Targeting leucine-rich repeat serine/threonine-protein kinase 2 sensitizes pancreatic ductal adenocarcinoma to anti-PD-L1 immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is not sensitive to immune checkpoint blockade therapy, and negative feedback of tumor immune evasion might be partly responsible. We isolated CD8+ T cells and cultured them in vitro. Proteomics analysis was performed to compare changes in Panc02 cell lines cultured with conditioned medium, and leucine-rich repeat kinase 2 (LRRK2) was identified as a differential gene. LRRK2 expression was related to CD8+ T cell spatial distribution in PDAC clinical samples and upregulated by CD8+ T cells via interferon gamma (IFN-γ) simulation in vitro. Knockdown or pharmacological inhibition of LRRK2 activated an anti-pancreatic cancer immune response in mice, which meant that LRRK2 acted as an immunosuppressive gene. Mechanistically, LRRK2 phosphorylated PD-L1 at T210 to inhibit its ubiquitination-mediated proteasomal degradation. LRRK2 inhibition attenuated PD-1/PD-L1 blockade-mediated, T cell-induced upregulation of LRRK2/PD-L1, thus sensitizing the mice to anti-PD-L1 therapy. In addition, adenosylcobalamin, the activated form of vitamin B12, which was found to be a broad-spectrum inhibitor of LRRK2, could inhibit LRRK2 in vivo and sensitize PDAC to immunotherapy as well, which potentially endows LRRK2 inhibition with clinical translational value. Therefore, PD-L1 blockade combined with LRRK2 inhibition could be a novel therapy strategy for PDAC.

Percutaneous Ultrasound-Guided Medication Injection, a Potential Technique for Subglottic Stenosis.

INTRODUCTION: Subglottic stenosis, manifested by granulation tissue hyperplasia, is challenging and requires multiple repeated treatments and stent maintenance at times. Corticosteroids prevent severe subglottic stenosis development owing to their antifibrotic and antiinflammatory properties. Submucosal injection of glucocorticoids or mitomycin, a useful adjuvant therapeutic method, improves the mean interval between endoscopic procedures and reduces airway restenosis risks. CASE PRESENTATION: We report a rare case of a man with complex subglottic stenosis who underwent balloon dilatation combined with cryotherapy, stent placement, and adjuvant submucosal triamcinolone injection. The drug was injected efficiently and safely into the submucosal layer under percutaneous ultrasound guidance, and subglottic stenosis was well-controlled at a low cost. CONCLUSION: POCUS-guided medication injections may be a useful adjuvant medical therapy for subglottic stenosis.

Cetrimonium bromide promotes the clearance of lipids by activating the TFEB-mediated autophagosome-lysosome pathway in hepatic cells.

Autophagy plays a key role in the metabolism of macromolecules via the degradative abilities of the lysosome. Transcription factor EB (TFEB) regulates autophagosome biogenesis and lysosome function, and promoting TFEB activity has emerged as a potential strategy for the treatment of metabolic disorders. Herein, we report that cetrimonium bromide (CTAB; a quaternary ammonium compound) promotes autophagy and lysosomal biogenesis by inducing the nuclear translocation of TFEB in hepatic cells. Knockdown of TFEB mediated by short hairpin RNA inhibits CTAB-induced autophagy and lysosomal biogenesis. Mechanistically, CTAB treatment inhibits the Akt-mTORC1 signaling pathway. Moreover, CTAB treatment significantly increases lipid metabolism in both palmitate- and oleate-treated HepG2 cells, and this increase was attenuated by knockdown of TFEB. Collectively, our results indicate that CTAB activates the autophagosome-lysosome pathway via inducing the nuclear translocation of TFEB by inhibiting the mTORC1 signaling pathway. These results add to the collective understanding of TFEB function and provide new insights into CTAB-mediated lipid metabolism.

Outer membrane protein A inhibits the degradation of caspase-1 to regulate NLRP3 inflammasome activation and exacerbate the Acinetobacter baumannii pulmonary inflammation.

Acinetobacter baumannii (A. baumannii), one of the major pathogens that causes severe nosocomial infections, is characterised by a high prevalence of drug resistance. It has been reported that A. baumannii triggers the NOD-like receptor 3 (NLRP3) inflammasome, but the role of its virulence-related outer membrane protein A (ompA) remains unclear. Therefore, this study aimed to explore the effects of ompA on the NLRP3 inflammasome and its underlying molecular mechanisms. Results showed that ompA enhanced inflammatory damage, which was reduced as a result of knockout of the ompA gene. Additionally, ompA-stimulated expression of NLRP3 inflammasome was significantly blocked by silencing caspase-1, but activation of NLRP3 inflammasome was not altered after silencing ASC; this indicated that ompA was dependent on the caspase-1 pathway to activate the inflammatory response. Simultaneously, the wild-type (WT) strains triggered NLRP3 inflammasome after inhibition of caspase-1 degradation by proteasome inhibitor MG-132, aggravating tissue damage. These findings indicated that ompA may be dependent on the caspase-1 pathway to enhance inflammation and exacerbate tissue damage. Taken together, these results confirmed a novel capsase-1-modulated mechanism underpinning ompA activity, which further reveals the NLRP3 inflammasome pathway as a potential immunomodulatory target against A. baumannii infections.

Quercetin inhibiting the PD-1/PD-L1 interaction for immune-enhancing cancer chemopreventive agent.

Targeting the PD-1/PD-L1 immune checkpoints has achieved significant positive results in the treatment of multiple cancers. Quercetin is one of the most abundant dietary flavonoids found in various vegetables and fruits, and has a wide range of biological activities including immunomodulation. Here we report that quercetin dihydrate was screened and shown to inhibit the PD-1/PD-L1 interaction. Treatment with quercetin dihydrate promoted the killing activity of T cells on MDA-MB-231 and NCI-H460 cancer cells. Experiments using the xenograft mouse model showed that the growth rate of tumor volumes and masses in the quercetin dihydrate-treated mice were decreased. Immunohistochemistry of the tumors showed that CD8, GZMB, and IFN-γ were increased in the quercetin dihydrate-treated mice. These results suggest that quercetin dihydrate attenuates the inhibitory effect of PD-L1 on T cells by inhibiting the PD-1/PD-L1 interaction, which has an exciting potential to be used as a cancer chemopreventive agent.

Chemical Composition, Antioxidant, and Antimicrobial Activities of Vetiveria zizanioides (L.) Nash Essential Oil Extracted by Carbon Dioxide Expanded Ethanol.

In the present study, the composition of essential oil isolated from the roots of Vetiveria zizanioides (L.) Nash, harvested in China, was studied, along with the bioactivities. A green novel method using an eco-friendly solvent, CO2-pressurized ethanol, or carbon dioxide expanded ethanol (CXE) was employed to isolate the essential oil from the root of Vetiveria zizanioides (L.) Nash with the purpose of replacing the traditional method and supercritical fluid extraction (SFE). After investigating the major operating factors of CXE, the optimal conditions were obtained as follows: 8.4 MPa, 50 °C, 5 mL/min ethanol, and 0.22 mole fraction of CO2, presenting an extraction oil that ranged from 5.12% to 7.42%, higher than that of hydrodistillation (HD) or indirect vapor distillation (IVD). The Gas Chromatography-Mass Spectrometry (GC-MS) analysis showed that three major components, including valerenol (18.48%), valerenal (10.21%), and ß-Cadinene (6.23%), are found in CXE oil, while a total of 23 components were identified, 48 components less than using conventional hydrodistillation. Furthermore, the antimicrobial activities of root oils were evaluated by the microdilution method, which showed that CXE oil exhibited an ability against Gram-positive bacteria, especially Staphylococcus aureus, approximately equivalent to traditional samples. Additionally, the DPPH free radical scavenging assay demonstrated that the antioxidant abilities of root oils were sorted in the descending order: IVD > HD > CXE > SFE. In conclusion, after a comprehensive comparison with the conventional methods, the CXE-related technique might be a promising green manufacturing pattern for the production of quality vetiver oil, due to the modification of ethanol by the variable addition of non-polar compressible CO2, ultimately resulting in a prominent dissolving capability for the extraction of vetiver solutes.

Development of competitive ELISA for the detection of bovine serum albumin using single-chain variable fragments.

Soluble anti-bovine serum albumin (BSA) single-chain variable fragments (scFvs) were expressed in E. Coli. HB2151. The antigen-binding equilibrium dissociation constant of the scFvs was determined to be 2.9 × 10-8 M by surface plasmon resonance analysis. A competitive ELISA for the detection of BSA was developed using the antibody fragment above. The limits of detection (I10) and I50 were 0.002 and 0.74 µg/ml respectively, with a recovery between 87.8 and 119.2% in spiked milk samples. The assay has the potential to be used to detect concentration of BSA in milk or other matrix instead of the ELISA based on traditional antibodies.

Assessment of a randomized controlled trial on the safety of pre-placing bronchial balloons in transbronchial lung cryobiopsy for diagnosing interstitial lung disease.

RATIONALE AND OBJECTIVES: Bleeding is a major complication of transbronchial lung cryobiopsy (TBLC), and pre-placing a bronchial balloon is one of the clinical practices used to prevent it, but with very weak evidence, which should be confirmed. This study aimed to conduct whether pre-placing a bronchial balloon in TBLC for diagnosing interstitial lung disease (ILD) is more safety. MATERIALS AND METHODS: In this prospective, single-center, randomized controlled trial, patients with suspected ILD were enrolled and randomly assigned to pre-placed balloon and none-pre-placed balloon groups. The primary outcome was incidence of moderate bleeding in each group. The secondary endpoints were the incidence of severe bleeding, pneumothorax, and other procedural complications. RESULTS: Exactly 250 patients were enrolled between August 2019 and March 2022, with 125 in each group. There were no significant differences in severe bleeding between the none-pre-placed balloon group and pre-placed balloon group (1.6% vs. 0.8%; adjusted p = 0.520), while more moderate bleeding occurred in the none-pre-placed balloon group (26.4% vs. 6.4%, adjusted p = 0.001), as well as more use of hemostatic drug (28.0% vs. 6.4%, adjusted p = 0.001). Three patients in the none-pre-placed balloon group used the bronchial balloon. More samples could be acquired in the pre-placed balloon group than in the none-pre-placed balloon group (3.8 ± 0.9 vs. 3.1 ± 0.9, p < 0.001). There were no significant differences in multidisciplinary discussion (MDD) between the two groups (89.6% vs. 91.2%, adjusted p = 0.182). CONCLUSION: A pre-placed bronchial balloon can reduce the incidence of moderate bleeding and increase the confidence of the bronchoscopists. However, it had no effect on increasing the diagnostic rate of MDD and reducing severe bleeding. REGISTRATION NUMBER: NCT04047667 ( www. CLINICALTRIALS: gov identifier).

Severe Pediatric Neurological Manifestations With SARS-CoV-2 or MIS-C Hospitalization and New Morbidity.

Importance: Neurological manifestations during acute SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity. Objective: To assess the association of severe neurological manifestations during a SARS-CoV-2-related hospital admission with new neurocognitive or functional morbidities at discharge. Design, Setting, and Participants: This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021. Exposure: Severe neurological manifestations, which included acute encephalopathy, seizures or status epilepticus, meningitis or encephalitis, sympathetic storming or dysautonomia, cardiac arrest, coma, delirium, and stroke. Main Outcomes and Measures: The primary outcome was new neurocognitive (based on the Pediatric Cerebral Performance Category scale) and/or functional (based on the Functional Status Scale) morbidity at hospital discharge. Multivariable logistic regression analyses were performed to examine the association of severe neurological manifestations with new morbidity in each SARS-CoV-2-related condition. Results: Overall, 3568 patients younger than 18 years (median age, 8 years [IQR, 1-14 years]; 54.3% male) were included in this study. Most (2980 [83.5%]) had acute SARS-CoV-2; the remainder (588 [16.5%]) had MIS-C. Among the patients with acute SARS-CoV-2, 536 (18.0%) had a severe neurological manifestation during hospitalization, as did 146 patients with MIS-C (24.8%). Among survivors with acute SARS-CoV-2, those with severe neurological manifestations were more likely to have new neurocognitive or functional morbidity at hospital discharge compared with those without severe neurological manifestations (27.7% [n = 142] vs 14.6% [n = 356]; P < .001). For survivors with MIS-C, 28.0% (n = 39) with severe neurological manifestations had new neurocognitive and/or functional morbidity at hospital discharge compared with 15.5% (n = 68) of those without severe neurological manifestations (P = .002). When adjusting for risk factors in those with severe neurological manifestations, both patients with acute SARS-CoV-2 (odds ratio, 1.85 [95% CI, 1.27-2.70]; P = .001) and those with MIS-C (odds ratio, 2.18 [95% CI, 1.22-3.89]; P = .009) had higher odds of having new neurocognitive and/or functional morbidity at hospital discharge. Conclusions and Relevance: The results of this study suggest that children and adolescents with acute SARS-CoV-2 or MIS-C and severe neurological manifestations may be at high risk for long-term impairment and may benefit from screening and early intervention to assist recovery.

Unveiling the treatment-driven secondary risks of pharmaceuticals: New lessons from calcium channel blocker transformation by multiple oxidants.

The worldwide detection of numerous pharmaceuticals and their transformation products (TPs) in different environmental matrices has gained considerable concern about their potential ecological hazards. Increasing evidence suggested that calcium channel blockers (CCBs) are ubiquitous pharmaceutical pollutants in natural waters. However, their TPs, reaction pathways, and secondary risks have been limitedly known during oxidative water treatment. This study systematically assessed the TP formation and transformation mechanisms of two typical CCBs (i.e., amlodipine, AML; verapamil, VER) oxidized by ferrate(VI), permanganate, and ozone, as well as the in silico prediction on the TPs' properties. The high-resolution mass spectrometer analysis suggested a total of 16 TPs of AML and 8 TPs of VER identified for these reaction systems. Transformation of AML mainly proceeded through hydroxylation of the aromatic ring, ether bond cleavage, NH2 substitution by a hydroxyl group, and H-abstraction, while VER was oxidized via hydroxylation/opening of the aromatic ring and cleavage of the CN bond. Notably, certain TPs of both CCBs were estimated with low biodegradation, multi-endpoint toxicity, and high persistence and bioaccumulation, suggesting their severe risks to aquatic ecosystems. This study has implications for understanding the environmental behaviors, fate, and secondary risks of the globally prevalent and concerned CCBs under oxidative water treatment scenarios.

Clinical Characteristics and Genotyping of Pediatric Adenovirus Pneumonia Disease and Coinfection in Southeast China.

Introduction: Human adenovirus (HAdV) is a common pathogen that can cause acute respiratory infections (ARIs) in children. Adenovirus pneumonia is the most severe respiratory disease associated with HAdV. Objective: We aimed to investigate the clinical characteristics of children hospitalized with adenovirus pneumonia in Quanzhou, China, in 2019. We also sought to determine the viral genotype in these cases and explore cases associated with severe adenovirus pneumonia. Methods: We collected oropharyngeal swabs from 99 children who were hospitalized with pneumonia in Quanzhou Women and Children's Hospital, these samples were tested for the presence of HAdV. Genotyping of the viruses was performed by real-time polymerase chain reaction. Logistic regression analysis was employed to analyze risk factors related to severe adenovirus pneumonia. The epidemiological data were examined using the Statistical Package for Social Sciences software (SPSS). Results: Among the 99 patients in our study, the median age was 21 months. We observed a 4% mortality rate among those diagnosed with adenovirus pneumonia. Adenovirus pneumonia often presents as a coinfection. Lactate dehydrogenase and neutrophil percentages of WBC's were significantly increased in patients with severe adenovirus pneumonia compared with mild HAdV disease. The predominant viral genotypes identified were type 3 and type 7. Conclusions: In the Quanzhou area of southeast China, the incidence of adenovirus pneumonia was found to be high among children younger than two years old. Type 7 HAdV was identified as the primary pathogen. A long duration of fever, dyspnea and digestive system complications were risk factors for severe adenovirus pneumonia after HAdV infection. Clinical Trial Registration number: ChiCTR2200062358.

Diagnosis based on electromagnetic navigational bronchoscopy-guided biopsied peripheral lung lesions in a 10-year-old girl: A case report.

BACKGROUND: Electromagnetic navigational bronchoscopy (ENB) is an emerging diagnostic tool that enables practitioners to biopsy peripheral lung tissues that were previously only accessible under computed tomography (CT) guidance. However, few studies have investigated ENB use in children. Here, we report a case of a 10-year-old girl with peripheral lung lesions who complained of a 7-d persistent fever. She was diagnosed with Streptococcus parasanguinis infection based on findings obtained using ENB-guided transbronchial lung biopsy (TBLB). CASE SUMMARY: A 10-year-old girl presented with constitutional symptoms of cough and fever of 7 days' duration. Chest CT scans detected peripheral lung lesions and no endobronchial lesions. TBLB performed under the guidance of an ENB Lungpro navigation system was safe, well-tolerated, and effective for biopsying peripheral lung lesions. Examination of biopsied samples indicated the patient had a pulmonary Streptococcus parasanguinis infection, which was treated with antibiotics instead of more invasive treatment interventions. The patient's symptoms resolved after she received a 3-wk course of oral linezolid. Comparisons of pre-treatment and post-treatment CT scans revealed absorption of some lung lesions within 7 mo of hospital discharge. CONCLUSION: ENB-guided TBLB biopsying of peripheral lung lesions in this child is a safe, well-tolerated, and effective alternative to conventional interventions.

Prevalence and Risk Factors of Neurologic Manifestations in Hospitalized Children Diagnosed with Acute SARS-CoV-2 or MIS-C.

BACKGROUND: Our objective was to characterize the frequency, early impact, and risk factors for neurological manifestations in hospitalized children with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or multisystem inflammatory syndrome in children (MIS-C). METHODS: Multicenter, cross-sectional study of neurological manifestations in children aged <18 years hospitalized with positive SARS-CoV-2 test or clinical diagnosis of a SARS-CoV-2-related condition between January 2020 and April 2021. Multivariable logistic regression to identify risk factors for neurological manifestations was performed. RESULTS: Of 1493 children, 1278 (86%) were diagnosed with acute SARS-CoV-2 and 215 (14%) with MIS-C. Overall, 44% of the cohort (40% acute SARS-CoV-2 and 66% MIS-C) had at least one neurological manifestation. The most common neurological findings in children with acute SARS-CoV-2 and MIS-C diagnosis were headache (16% and 47%) and acute encephalopathy (15% and 22%), both P < 0.05. Children with neurological manifestations were more likely to require intensive care unit (ICU) care (51% vs 22%), P < 0.001. In multivariable logistic regression, children with neurological manifestations were older (odds ratio [OR] 1.1 and 95% confidence interval [CI] 1.07 to 1.13) and more likely to have MIS-C versus acute SARS-CoV-2 (OR 2.16, 95% CI 1.45 to 3.24), pre-existing neurological and metabolic conditions (OR 3.48, 95% CI 2.37 to 5.15; and OR 1.65, 95% CI 1.04 to 2.66, respectively), and pharyngeal (OR 1.74, 95% CI 1.16 to 2.64) or abdominal pain (OR 1.43, 95% CI 1.03 to 2.00); all P < 0.05. CONCLUSIONS: In this multicenter study, 44% of children hospitalized with SARS-CoV-2-related conditions experienced neurological manifestations, which were associated with ICU admission and pre-existing neurological condition. Posthospital assessment for, and support of, functional impairment and neuroprotective strategies are vitally needed.

5-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-3,7-dimethoxy-4H-chromen-4-one (MSF-2) suppresses fMLP-mediated respiratory burst in human neutrophils by inhibiting phosphatidylinositol 3-kinase activity.

Respiratory burst mediates crucial bactericidal mechanism in neutrophils. However, undesirable respiratory burst leads to pathological inflammation and tissue damage. This study investigates the effect and the underlying mechanism of 5-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-3,7-dimethoxy-4H-chromen-4-one (MSF-2), a lignan extracted from the fruit of Melicope Semecarprifolia, on fMLP-induced respiratory burst in human neutrophils and suggests a possible therapeutic approach to ameliorate disease associated with neutrophil hyperactivation. MSF-2 inhibited fMLP-induced neutrophil superoxide anion production, cathepsin G release and migration in human neutrophils isolated from healthy volunteers, reflecting inhibition of phosphatidylinositol 3-kinase (PI3K) activation. Specifically, PI3K/AKT activation results in migration, degranulation and superoxide anion production in neutrophils. MSF-2 suppresses PI3K activation and phosphatidylinositol (3,4,5)-trisphosphate (PIP3) production, and consequently inhibits downstream activation of PDK1 and AKT. Further, PI3K also stimulates respiratory burst via PLC-dependent elevation of intracellular calcium. MSF-2 reduces fMLP-mediated PLCγ2 activation and intracellular calcium accumulation notably through extracellular calcium influx in a PI3K and PLC-dependent manner. However, MSF-2 is not a competitive or allosteric antagonist of fMLP. Additionally, in an in vivo study, MSF-2 prevents fMLP-induced neutrophil infiltration and inflammation in mice. In conclusion, MSF-2 opposes fMLP-mediated neutrophil activation and inflammation by inhibiting PI3K activation and subsequent activation of AKT and PLCγ2.

The hormone receptor GUCY2C suppresses intestinal tumor formation by inhibiting AKT signaling.

BACKGROUND & AIMS: GUCY2C is the intestinal receptor for the paracrine hormones guanylin and uroguanylin that converts guanosine-5'-triphosphate to cyclic guanosine monophosphate (cGMP). It functions as a tumor suppressor; its loss disrupts intestinal homeostasis and promotes tumorigenesis. We investigated the effects of GUCY2C loss on intestinal cell proliferation, metabolism, signaling, and tumorigenesis in mice. METHODS: Intestinal cell proliferation and metabolism were examined in Gucy2c(-/-) and colon cancer cells by microscopy, immunoblot, and functional analyses. Microarray analyses compared gene expression profiles of intestine cell from Gucy2c(-/-) and wild-type mice. v akt murine thymoma viral oncogene homolog (AKT) regulation and signaling were examined, and the role of AKT in GUCY2C-dependent tumorigenesis was defined in Gucy2c(-/-)Akt1(-/-) mice. RESULTS: The size and number of intestinal crypts increased in Gucy2c(-/-) mice; the associated epithelial cells showed accelerated proliferation, increased glycolysis, and reduced oxidative phosphorylation, which was reversed by oral administration of cGMP. Conversely, activating guanylyl cyclase C in human colon cancer cells delayed cell-cycle progression, decreased DNA synthesis and colony formation, reduced glycolysis, and increased mitochondrial adenosine triphosphate production. AKT signaling pathways were activated in intestines of Gucy2c(-/-) mice, associated with increased AKT phosphorylation. Disruption of AKT activity, pharmacologically or genetically, reduced DNA synthesis, proliferation, and glycolysis, and increased mitochondrial biogenesis. Intestinal tumorigenesis increased after administration of azoxymethane to Gucy2c(-/-) mice, compared with wild-type mice, but was eliminated in Gucy2c(-/-)Akt1(-/-) mice. CONCLUSIONS: GUCY2C is a tumor suppressor that controls proliferation and metabolism of intestinal epithelial cells by inactivating AKT signaling. This receptor and its ligands, which are paracrine hormones, might be novel candidates for anticolorectal cancer therapy.

Outer membrane protein a in Acinetobacter baumannii induces autophagy through mTOR signalling pathways in the lung of SD rats.

Outer membrane protein A (OmpA) of Acinetobacter baumannii (A. baumannii) is associated with autophagy, which plays an important role in its pathogenicity. However, its exact pathophysiological role in the process of lung tissue cell autophagy remains unclear. In this study, animal and cell infection models were established by wild A. baumannii strain and An OmpA knockout mutant (OmpA-/- A. baumannii) strain. The expression levels of markers autophagy, histological change, cell viability and protein expression levels of inflammatory cytokines were examined. OmpA-/-A. baumannii was successfully constructed. The capacities of bacterial adhesion and invasion to host cells increased more obviously in the AB group and the AB + Rapa group than in the OmpA-/- AB group and AB + CQ group. The AB group and AB + Rapa group could produce double membrane vacuoles, endoplasmic reticulum dilation, mitochondrial ridge rupture, and mitochondrial vacuoles. OmpA could lead to increased LC3, AMPK, and PAMPK protein release, and decreased levels of P62, mTOR and pmTOR proteins in vivo and in vitro. OmpA caused lung pathology and the release of inflammatory cytokines. A. baumannii OmpA promotes autophagy in lung cells through the mTOR signalling pathway, which increases the bacterial colonization ability in the double-layer membrane autophagosome formed by the autophagy reaction to escape the clearance of bacteria by the host, promote the release of inflammatory mediators and aggravate the damage to the host.

Intermittent Hypoxia Exposure Helps to Restore the Reduced Hemoglobin Concentration During Intense Exercise Training in Trained Swimmers.

In prolonged intense exercise training, the training load of athletes may be reduced once their hemoglobin concentrations ([Hb]s) are decreased dramatically. We previously reported that intermittent hypoxia exposure (IHE) could be used to alleviate the decrease of [Hb] and help to maintain the training load in rats. To further explore the feasibility of applying IHE intervention to athletes during prolonged intense exercise training, 6 trained swimmers were recruited to conduct a 4-week IHE intervention at the intervals after their [Hb] dropped for 10% or more during their training season. IHE intervention lasted 1 h and took place once a day and five times a week. Hematological and hormonal parameters, including [Hb], red blood cells (RBC), hematocrit (Hct), reticulocytes, serum erythropoietin (EPO), testosterone (T) and cortisol (C) were examined. After the IHE intervention was launched, [Hb], RBC and Hct of the subjects were increased progressively with their maximum levels (P < 0.01) showing at the third or fourth week, respectively. An increase in reticulocyte count (P < 0.01) suggests that IHE intervention promotes erythropoiesis to increase [Hb]. Besides, serum level of EPO, the hormone known to stimulate erythropoiesis, was overall higher than that before the IHE intervention, although it was statistically insignificant. Furthermore, the serum level of T, another hormone known to stimulate erythropoiesis, was increased progressively with the maximum level showing at the fourth week. Collectively, this study further confirms that IHE intervention may be used as a new strategy to prevent intense exercise training-induced reductions in [Hb].

Neurological issues in children with COVID-19.

Coronavirus disease 2019 (COVID-19) usually leads to a mild infectious disease course in children, but serious complications may occur in conjunction with both acute infection and associated phenomena such as the multisystem inflammatory syndrome in children (MIS-C). Neurological symptoms, which have been predominantly reported in adults, range from mild headache to seizure, peripheral neuropathy, stroke, demyelinating disorders, and encephalopathy. Similar to respiratory and cardiac manifestations of COVID-19, neurological complications present differently based on age and underlying comorbidities. This review provides a concise overview of the neurological conditions seen in the context of COVID-19, as well as potential mechanisms and long-term implications of COVID-19 in the pediatric population from literature reviews and primary data collected at NewYork-Presbyterian Morgan Stanley Children's Hospital.

Guanylyl cyclase C in colorectal cancer: susceptibility gene and potential therapeutic target.

Colorectal cancer is one of the leading causes of tumor-related morbidity and mortality worldwide. While mechanisms underlying this disease have been elucidated over the past two decades, these molecular insights have failed to translate into efficacious therapy. The oncogenomic view of cancer suggests that terminal transformation reflects the sequential corruption of signal transduction circuits regulating key homeostatic mechanisms, whose multiplicity underlies the therapeutic resistance of most tumors to interventions targeting individual pathways. Conversely, the paucity of mechanistic insights into proximal pathophysiological processes that initiate and amplify oncogenic circuits preceding accumulation of mutations and transformation impedes development of effective prevention and therapy. In that context, guanylyl cyclase C (GCC), the intestinal receptor for the paracrine hormones guanylin and uroguanylin, whose early loss characterizes colorectal transformation, has emerged as a component of lineage-specific homeostatic programs organizing spatiotemporal patterning along the crypt-surface axis. Dysregulation of GCC signaling, reflecting hormone loss, promotes tumorigenesis through reprogramming of replicative and bioenergetic circuits and genomic instability. Compensatory upregulation of GCC in response to hormone loss provides a unique translational opportunity for prevention and treatment of colorectal tumors by hormone-replacement therapy.