* of 1.08 × 1013 Jones are obtained at Vds = 1 V. This can be attributed to the built-in electric fields in the configuration, which accelerate the flow of photogenerated carriers into the AlN/U-GaN channel. Additionally, the device showcases stable durability, repeatability, and a low driving voltage, making it highly suitable for applications in UV communication and space exploration.

Polarization-Resolved p-Se/n-WS2 Heterojunctions toward Application in Microcomputer System as Multivalued Signal Trigger.

Polarization-sensitive photodetectors based on van der Waals heterojunctions (vdWH) have excellent polarization-resolved optoelectronic properties that can enable the applications in polarized light identification and imaging. With the development of optical microcomputer control systems (OMCS), it is crucial and energy efficient to adopt the self-powered and polarization-resolved signal-generators to optimize the circuit design of OMCS. In this work, the selenium (Se) flakes with in-plane anisotropy and p-type character are grown and incorporated with n-type tungsten disulfide (WS2 ) to construct the type-II vdWH for polarization-sensitive and self-powered photodetectors. Under 405 nm monochrome laser with 1.33 mW cm-2 power density, the photovoltaic device exhibits superior photodetection performance with the photoelectric conversion efficiency (PCE) of 3.6%, the responsivity (R) of 196 mA W-1 and the external quantum efficiency (EQE) of about 60%. The strong in-plane anisotropy of Se crystal structure gives rise to the capability of polarized light detection with anisotropic photocurrent ratio of ≈2.2 under the 405 nm laser (13.71 mW cm-2 ). Benefiting from the well polarization-sensitive and photovoltaic properties, the p-Se/n-WS2 vdWH is successfully applied in the OMCS as multivalued signal trigger. This work develops the new anisotropic vdWH and demonstrates its feasibility for applications in logic circuits and control systems.

Shape- and Size-Dependent Refractive Index Sensing and SERS Performance of Gold Nanoplates.

Plasmonic sensors are promising for ultrasensitive chemical and biological analysis. Gold nanoplates (Au NPLs) show unique geometrical structures with high ratios of surface to bulk atoms, which display fascinating plasmonic properties but require optimization. This study presented a systematic investigation of the influence of different parameters (shape, aspect ratio, and resonance mode) on localized surface plasmon resonance properties, refractive index (RI, n) sensitivities, and surface-enhanced Raman scattering (SERS) enhancement ability of different types of Au NPLs through finite-difference time-domain (FDTD) simulations. As a proof of concept, triangular, circular, and hexagonal Au NPLs with varying aspect ratios were fabricated via a three-step seed-mediated growth method by the experiment. Both FDTD-simulated and measured experimental results confirm that the RI sensitivities increase with the aspect ratio. Furthermore, choosing a lower order resonance mode of Au NPLs benefits higher RI sensitivities. The SERS enhancement abilities of Au NPLs also predicted to be highly dependent on the shape and aspect ratio. The triangular Au NPLs showed the highest SERS enhancement ability, while it drastically decreased for circular Au NPLs after the rounding process. The SERS enhancement ability gradually became more intense as the hexagonal Au NPLs overgrown on circular Au NPLs with increasing volumes of HAuCl4 solution. The results are expected to help develop effective biosensors.

Staphylococcus aureus mediates pyroptosis in bovine mammary epithelial cell via activation of NLRP3 inflammasome.

Cell death and inflammation are intimately linked during mastitis due to Staphylococcus aureus (S. aureus). Pyroptosis, a programmed necrosis triggered by gasdermin protein family, often occurs after inflammatory caspase activation. Many pathogens invade host cells and activate cell-intrinsic death mechanisms, including pyroptosis, apoptosis, and necroptosis. We reported that bovine mammary epithelial cells (MAC-T) respond to S. aureus by NOD-like receptor protein 3 (NLRP3) inflammasome activation through K+ efflux, leading to the recruitment of apoptosis-associated speck-like protein (ASC) and the activation of caspase-1. The activated caspase-1 cleaves gasdermin D (GSDMD) and forms a N-terminal pore forming domain that drives swelling and membrane rupture. Membrane rupture results in the release of the pro-inflammatory cytokines IL-18 and IL-1ß, which are activated by caspase-1. Can modulate GSDMD activation by NLRP3-dependent caspase-1 activation and then cause pyroptosis of bovine mammary epithelial cells.

Hypoxia-induced miR-182-5p regulates vascular smooth muscle cell phenotypic switch by targeting RGS5.

In response to vascular injury or alterations in the local environment, such as hypoxia and hypertension, contractile vascular smooth muscle cells (VSMCs) are able to switch to a synthetic phenotype characterized by increased extracellular matrix synthesis with decreased expression of contractile markers. miR-182-5p has recently been reported to play a regulatory role in VSMCs proliferation. However, little is known about its target genes and related pathways in VSMCs phenotypic switch. Here, we investigated the function of miR-182-5p in VSMCs phenotypic switch. The results showed that upregulation of miR-182-5p promoted the switching of VSMCs from a contractile to a synthetic phenotype under hypoxic conditions. Mechanistically, hypoxia elevated miR-182-5p, leading to a reduction in expression of contractile markers and weakened RhoA signaling. Using bioinformatics analysis, dual-luciferase reporter assays and rescue assays, we demonstrated that miR-182-5p suppressed RhoA signaling by targeting RGS5. Collectively, the results from the present study indicated that miR-182-5p/RGS5/RhoA axis regulated hypoxia-induced VSMCs phenotypic switch.

The role of pulmonary mast cells activation and degranulation in the process of increased pulmonary artery pressure.

Hypoxia exposure often cause the increases of pulmonary arterial pressure (PAP). Studies reported that mast cells (MCs) participate in pulmonary vascular remodeling and promote the formation of chronic pulmonary hypertension. Current studies mainly focus on the change of MCs under chronic hypoxia, but few studies on the regulatory role and mechanism of MCs under acute hypoxia. Therefore, present study investigated the dynamic change of MCs in lung tissues under acute hypoxia and the role of MCs activation in the increasement of PAP. In our study, we established an experimental rat model of acute hypobaric hypoxia using a hypobaric chamber (simulated altitude of 7,000 m) and pretreated with MCs degranulation inhibitor sodium cromoglycate (SCG) to study the MCs changes under acute hypoxic exposure. We found that acute hypobaric hypoxia contributed to the increased quantity, activity, and degranulation of MCs and SCG pretreatment showed attenuated PAP elevation under acute hypoxia. Our findings implied that there is a possible mechanism of acute hypoxia cause rapid recruitment of MCs, activation, and explosive degranulation to release Tryptase, Chymase, IL-6, His, 5-HT, and Ang II, which further contributed to pulmonary microvascular contraction and increase in PAP. This work extends the knowledge about MCs, providing a potential profile of MCs as an alternative treatment for high-altitude pulmonary edema (HAPE)-related increased pulmonary artery pressure.

Intracellular Staphylococcus aureus inhibits autophagy of bovine mammary epithelial cells through activating p38α.

Staphylococcus aureus is a common pathogen of bovine mastitis which can induce autophagy and inhibit autophagy flux, resulting in intracellular survival and persistent infection. The aim of the current study was to investigate the role of p38α in the autophagy induced by intracellular S. aureus in bovine mammary epithelial cells. An intracellular infection model of MAC-T cells was constructed, and activation of p38α was examined after S. aureus invasion. Through activating/inhibiting p38α by anisomycin/SB203580, the autophagosomes, LC3 and p62 level were analyzed by immunofluorescence and western blot. To further study the detailed mechanism of p38α, phosphorylation of ULK1ser757 was also detected. The results showed that intracellular S. aureus activated p38α, and the activation developed in a time-dependent manner. Inhibition of p38α promoted intracellular S. aureus-induced autophagy flow, up-regulated the ratio of LC3 II/I, reduced the level of p62 and inhibited the phosphorylation of ULK1ser757, whereas the above results were reversed after activation of p38α. The current study indicated that intracellular S. aureus can inhibit autophagy flow by activating p38α in bovine mammary epithelial cells.

Mitophagy is involved in chromium (VI)-induced mitochondria damage in DF-1 cells.

Cr (VI), which is a common heavy metal pollutant with strong oxidizing property, exists widely in nature. Organisms can be exposed to Cr (VI) through various means. Cr (VI) causes mitochondrial dysfunction after being absorbed by cells. Whether Cr (VI) induces the selective autophagic degradation of mitochondria, which is a biological process called mitophagy, remains unclear. Mitophagy not only recycles intracellularly damaged mitochondria to compensate for nutrient deprivation but also is involved in mitochondria quality control. Thus, this study investigated whether Cr (VI) could induce mitophagy in DF-1 cells. Carbonyl cyanide m-chlorophenylhydrazone, which is a mitochondrial-uncoupling reagent that induces mitophagy, was used. DF-1 cells were incubated with different doses of Cr (VI) for varying durations. The autophagy-related proteins LC3-II and p62 levels decreased after 6 h of Cr (VI) treatment but recovered within 24 h. The mitochondrial membrane potential, which is an indicator of mitochondrial damage, was detected by flow cytometry. We found that different durations of Cr (VI) treatment induced mitochondrial mass decrease and depolarization. Furthermore, the expression of the protein translocase of outer mitochondrial membrane 20 (TOMM20), which is a mitochondrial outer membrane protein, was decreased significantly in the presence of Cr (VI). Our findings indicate that Cr (VI) may contribute to the mitochondrial morphology and function damage and may therefore lead to the autophagic clearance of mitochondria.

A cable-driven soft robot surgical system for cardiothoracic endoscopic surgery: preclinical tests in animals.

BACKGROUND: Minimally invasive surgery attracts more and more attention because of the advantages of minimal trauma, less bleeding and pain and low complication rate. However, minimally invasive surgery for beating hearts is still a challenge. Our goal is to develop a soft robot surgical system for single-port minimally invasive surgery on a beating heart. MATERIALS AND METHODS: The soft robot described in this paper is inspired by the octopus arm. Although the octopus arm is soft and has more degrees of freedom (DOFs), it can be controlled flexibly. The soft robot is driven by cables that are embedded into the soft robot manipulator and can control the direction of the end and middle of the soft robot manipulator. The forward, backward and rotation movement of the soft robot is driven by a propulsion plant. The soft robot can move freely by properly controlling the cables and the propulsion plant. The soft surgical robot system can perform different thoracic operations by changing surgical instruments. To evaluate the flexibility, controllability and reachability of the designed soft robot surgical system, some testing experiments have been conducted in vivo on a swine. RESULTS: Through the subxiphoid, the soft robot manipulator could enter into the thoracic cavity and pericardial cavity smoothly and perform some operations such as biopsy, ligation and ablation. The operations were performed successfully and did not cause any damage to the surrounding soft tissues. From the experiments, the flexibility, controllability and reachability of the soft robot surgical system have been verified. Also, it has been shown that this system can be used in the thoracic and pericardial cavity for different operations. CONCLUSIONS: Compared with other endoscopy robots, the soft robot surgical system is safer, has more DOFs and is more flexible for control. When performing operations in a beating heart, this system maybe more suitable than traditional endoscopy robots.

Effects of pyruvate-enriched peritoneal dialysis solution on intestinal barrier in peritoneal resuscitation from hemorrhagic shock in rats.

BACKGROUND: To investigate protective effects of pyruvate-enriched peritoneal dialysis solution (P-PDS), compared with lactate-PDS (L-PDS), on the intestinal mucosal barrier in peritoneal resuscitation (PR) from severe hemorrhagic shock (HS) in rats. MATERIALS AND METHODS: Fifty male SD rats were randomly divided into five groups (n = 10): group sham, group control (HS without fluid resuscitation), group intravenous resuscitation (IVR) (HS with IVR only), group L-PDS (HS with i.v. infusion plus PR with L-PDS), and group P-PDS (HS with i.v. infusion plus PR with P-PDS). HS was induced by hemorrhage with mean arterial pressure 40 mm Hg for 60 min. In three groups with fluid rehydration, IVR included shed blood and dl-lactate Ringer solution equal to two times the volume of shed blood during 60 min; in two groups with PR, 20 mL of L-PDS, or P-PDS were infused when i.v. infusion started after HS into the peritoneal cavity in 20 min, respectively. Blood samples were taken for determinations of pH, base excess, PaCO2, PaO2, and D-LA 60 min post fluid resuscitation. After rats were sacrificed, a segment of intestine was harvested for the detection of expressions of intestinal barrier proteins: zonula occludens-1 (ZO-1) and phosphorylated vasodilator-stimulated phosphoprotein (p-VASP) by Western blot and immunohistochemistry. Intestinal morphologic alterations were also observed. RESULTS: Blood pH, base excess, and PaO2 were higher, whereas PaCO2 and D-LA were lower in group P-PDS than in other three HS groups (P < 0.05 and P < 0.01, respectively). Severe acidosis was nearly corrected in group P-PDS. Intestinal barrier proteins ZO-1 and p-VASP were significantly preserved in group P-PDS than in group L-PDS (P < 0.05) although they were improved in group L-PDS in comparison with other two HS groups (P < 0.05 or P < 0.01). Expressions of barrier proteins by Western blotting in group P-PDS were reversed to normal. The score of intestinal epithelial damage index was reduced in group L-PDS, compared with other two HS groups (P < 0.05), however, it was significantly lower in group P-PDS than in group L-PDS (P < 0.05). CONCLUSIONS: Pyruvate was superior to lactate in PDS in the correction of severe acidosis with PR. P-PDS was more preservative of expressions of intestinal ZO-1 and p-VASP and mucosal barrier function, compared with L-PDS in PR from severe HS in rats.

N-cadherin is a novel ERα anchor that protects against 6-OHDA damage to dopaminergic cells.

Parkinson's disease is a neurodegenerative disorder caused by the selective loss of dopaminergic (DA) neurons. In this study, we investigated the protective roles of glial cell line-derived neurotrophic factor (GDNF) and 17ß-estradiol (E2) in the neuron cell line MN9D following treatment with 6-hydroxydopamine. This result showed that phosphorylation of protein kinase B (Akt) was significantly increased in treated MN9D cells following co-application of GDNF and E2 compared with only GDNF or E2. Moreover, GDNF enhanced the E2-induced translocation of estrogen receptor α (ERα) from the cytosol to the membrane. Immunoprecipitation experiments showed that the translocated ERα interacted with neural cadherin (N-cadherin) in the membrane. Site-directed mutagenesis of Tyr860 (Y860) in N-cadherin inhibited its interaction with ERα. Combined with the fact that GDNF can stimulate N-cadherin Y860 phosphorylation, we hypothesize that N-cadherin is a novel anchor for ERα, and phosphorylation at Y860 further increases ER's capacity to activate the neuroprotective phosphatidyl inositol-3 kinase/Akt pathway. This study provides evidence that co-application of GDNF and E2 exert important protective effects on DA neurons by increasing the interaction between ERα and N-cadherin.

Simple and rapid detection of Salmonella by direct PCR amplification of gene fimW.

This study established a simple method of specifically detecting Salmonella species by amplifying fimW gene, which was involved in regulating Salmonella type I fimbriae expression. A pair of primers was designed to target and discriminate the 68 Salmonella strains of 23 Salmonella serovars available to us from 12 non-Salmonella strains of five different kinds of bacteria by polymerase chain reaction (PCR) amplification. Results showed that specific DNA fragment with an expected size of 477 bp was successfully amplified from all Salmonella serovars, while no target band was detected in non-Salmonella species. The sensitivity of this PCR-amplifying system reached to 1 pg DNA chromosome and 10(2) cfu of Salmonella enteritis strain CMCC(B) 50336. The above results demonstrated the method as a simple, sensitive, and specific way for Salmonella detection.

Exploring the role of myeloperoxidase in the atherosclerotic process in hypoxic mice based on the MAPK signaling pathway.

Atherosclerosis (AS) is the common pathophysiological basis of various cardiovascular diseases and the leading cause of death from cardiovascular disease worldwide. When the body is in a hypoxic environment, enhanced oxidative stress and significant accumulation of reactive oxygen species (ROS) in tissue cells exacerbate the inflammatory response, resulting in increased release of myeloperoxidase (MPO), catalyzing the formation of large quantities of hypochlorous acid (HOCl), further oxidative modification of low-density lipoprotein (LDL), and exacerbating the formation and progression of atherosclerotic plaques. The MAPK signaling pathway is important in oxidative stress-mediated promotion of atherogenesis. MPO -/- mice were used in this study to establish a hypoxia model simulating 5000 m altitude and a Western high-fat diet-induced atherosclerosis model for 12 weeks. Exploring the role of MPO in the atherosclerotic process in hypoxic mice by observing the MAPK signaling pathway to provide a therapeutic target for the prevention and treatment of hypoxic atherosclerotic disease in the plateau. We found that hypoxia promotes the formation of atherosclerosis in mice, and the mechanism may be that increased MPO in vivo promotes an inflammatory response, which plays a crucial role in the formation of atherosclerosis. In addition, hypoxia further exacerbates plaque instability by activating the MAPK signaling pathway to upregulate vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP9), which in turn promotes angiogenesis within the plaque. Therefore, a potential target for preventing and treating hypoxic atherosclerotic disease is the inhibition of MPO.

Staphylococcus aureus promotes its intracellular survival by inhibiting Rab11-Rab11FIP4-mediated vesicle trafficking.

Mastitis in dairy cows is mainly caused by bacteria, in which Staphylococcus aureus appears frequently. Epithelial cells, as a major physical barrier of mammary gland, play an important role in preventing mastitis in dairy cows. Our previous study reported that Rab11fip4 (an effector of Rab11) was significantly changed in response to stimulation by S. aureus. So, in this study, the role of Rab11A in phagocytosis of bovine mammary epithelial cells (MAC-T) against S. aureus was evaluated. First, changes of Rab11A and Rab11fip4 were analyzed in response to S. aureus by immunofluorescence and western blotting. Subsequently, the effects of Rab11A and Rab11fip4 on proliferation of S. aureus, as well as formation and function of late endosomes (LEs) and lysosomes (LYSs) were investigated. The results showed that, after infection, Rab11A and Rab11fip4 were recruited to phagosomes containing S. aureus. Rab11A promoted bacterial clearance and rescues the destruction of LEs and LYSs by S. aureus, whereas Rab11fip4 did the opposite. These findings provide new insights into phagocytosis and control of S. aureus in host cells, thus lay the foundation to elucidate the pathogenesis of S. aureus in bovine mastitis.

Research on Bacterial Diversity and Antibiotic Resistance in the Dairy Farm Environment in a Part of Shandong Province.

Antimicrobials are extensively utilized in dairy farms to prevent and control diseases in cattle. However, their use contributes to the emergence of antimicrobial-resistant bacteria (ARB) and antimicrobial-resistant genes (ARG), and these can be transmitted to the environment. Regular monitoring of antimicrobial resistance (AMR) is crucial for implementing effective mitigation strategies. This research aimed to assess the environmental microbial species present on dairy farms in Shandong Province and characterize the antimicrobial resistance profiles of the isolates. Five dairy farms located in Shandong Province were selected, representing the prevalent large-scale farming patterns in the area. Sampling took place from April to June 2022, with a total of 223 isolates collected from various environmental locations within each farm (bedding, sports field, and milking parlor). Matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) was employed to identify the species of the clinical isolates. The main pathogens isolated were Aerococcus viridans (5.38%, n = 12), Corynebacterium xerosis (4.93%, n = 11), and Acinetobacter lwoffii (4.03%, n = 9). Among the bacterial isolates, resistance to lincomycin was highest at 91%, and 88% were resistant to sulfadiazine. Antimicrobial resistance genes were detected in only a small proportion of the isolates, the most common of which was sul1. These findings highlight the necessity for careful evaluation of antimicrobial usage in maintaining their effectiveness in human medicine. Understanding the microbial species present and their antimicrobial resistance profiles aids in focusing efforts toward sustainable antimicrobial use and safeguarding human health.

Hepatocyte nuclear factor 1B deletion, but not intragenic mutation, might be more susceptible to hypomagnesemia.

AIMS: HNF1B syndrome is caused by defects in the hepatocyte nuclear factor 1B (HNF1B) gene, which leads to maturity-onset diabetes of the young type 5 and congenital organ malformations. This study aimed to identify a gene defect in a patient presenting with diabetes and severe diarrhea, while also analyzing the prevalence of hypomagnesemia and its correlation with the HNF1B genotype. MATERIALS AND METHODS: Whole exome sequencing was used to identify responsible point mutations and small indels in the proband and their family members. Multiplex ligation-dependent probe amplification was carried out to identify HNF1B deletions. Furthermore, an analysis of published data on 539 cumulative HNF1B cases, from 29 literature sources, was carried out to determine the correlation between the HNF1B genotype and the phenotype of serum magnesium status. RESULTS: Using multiplex ligation-dependent probe amplification, we identified a de novo heterozygous HNF1B deletion in the patient, who showed dorsal pancreas agenesis and multiple kidney cysts, as detected by magnetic resonance imaging. Magnesium supplementation effectively alleviated the symptoms of diarrhea. Hypomagnesemia was highly prevalent in 192 out of 354 (54.2%) patients with HNF1B syndrome. Compared with patients with intragenic mutations, those with HNF1B deletions were more likely to suffer from hypomagnesemia, with an odds ratio of 3.1 (95% confidence interval 1.8-5.4). CONCLUSIONS: Hypomagnesemia is highly prevalent in individuals with HNF1B syndrome, and those with HNF1B deletion are more susceptible to developing hypomagnesemia compared with those with intragenic mutations. The genotype-phenotype associations in HNF1B syndrome have significant implications for endocrinologists in terms of genotype detection, treatment decisions and prognosis assessment.

Cr(VI) induces ferroptosis in DF-1 cells by simultaneously perturbing iron homeostasis of ferritinophagy and mitophagy.

Hexavalent chromium [Cr(VI)] is an environmental pollutant known for its strong oxidizing and carcinogenic effects. However, its potential to induce ferroptosis in poultry remains poorly understood. This study aims to investigate the induction of ferroptosis by Cr(VI) in DF-1 cells and elucidate the underlying mechanisms. DF-1 cells exposed to Cr(VI) showed increased lipid reactive oxygen species and changes in ferroptosis marker genes (decreased expression of GPX4 and increased expression of COX2). Notably, the addition of the ferroptosis-specific inhibitor ferrostatin-1 (Fer-1) can reverse this effect. During the cell death process, Cr(VI) induced ferritinophagy, disrupting iron homeostasis and releasing labile iron ions. We predicted by docking that these iron ions would bind to mitochondrial membrane proteins through virtual docking. This binding was validated through colocalization analysis. In addition, Cr(VI) caused mitophagy, which releases additional ferrous ions. Therefore, Cr(VI) can induce the simultaneous release of ferrous ions through these pathways, thereby exacerbating lipid peroxidation and ultimately triggering ferroptosis in DF-1 cells. This study demonstrates that Cr(VI) can induce ferroptosis in DF-1 cells by disrupting intracellular iron homeostasis and providing valuable insights into the toxic effects of Cr(VI) in poultry and potentially other organisms.

Hypoxia Attenuates Colonic Innate Immune Response and Inhibits TLR4/NF-κB Signaling Pathway in Lipopolysaccharide-Induced Colonic Epithelial Injury Mice.

High altitude hypoxia can lead to a spectrum of gastrointestinal problems. As the first line of host immune defense, innate immune response in the intestinal mucosa plays a pivotal role in maintaining intestinal homeostasis and protecting against intestinal injury at high altitude. This study aimed to investigate the effect of hypoxia on the colonic mucosal barrier and toll-like receptor 4 (TLR4)-mediated innate immune responses in the colon. The mice were exposed to a hypobaric chamber to simulate a 5,000 m plateau environment for 7 days, and the colonic mucosa changes were recorded. At the same time, the inflammation model was established by lipopolysaccharide (LPS) to explore the effects of hypoxia on the TLR4/nuclear factor kappa B (NF-κB) signaling pathway and its downstream inflammatory factors [tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and interferon (IFN)-γ] in the colon. We found that hypoxic exposure caused weight loss and structural disturbance of the colonic mucosa in mice. Compared with the control group, the protein levels of TLR4 [fold change (FC) = 0.75 versus FC = 0.23], MyD88 (FC = 0.80 versus FC = 0.30), TIR-domain-containing adaptor protein inducing interferon-ß (TRIF: FC = 0.89 versus FC = 0.38), and NF-κB p65 (FC = 0.75 versus FC = 0.24) in the colon of mice in the hypobaric hypoxia group were significantly decreased. LPS-induced upregulation of the TLR4/NF-κB signaling and its downstream inflammatory factors was inhibited by hypoxia. Specifically, compared with the LPS group, the protein levels of TLR4 (FC = 1.18, FC = 0.86), MyD88 (FC = 1.20, FC = 0.80), TRIF (FC = 1.20, FC = 0.86), and NF-κB p65 (FC = 1.29, FC = 0.62) and the mRNA levels of IL-1ß (FC = 7.38, FC = 5.06), IL-6 (FC = 16.06, FC = 9.22), and IFN-γ (FC = 2.01, FC = 1.16) were reduced in the hypobaric hypoxia plus LPS group. Our findings imply that hypoxia could lead to marked damage of the colonic mucosa and a reduction of TLR4-mediated colonic innate immune responses, potentially reducing host defense responses to colonic pathogens.

Hypoxia exacerbates intestinal injury and inflammatory response mediated by myeloperoxidase during Salmonella Typhimurium infection in mice.

BACKGROUND: High-altitude exposure can cause oxidative stress damage in the intestine, which leads to increased intestinal permeability and bacterial translocation, resulting in local and systemic inflammation. Control of infection is critically dependent on the host's ability to kill pathogens with reactive oxygen species (ROS). Myeloperoxidase (MPO) targets ROS in pathogens. This study aimed to investigate the effects of hypoxia on the colonic mucosal barrier and myeloperoxidase (MPO)-mediated innate immune response in the colon. METHODS AND RESULTS: Genetically engineered mice were exposed to a hypobaric oxygen chamber for 3 days and an inflammation model was established using Salmonella Typhimurium infection. We found that hypoxic exposure caused the development of exacerbated bacterial colitis and enhanced bacterial dissemination in MPO-deficient mice. Infection and disease severity were associated with significantly increased Ly6G+ neutrophil and F4/80+ macrophage counts in infected tissues, which is consistent with elevated proinflammatory cytokines and chemoattractant molecules. Hypoxia restrained antioxidant ability and MPO deficiency aggravated the respiratory burst in the colon. CONCLUSION: Hypoxia can damage the colonic mucosa. MPO mediates the innate immune response and regulates the mucosal and systemic inflammatory responses to Salmonella infection during hypoxia.

Staphylococcus aureus extracellular vesicles induce apoptosis and restrain mitophagy-mediated degradation of damaged mitochondria.

Extracellular vesicles (EVs) are nano-sized bilayer EVs with various components. EV secretion in pathogenic Gram-positive bacteria is a universal feature that can cause disease and damage the targeted host. In this study, we isolated and purified Staphylococcus aureus (S. aureus) EVs, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyzed Ev's protein composition. After that, the pathway of EVs internalized into MAC-T cells was evaluated. Moreover, the activation of mitogen-activated protein kinase (MAPK) and the nuclear factor κB (NF-κB) pathway was measured by Western blot. Meanwhile, Western blot and confocal microscopy detected mitochondrial damage, apoptosis, and Parkin-mediated mitophagy. Results showed that purified S. aureus EVs exhibited a typical cup-shaped structure and internalized into MAC-T cells by lipid raft-mediated endocytic pathway. S. aureus EVs caused mitochondrial damage and apoptosis in MAC-T cells. However, degradation of the damaged mitochondria was impeded due to the Parkin-mediated mitophagy pathway being restrained by the disruption of the acidic environment of lysosomes by S. aureus EVs. Hence, our study reveals the role of S. aureus EVs in immune stimulation, disruption of mitochondria, and lysosomal acidic environment in bovine mammary epithelial cells. These findings help us understand the role of EVs in the pathogenic mechanism of S. aureus.