[Two kinds of percutaneous endoscopic lumbar decompression in the treatment of single level lumbar lateral recess stenosis].

OBJECTIVE: To prospectively compare the clinical efficacy and radiographic outcomes between interlaminar percutaneous endoscopic lumbar decompression(IL-PELD) and transforaminar percutaneous endoscopic lumbar decompression(TF-PELD) in the treatment of single-segment lumbar lateral recess stenosis. METHODS: From April 2018 to July 2021, 85 patients with single-segment lumbar lateral recess stenosis underment percutaneous endoscopic lumbar decompression.There were 44 males and 41 females, aged from 49 to 81 years old with an average of (65.5±8.3) years old, duration of lumbar lateral recess stenosis ranging from 3 to 83 months with an average of (26.7±16.5) months. They were divided into IL-PELD group and TF-PELD group according to the different operation methods. There were 47 patients in the IL-PELD group, including 28 males and 19 females aged from 50 to 80 yeaes old with an average age was (66.7±9.3) years old. The disease duration ranged from 3 to 65 months with an average of (25.7±15.0) months. There were 38 patients in the TF-PELD group, including 16 males and 22 females, aged from 51 to 78 years old with an average of(64.1±7.6) years old. The disease duration ranged from 4 to 73 months with an average of (27.9±18.3) months The operation time, intraoperative blood loss, intraoperative fluoroscopy, hospitalization day and complications of the two groups were recorded. Visual analogue scale (VAS) to evaluate low back pain and lower limb pain, Oswestry disability index(ODI) to evaluate lumbar function in preoperative and postoperative period(1month, 6 months and last follow-up)were recorded. the sagittal diameter of the lateral recess of the responsible intervertebral space in preoperative and 1 week after the operation were recorded. RESULTS: The operation was successfully completed in both groups without serious complications such as vascular injury, dural sac tear and nerve injury. The operation time in IL-PED group(69.3±19.3)min was significantly longer than that in TF-PELD group(57.5±14.5)min (P<0.05). There was no significant difference in the intraoperative blood loss between the two groups (P>0.05). The number of intraoperative fluoroscopy in TF-PELD group (8.8±2.6)times was significantly higher than that in IL-PED group(4.8±1.2)times (P<0.05). The hospitalization days of the two groups were not statistically significant (P>0.05). VAS for low back and lower extremity pain and ODI were (5.1±2.2), (6.9±1.3) scores and (71.4±12.6) % in IL-PELD group, and (4.7±1.8), (6.9±1.3) scores and (68.4±13.9)% in TF-PELD group. In the IL-PELD group, the VAS of low back pain was (2.4±1.5), (1.6±0.8), (1.4±0.9) scores, and the VAS of lower extremity pain was (3.0±1.2), (1.6±0.7), (1.5±1.0) scores, ODI was (32.6±11.9) %, (17.4±6.5) %, (19.3±9.3)%;In TF-PELD group, the VAS of low back pain was (2.6±1.4), (1.5±0.6), (1.4±1.0) scores, and the VAS of lower extremity pain was (2.8±1.2), (1.6±0.6), (1.5±1.2) scores, The ODI was (32.0±11.2) %, (15.0±6.1) %, and (20.0±11.3) %. The VAS and ODI of the two groups at each time point after operation were significantly improved compared with those before operation (P<0.05), but there was no statistically significant difference between the groups (P>0.05), and there was no statistically significant difference in the interaction between different time points and groups (P>0.05). At 1 week after operation, the sagittal diameter of lateral recess in both groups was significantly increased compared with that before operation (P<0.05), but there was no significant difference between the two groups at each time point (P>0.05). According to the modified Macnab criteria, IL-PELD group was rated as excellent in 24 cases, good in 19 cases and fair in 4 cases. In TF-PELD group the results were excellent in 19 cases, good in 15 cases, fair in 3 cases and poor in 1 case. There was no significant difference between the two groups (P>0.05). CONCLUSION: IL-PELD and TF-PELD can expand the lateral recess in the treatment of single level lumbar lateral recess stenosis, and have achieved good clinical effects.

Role of transient receptor potential ankyrin 1 in idiopathic pulmonary fibrosis: modulation of M2 macrophage polarization.

Idiopathic pulmonary fibrosis (IPF) poses significant challenges due to limited treatment options despite its complex pathogenesis involving cellular and molecular mechanisms. This study investigated the role of transient receptor potential ankyrin 1 (TRPA1) channels in regulating M2 macrophage polarization in IPF progression, potentially offering novel therapeutic targets. Using a bleomycin-induced pulmonary fibrosis model in C57BL/6J mice, we assessed the therapeutic potential of the TRPA1 inhibitor HC-030031. TRPA1 upregulation was observed in fibrotic lungs, correlating with worsened lung function and reduced survival. TRPA1 inhibition mitigated fibrosis severity, evidenced by decreased collagen deposition and restored lung tissue stiffness. Furthermore, TRPA1 blockade reversed aberrant M2 macrophage polarization induced by bleomycin, associated with reduced Smad2 phosphorylation in the TGF-ß1-Smad2 pathway. In vitro studies with THP-1 cells treated with bleomycin and HC-030031 corroborated these findings, highlighting TRPA1's involvement in fibrotic modulation and macrophage polarization control. Overall, targeting TRPA1 channels presents promising therapeutic potential in managing pulmonary fibrosis by reducing pro-fibrotic marker expression, inhibiting M2 macrophage polarization, and diminishing collagen deposition. This study sheds light on a novel avenue for therapeutic intervention in IPF, addressing a critical need in the management of this challenging disease.

Trends in the Prevalence of Common Retinal and Optic Nerve Diseases in China: An Artificial Intelligence Based National Screening.

Purpose: Retinal and optic nerve diseases have become the primary cause of irreversible vision loss and blindness. However, there is still a lack of thorough evaluation regarding their prevalence in China. Methods: This artificial intelligence-based national screening study applied a previously developed deep learning algorithm, named the Retinal Artificial Intelligence Diagnosis System (RAIDS). De-identified personal medical records from January 2019 to December 2021 were extracted from 65 examination centers in 19 provinces of China. Crude prevalence and age-sex-adjusted prevalence were calculated by mapping to the standard population in the seventh national census. Results: In 2021, adjusted referral possible glaucoma (63.29, 95% confidence interval [CI] = 57.12-68.90 cases per 1000), epiretinal macular membrane (21.84, 95% CI = 15.64-29.22), age-related macular degeneration (13.93, 95% CI = 11.09-17.17), and diabetic retinopathy (11.33, 95% CI = 8.89-13.77) ranked the highest among 10 diseases. Female participants had significantly higher adjusted prevalence of pathologic myopia, yet a lower adjusted prevalence of diabetic retinopathy, referral possible glaucoma, and hypertensive retinopathy than male participants. From 2019 to 2021, the adjusted prevalence of retinal vein occlusion (0.99, 95% CI = 0.73-1.26 to 1.88, 95% CI = 1.42-2.44), macular hole (0.59, 95% CI = 0.41-0.82 to 1.12, 95% CI = 0.76-1.51), and hypertensive retinopathy (0.53, 95% CI = 0.40-0.67 to 0.77, 95% CI = 0.60-0.95) significantly increased. The prevalence of diabetic retinopathy in participants under 50 years old significant increased. Conclusions: Retinal and optic nerve diseases are an important public health concern in China. Further well-conceived epidemiological studies are required to validate the observed increased prevalence of diabetic retinopathy, hypertensive retinopathy, retinal vein occlusion, and macular hole nationwide. Translational Relevance: This artificial intelligence system can be a potential tool to monitor the prevalence of major retinal and optic nerve diseases over a wide geographic area.

A Novel DNA Synthesis Platform Design with High-Throughput Paralleled Addressability and High-Density Static Droplet Confinement.

Using DNA as the next-generation medium for data storage offers unparalleled advantages in terms of data density, storage duration, and power consumption as compared to existing data storage technologies. To meet the high-speed data writing requirements in DNA data storage, this paper proposes a novel design for an ultra-high-density and high-throughput DNA synthesis platform. The presented design mainly leverages two functional modules: a dynamic random-access memory (DRAM)-like integrated circuit (IC) responsible for electrode addressing and voltage supply, and the static droplet array (SDA)-based microfluidic structure to eliminate any reaction species diffusion concern in electrochemical DNA synthesis. Through theoretical analysis and simulation studies, we validate the effective addressing of 10 million electrodes and stable, adjustable voltage supply by the integrated circuit. We also demonstrate a reaction unit size down to 3.16 × 3.16 µm2, equivalent to 10 million/cm2, that can rapidly and stably generate static droplets at each site, effectively constraining proton diffusion. Finally, we conducted a synthesis cycle experiment by incorporating fluorescent beacons on a microfabricated electrode array to examine the feasibility of our design.

A Novel Microfluidic Strategy for Efficient Exosome Separation via Thermally Oxidized Non-Uniform Deterministic Lateral Displacement (DLD) Arrays and Dielectrophoresis (DEP) Synergy.

Exosomes, with diameters ranging from 30 to 150 nm, are saucer-shaped extracellular vesicles (EVs) secreted by various type of human cells. They are present in virtually all bodily fluids. Owing to their abundant nucleic acid and protein content, exosomes have emerged as promising biomarkers for noninvasive molecular diagnostics. However, the need for exosome separation purification presents tremendous technical challenges due to their minuscule size. In recent years, microfluidic technology has garnered substantial interest as a promising alternative capable of excellent separation performance, reduced reagent consumption, and lower overall device and operation costs. In this context, we hereby propose a novel microfluidic strategy based on thermally oxidized deterministic lateral displacement (DLD) arrays with tapered shapes to enhance separation performance. We have achieved more than 90% purity in both polystyrene nanoparticle and exosome experiments. The use of thermal oxidation also significantly reduces fabrication complexity by avoiding the use of high-precision lithography. Furthermore, in a simulation model, we attempt to integrate the use of dielectrophoresis (DEP) to overcome the size-based nature of DLD and distinguish particles that are close in size but differ in biochemical compositions (e.g., lipoproteins, exomeres, retroviruses). We believe the proposed strategy heralds a versatile and innovative platform poised to enhance exosome analysis across a spectrum of biochemical applications.

Rapid identification of inflammatory arthritis and associated adverse events following immune checkpoint therapy: a machine learning approach.

Introduction: Immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) poses a major clinical challenge to ICI therapy for cancer, with 13% of cases halting ICI therapy and ICI-IA being difficult to identify for timely referral to a rheumatologist. The objective of this study was to rapidly identify ICI-IA patients in clinical data and assess associated immune-related adverse events (irAEs) and risk factors. Methods: We conducted a retrospective study of the electronic health records (EHRs) of 89 patients who developed ICI-IA out of 2451 cancer patients who received ICI therapy at Northwestern University between March 2011 to January 2021. Logistic regression and random forest machine learning models were trained on all EHR diagnoses, labs, medications, and procedures to identify ICI-IA patients and EHR codes indicating ICI-IA. Multivariate logistic regression was then used to test associations between ICI-IA and cancer type, ICI regimen, and comorbid irAEs. Results: Logistic regression and random forest models identified ICI-IA patients with accuracies of 0.79 and 0.80, respectively. Key EHR features from the random forest model included ICI-IA relevant features (joint pain, steroid prescription, rheumatoid factor tests) and features suggesting comorbid irAEs (thyroid function tests, pruritus, triamcinolone prescription). Compared to 871 adjudicated ICI patients who did not develop arthritis, ICI-IA patients had higher odds of developing cutaneous (odds ratio [OR]=2.66; 95% Confidence Interval [CI] 1.63-4.35), endocrine (OR=2.09; 95% CI 1.15-3.80), or gastrointestinal (OR=2.88; 95% CI 1.76-4.72) irAEs adjusting for demographics, cancer type, and ICI regimen. Melanoma (OR=1.99; 95% CI 1.08-3.65) and renal cell carcinoma (OR=2.03; 95% CI 1.06-3.84) patients were more likely to develop ICI-IA compared to lung cancer patients. Patients on nivolumab+ipilimumab were more likely to develop ICI-IA compared to patients on pembrolizumab (OR=1.86; 95% CI 1.01-3.43). Discussion: Our machine learning models rapidly identified patients with ICI-IA in EHR data and elucidated clinical features indicative of comorbid irAEs. Patients with ICI-IA were significantly more likely to also develop cutaneous, endocrine, and gastrointestinal irAEs during their clinical course compared to ICI therapy patients without ICI-IA.

Short- and Long-term survival prediction in patients with acute type A aortic dissection undergoing open surgery.

BACKGROUND: Acute Type A aortic dissection (ATAAD) is a life-threatening cardiovascular disease associated with high mortality rates, where surgical intervention remains the primary life-saving treatment. However, the mortality rate for ATAAD operations continues to be alarmingly high. To address this critical issue, our study aimed to assess the correlation between preoperative laboratory examination, clinical imaging data, and postoperative mortality in ATAAD patients. Additionally, we sought to establish a reliable prediction model for evaluating the risk of postoperative death. METHODS: In this study, a total of 384 patients with acute type A aortic dissection (ATAAD) who were admitted to the emergency department for surgical treatment were included. Based on preoperative laboratory examination and clinical imaging data of ATAAD patients, logistic analysis was used to obtain independent risk factors for postoperative in-hospital death. The survival prediction model was based on cox regression analysis and displayed as a nomogram. RESULTS: Logistic analysis identified several independent risk factors for postoperative in-hospital death, including Marfan syndrome, previous cardiac surgery history, previous renal dialysis history, direct bilirubin, serum phosphorus, D-dimer, white blood cell, multiple aortic ruptures and age. A survival prediction model based on cox regression analysis was established and presented as a nomogram. The model exhibited good discrimination and significantly improved the prediction of death risk in ATAAD patients. CONCLUSIONS: In this study, we developed a novel survival prediction model for acute type A aortic dissection based on preoperative clinical features. The model demonstrated good discriminatory power and improved accuracy in predicting the risk of death in ATAAD patients undergoing open surgery.

A mix & act liposomes of phospholipase A2-phosphatidylserine for acute brain detoxification by blood‒brain barrier selective-opening.

In the treatment of central nervous system disease, the blood-brain barrier (BBB) is a major obstruction to drug delivery that must be overcome. In this study, we propose a brain-targeted delivery strategy based on selective opening of the BBB. This strategy allows some simple bare nanoparticles to enter the brain when mixed with special opening material; however, the BBB still maintains the ability to completely block molecules from passing through. Based on the screening of BBB opening and matrix delivery materials, we determined that phospholipase A2-catalyzed 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine liposomes can efficiently carry drugs into the brain immediately. At an effective dose, this delivery system is safe, especially with its effect on the BBB being reversible. This mix & act delivery system has a simple structure and rapid preparation, making it a strong potential candidate for drug delivery across the BBB.

Trichoderma harzianum prevents red kidney bean root rot by increasing plant antioxidant enzyme activity and regulating the rhizosphere microbial community.

Root rot is one of the main reasons for yield losses of red kidney bean (Phaseolus vulgaris) production. Pre-inoculation with Trichoderma harzianum can effectively lower the incidence of red kidney bean root rot. In this study, four treatments including CK (control), Fu13 (Fusarium oxysporum), T891 (T. harzianum) and T891 + Fu13 (T. harzianum + F. oxysporum) were arranged in a pot experiment to investigate how T891 affected the incidence and severity of root rot, plant growth, and changes of defense enzyme activity in red kidney bean plants. Community composition and diversity of the rhizosphere microbiota was evaluated through high-throughput sequencing, and co-occurrence network was analyzed. The results showed that when compared to the Fu13 treatment, pre-inoculation with T891 reduced the incidence and severity of red kidney bean root rot by 40.62 and 68.03% (p < 0.05), increased the root length, shoot length, total dry biomass by 48.63, 97.72, 122.17%. Upregulated activity of super-oxide dismutase (SOD), peroxidase (POD), catalase (CAT) by 7.32, 38.48, 98.31% (p < 0.05), and reduced malondialdehyde (MDA) by 23.70% (p < 0.05), respectively. Microbiological analyses also showed that F. oxysporum reduced alpha diversity resulting in alteration the composition of the rhizosphere microbial community in red kidney bean. T891 significantly reduced abundance of F. oxysporum, allowing the enrichment of potentially beneficial bacteria Porphyrobacter (ASV 46), Lysobacter (ASV 85), Microbacteriaceae (ASV 105), and Gemmatimonas (ASV 107), resulting in a more stable structure of the microbial network. The results of random forest analysis further revealed that ASV 46 (Porphyrobacter) was the primary influencing factor for the incidence of root rot after inoculation with T891, while ASV 85 (Lysobacter) was the primary influencing factor for the biomass of red kidney bean. In conclusion, T. harzianum promotes the growth of red kidney bean and inhibits root rot by improving plant antioxidant enzyme activity and regulating the rhizosphere microbial community.

Detection of Personal and Family History of Suicidal Thoughts and Behaviors using Deep Learning and Natural Language Processing: A Multi-Site Study.

Objective: Personal and family history of suicidal thoughts and behaviors (PSH and FSH, respectively) are significant risk factors associated with future suicide events. These are often captured in narrative clinical notes in electronic health records (EHRs). Collaboratively, Weill Cornell Medicine (WCM), Northwestern Medicine (NM), and the University of Florida (UF) developed and validated deep learning (DL)-based natural language processing (NLP) tools to detect PSH and FSH from such notes. The tool's performance was further benchmarked against a method relying exclusively on ICD-9/10 diagnosis codes. Materials and Methods: We developed DL-based NLP tools utilizing pre-trained transformer models Bio_ClinicalBERT and GatorTron, and compared them with expert-informed, rule-based methods. The tools were initially developed and validated using manually annotated clinical notes at WCM. Their portability and performance were further evaluated using clinical notes at NM and UF. Results: The DL tools outperformed the rule-based NLP tool in identifying PSH and FHS. For detecting PSH, the rule-based system obtained an F1-score of 0.75 ± 0.07, while the Bio_ClinicalBERT and GatorTron DL tools scored 0.83 ± 0.09 and 0.84 ± 0.07, respectively. For detecting FSH, the rule-based NLP tool's F1-score was 0.69 ± 0.11, compared to 0.89 ± 0.10 for Bio_ClinicalBERT and 0.92 ± 0.07 for GatorTron. For the gold standard corpora across the three sites, only 2.2% (WCM), 9.3% (NM), and 7.8% (UF) of patients reported to have an ICD-9/10 diagnosis code for suicidal thoughts and behaviors prior to the clinical notes report date. The best performing GatorTron DL tool identified 93.0% (WCM), 80.4% (NM), and 89.0% (UF) of patients with documented PSH, and 85.0%(WCM), 89.5%(NM), and 100%(UF) of patients with documented FSH in their notes. Discussion: While PSH and FSH are significant risk factors for future suicide events, little effort has been made previously to identify individuals with these history. To address this, we developed a transformer based DL method and compared with conventional rule-based NLP approach. The varying effectiveness of the rule-based tools across sites suggests a need for improvement in its dictionary-based approach. In contrast, the performances of the DL tools were higher and comparable across sites. Furthermore, DL tools were fine-tuned using only small number of annotated notes at each site, underscores its greater adaptability to local documentation practices and lexical variations. Conclusion: Variations in local documentation practices across health care systems pose challenges to rule-based NLP tools. In contrast, the developed DL tools can effectively extract PSH and FSH information from unstructured clinical notes. These tools will provide clinicians with crucial information for assessing and treating patients at elevated risk for suicide who are rarely been diagnosed.

[Feasibility Analysis of Establishing Combat Readiness Blood Bank Based on Low Titer Group O Whole Blood and Group A Plasma].

OBJECTIVE: To explore the feasibility of establishing combat readiness blood bank with low titer group O whole blood and group A plasma. METHODS: The Galileo automatic blood analyzer was used to detect the titers of IgM anti-A and anti-B antibodies in the samples of group O blood donors and IgM anti-B titer in the samples of group A blood donors. Group O blood donors with antibody titers below 128 were selected and included in the mobile blood bank for combat readiness, group A plasma with anti-B titer lower than 128 and group O whole blood with antibody titers below 128 were included in the combat readiness entity blood bank. RESULTS: A total of 1 452 group O blood donors were selected, and the anti-A/B antibody titers were detected. Both antibody titers were distributed below 512, and both peak values of sample distribution were at titer 4. The proportion of samples with titers>128 for both antibodies was relatively low. There was a significant positive correlation between the titers of the two antibodies (r =0.383), and the proportion of samples with IgM anti-A titer higher than IgM anti-B titer was relatively high. 1 335(91.94%) group O blood donors with IgM anti-A and anti-B antibody titers <128 could be included in the mobile blood bank. The anti-B titer of group A blood was detected in 512 cases and the results showed that as the antibody titer increased, the proportion of blood donors gradually decreased. 99.8% of group A blood donors had anti-B antibody titer less than 128, and only one case did not meet the inclusion criteria. CONCLUSION: The proportion of group O blood donors whose whole blood meet the low antibody titer standard is high, and almost all plasma of group A blood donors meet the low titer standard, which improves the blood supply rate in emergencies.

The predominant Quillaja Saponaria fraction, QS-18, is safe and effective when formulated in a liposomal murine cancer peptide vaccine.

Extracts of the Chilean soapbark tree, Quillaja Saponaria (QS) are the source of potent immune-stimulatory saponin compounds. This study compared the adjuvanticity and toxicity of QS-18 and QS-21, assessing the potential to substitute QS-18 in place of QS-21 for vaccine development. QS-18, the most abundant QS saponin fraction, has been largely overlooked due to safety concerns. We found that QS-18 spontaneously inserted into liposomes, thereby neutralizing hemolytic activity, and following administration did not induce local reactogenicity in a footpad swelling test in mice. With high-dose intramuscular administration, transient weight loss was minor, and QS-18 did not induce significantly more weight loss compared to a liposome vaccine adjuvant system lacking it. Two days after administration, no elevation of inflammatory cytokines was detected in murine serum. In a formulation including cobalt-porphyrin-phospholipid (CoPoP) for short peptide sequestration, QS-18 did not impact the formation of peptide nanoparticles. With immunization, QS-18 peptide particles induced higher levels of cancer neoepitope-specific and tumor-associated antigen-specific CD8+ T cells compared to QS-21 particles, without indication of greater toxicity based on mouse body weight. T cell receptor sequencing of antigen-specific CD8+ T cells showed that QS-18 induced significantly more T cell transcripts. In two murine cancer models, vaccination with QS-18 peptide particles induced a similar therapeutic effect as QS-21 particles, without indication of increased toxicity. Antigen-specific CD8+ T cells in the tumor microenvironment were found to express the exhaustion marker PD-1, pointing to the rationale for exploring combination therapy. Taken together, these data demonstrate that QS-18, when formulated in liposomes, can be a safe and effective adjuvant to induce tumor-inhibiting cellular responses in murine models with potential to facilitate or diminish costs of production for vaccine adjuvant systems. Further studies are warranted to assess liposomal QS-18 immunogic, reactogenic and toxicological profiles in mice and other animal species.

Neurological diagnoses in hospitalized COVID-19 patients associated with adverse outcomes: A multinational cohort study.

Few studies examining the patient outcomes of concurrent neurological manifestations during acute COVID-19 leveraged multinational cohorts of adults and children or distinguished between central and peripheral nervous system (CNS vs. PNS) involvement. Using a federated multinational network in which local clinicians and informatics experts curated the electronic health records data, we evaluated the risk of prolonged hospitalization and mortality in hospitalized COVID-19 patients from 21 healthcare systems across 7 countries. For adults, we used a federated learning approach whereby we ran Cox proportional hazard models locally at each healthcare system and performed a meta-analysis on the aggregated results to estimate the overall risk of adverse outcomes across our geographically diverse populations. For children, we reported descriptive statistics separately due to their low frequency of neurological involvement and poor outcomes. Among the 106,229 hospitalized COVID-19 patients (104,031 patients ≥18 years; 2,198 patients <18 years, January 2020-October 2021), 15,101 (14%) had at least one CNS diagnosis, while 2,788 (3%) had at least one PNS diagnosis. After controlling for demographics and pre-existing conditions, adults with CNS involvement had longer hospital stay (11 versus 6 days) and greater risk of (Hazard Ratio = 1.78) and faster time to death (12 versus 24 days) than patients with no neurological condition (NNC) during acute COVID-19 hospitalization. Adults with PNS involvement also had longer hospital stay but lower risk of mortality than the NNC group. Although children had a low frequency of neurological involvement during COVID-19 hospitalization, a substantially higher proportion of children with CNS involvement died compared to those with NNC (6% vs 1%). Overall, patients with concurrent CNS manifestation during acute COVID-19 hospitalization faced greater risks for adverse clinical outcomes than patients without any neurological diagnosis. Our global informatics framework using a federated approach (versus a centralized data collection approach) has utility for clinical discovery beyond COVID-19.

Potential Common Mechanisms of Cytotoxicity Induced by Organophosphorus Pesticides via NLRP3 Inflammasome Activation.

The Multi-Threat Medical Countermeasure (MTMC) technique is crucial for developing common biochemical signaling pathways, molecular mediators, and cellular processes. This study revealed that the Nod-like receptor 3 (NLRP3) inflammasome pathway may be a significant contributor to the cytotoxicity induced by various organophosphorus pesticides (OPPs). The study demonstrated that exposure to six different types of OPPs (paraoxon, dichlorvos, fenthion, dipterex, dibrom, and dimethoate) led to significant cytotoxicity in BV2 cells, which was accompanied by increased expression of NLRP3 inflammasome complexes (NLRP3, ASC, Caspase-1) and downstream inflammatory cytokines (IL-1ß, IL-18), in which the order of cytotoxicity was dichlorvos > dipterex > dibrom > paraoxon > fenthion > dimethoate, based on the IC50 values of 274, 410, 551, 585, 2,158, and 1,527,566 µM, respectively. The findings suggest that targeting the NLRP3 inflammasome pathway could be a potential approach for developing broad-spectrum antitoxic drugs to combat multi-OPPs-induced toxicity. Moreover, inhibition of NLRP3 efficiently protected the cells against cytotoxicity induced by these six OPPs, and the expression of NLRP3, ASC, Caspase-1, IL-1ß, and IL-18 decreased accordingly. The order of NLRP3 affinity for OPPs was dimethoate > paraoxon > dichlorvos > dibrom > (fenthion and dipterex) based on K D values of 89.8, 325, 1,460, and 2,690 µM, respectively. Furthermore, the common molecular mechanism of NLRP3-OPPs was clarified by the presence of toxicity effector groups (benzene ring, nitrogen/oxygen-containing functional group); =O, -O-, or =S (active) groups; and combination residues (Gly271, Asp272). This finding provided valuable insights into exploring the common mechanisms of multiple threats and developing effective therapeutic strategies to prevent OPPs poisoning.

Sodium Sulfite as a Novel Hypoxia Revulsant Involved in Hypoxic Regulation in Escherichia coli.

As a reducing salt, sodium sulfite could deprive oxygen in solution, which could mimic hypoxic stress in Caenorhabditis elegans. In this study, the wild-type Escherichia coli strain MG1655 was used to examine the inhibition of sodium sulfite-induced hypoxia by observing the bacterial growth curves. We also analyzed the growth curves of mutant strains (for arcA/B, soxR/S, fnr, and oxyR) related to E. coli hypoxic pathways to reveal roles of the related genes during hypoxia. The ultrastructure of hypoxia-inhibited bacteria were also observed using transmission electron microscopy. Sodium sulfite could maintain hypoxic condition of bacterial culture for 8 h with concentrations over 40 mmol/L. Complete ultrastructure of the bacteria indicated sodium sulfite did inhibit bacterial growth and division. Among the hypoxia genes, fnr and arcB played key roles in sodium sulfite-induced hypoxia. This study showed that sodium sulfite could be used as a novel hypoxia revulsant for bacterial cultures.

Probiotic Pediococcus pentosaceus restored gossypol-induced intestinal barrier injury by increasing propionate content in Nile tilapia.

BACKGROUND: Intestinal barrier is a dynamic interface between the body and the ingested food components, however, dietary components or xenobiotics could compromise intestinal integrity, causing health risks to the host. Gossypol, a toxic component in cottonseed meal (CSM), caused intestinal injury in fish or other monogastric animals. It has been demonstrated that probiotics administration benefits the intestinal barrier integrity, but the efficacy of probiotics in maintaining intestinal health when the host is exposed to gossypol remains unclear. Here, a strain (YC) affiliated to Pediococcus pentosaceus was isolated from the gut of Nile tilapia (Oreochromis niloticus) and its potential to repair gossypol-induced intestinal damage was evaluated. RESULTS: A total of 270 Nile tilapia (2.20 ± 0.02 g) were allotted in 3 groups with 3 tanks each and fed with 3 diets including CON (control diet), GOS (control diet containing 300 mg/kg gossypol) and GP (control diet containing 300 mg/kg gossypol and 108 colony-forming unit (CFU)/g P. pentosaceus YC), respectively. After 10 weeks, addition of P. pentosaceus YC restored growth retardation and intestinal injury induced by gossypol in Nile tilapia. Transcriptome analysis and siRNA interference experiments demonstrated that NOD-like receptors (NLR) family caspase recruitment domain (CARD) domain containing 3 (Nlrc3) inhibition might promote intestinal stem cell (ISC) proliferation, as well as maintaining gut barrier integrity. 16S rRNA sequencing and gas chromatography-mass spectrometry (GC-MS) revealed that addition of P. pentosaceus YC altered the composition of gut microbiota and increased the content of propionate in fish gut. In vitro studies on propionate's function demonstrated that it suppressed nlrc3 expression and promoted wound healing in Caco-2 cell model. CONCLUSIONS: The present study reveals that P. pentosaceus YC has the capacity to ameliorate intestinal barrier injury by modulating gut microbiota composition and elevating propionate level. This finding offers a promising strategy for the feed industry to incorporate cottonseed meal into fish feed formulations.

Abrupt autofocusing beam from a phase-only mask.

Airy beams have become an important beam shape for structured light beams because of their interesting self-accelerating and parabolic propagation properties. Many variants of Airy beams have been proposed, among which the Airy beam with cylindrical symmetry [also known as the circular Airy beam or abrupt autofocusing (AAF) beam] is particularly peculiar and has attracted special attention due to its shape transformation during propagation. Much effort has been devoted to understanding the properties of the AAF beam. In this work, we present simulation results for generating the AAF beam using a phase-only mask. A cubic chirp-modulated axicon phase is used to create the mask. We found an optimal value for the axiconic phase, and the cubic phase is essential for controlling the AAF beam's shape. We demonstrate that a phase-only mask is an effective and simple method for generating high contrast between the initial and AAF plane. We present the results for beam formation and propagation dynamics of the AAF beam using the control parameters of the phase mask. We also discuss the design parameters and their influence on the AAF beam shapes. Our results pave the way for a deeper understanding of the beam formation and propagation dynamics of the AAF beam.

Common-path digital holographic microscopy based on a volume holographic grating for quantitative phase imaging.

Digital holographic microscopy (DHM) is a powerful quantitative phase imaging (QPI) technique that is capable of recording sample's phase information to enhance image contrast. In off-axis DHM, high-quality QPI images can be generated within a single recorded hologram, and the system stability can be enhanced by common-path configuration. Diffraction gratings are widely used components in common-path DHM systems; however, the presence of multiple diffraction beams leads to system power loss. Here, we propose and demonstrate implementation of a volume holographic grating (VHG) in common-path DHM, which provides single diffraction order. VHG in common-path DHM (i.e., VHG-DHM) helps in improving signal-to-noise ratio as compared to the conventional DHM. In addition, VHG, with inherently high angular selectivity, reduces image noise caused by stray light. With a simple fabrication process, it is convenient to utilize VHG to control the beam separation angle of DHM. Further, by using Bragg-matched wavelength degeneracy to avoid potential cell damaging effect in blue light, the VHG is designed for recording at a maximum sensitive wavelength of ∼488 nm, while our VHG-DHM is operated at the longer wavelength of red 632.8 nm for cell observation. Experimental results, measured by the VHG-DHM, show the measurement of target thickness ranging from 100 nm to 350 nm. In addition, stability of the system is quantitatively measured. High-contrast QPI images of human lung cancer cells are demonstrated.

Characterization of a pangolin SARS-CoV-2-related virus isolate that uses the human ACE2 receptor.

Various SARS-CoV-2-related coronaviruses have been increasingly identified in pangolins, showing a potential threat to humans. Here we report the infectivity and pathogenicity of the SARS-CoV-2-related virus, PCoV-GX/P2V, which was isolated from a Malayan pangolin (Manis javanica). PCoV-GX/P2V could grow in human hepatoma, colorectal adenocarcinoma cells, and human primary nasal epithelial cells. It replicated more efficiently in cells expressing human angiotensin-converting enzyme 2 (hACE2) as SARS-CoV-2 did. After intranasal inoculation to the hACE2-transgenic mice, PCoV-GX/P2V not only replicated in nasal turbinate and lungs, but also caused interstitial pneumonia, characterized by infiltration of mixed inflammatory cells and multifocal alveolar hemorrhage. Existing population immunity established by SARS-CoV-2 infection and vaccination may not protect people from PCoV-GX/P2V infection. These findings further verify the hACE2 utility of PCoV-GX/P2V by in vivo experiments using authentic viruses and highlight the importance for intensive surveillance to prevent possible cross-species transmission.

Efficacy, tolerability, and safety of the oral phosphate binder VS-505 (AP301).

BACKGROUND: VS-505 (AP301), an acacia and ferric oxyhydroxide polymer, is a novel fiber-iron-based phosphate binder. This two-part phase 2 study evaluated the tolerability, safety, and efficacy of oral VS-505 administered three times daily with meals in treating hyperphosphatemia in chronic kidney disease (CKD) patients receiving maintenance hemodialysis (MHD). METHODS: In Part 1, patients received dose-escalated treatment with VS-505 2.25, 4.50, and 9.00 g/day for 2 weeks each, guided by serum phosphorus levels. In Part 2, patients received randomized, open-label, fixed-dosage treatment with VS-505 (1.50, 2.25, 4.50, or 6.75 g/day) or sevelamer carbonate 4.80 g/day for 6 weeks. The primary efficacy endpoint was the change in serum phosphorus. RESULTS: The study enrolled 158 patients (Part 1: 25; Part 2: 133), with 130 exposed to VS-505 in total. VS-505 was well tolerated. The most common adverse events were gastrointestinal disorders, mainly feces discolored (56%) and diarrhea (15%; generally during weeks 1‒2 of treatment). Most gastrointestinal disorders resolved without intervention, and none were serious. In Part 1, serum phosphorus significantly improved (mean change -2.0 mg/dL; 95% confidence interval -2.7, -1.4) after VS-505 dose escalation. In Part 2, serum phosphorus significantly and dose-dependently improved in all VS-505 arms, with clinically meaningful reductions with VS-505 4.50 and 6.75 g/day, and sevelamer carbonate 4.80 g/day (mean change -1.6 (-2.2, -1.0), -1.8 (-2.4, -1.2), and -1.4 (-2.2, -0.5) mg/dL, respectively). In both Parts, serum phosphorus reductions occurred within 1 week of VS-505 initiation, returning to baseline within 2 weeks of VS-505 discontinuation. CONCLUSION: VS-505, a novel phosphate binder, was well tolerated with a manageable safety profile, and effectively and dose-dependently reduced serum phosphorus in CKD patients with hyperphosphatemia receiving MHD. Clinical Trial registration number: NCT04551300.