Aligned macrocycle pores in ultrathin films for accurate molecular sieving.

Polymer membranes are widely used in separation processes including desalination1, organic solvent nanofiltration2,3 and crude oil fractionation4,5. Nevertheless, direct evidence of subnanometre pores and a feasible method of manipulating their size is still challenging because of the molecular fluctuations of poorly defined voids in polymers6. Macrocycles with intrinsic cavities could potentially tackle this challenge. However, unfunctionalized macrocycles with indistinguishable reactivities tend towards disordered packing in films hundreds of nanometres thick7-9, hindering cavity interconnection and formation of through-pores. Here, we synthesized selectively functionalized macrocycles with differentiated reactivities that preferentially aligned to create well-defined pores across an ultrathin nanofilm. The ordered structure was enhanced by reducing the nanofilm thickness down to several nanometres. This orientated architecture enabled direct visualization of subnanometre macrocycle pores in the nanofilm surfaces, with the size tailored to ångström precision by varying the macrocycle identity. Aligned macrocycle membranes provided twice the methanol permeance and higher selectivity compared to disordered counterparts. Used in high-value separations, exemplified here by enriching cannabidiol oil, they achieved one order of magnitude faster ethanol transport and threefold higher enrichment than commercial state-of-the-art membranes. This approach offers a feasible strategy for creating subnanometre channels in polymer membranes, and demonstrates their potential for accurate molecular separations.

Dexmedetomidine ameliorates acute kidney injury by regulating mitochondrial dynamics via the α2-AR/SIRT1/PGC-1α pathway activation in rats.

BACKGROUND: Sepsis-associated acute kidney injury (AKI) is a serious complication of systemic infection with high morbidity and mortality in patients. However, no effective drugs are available for AKI treatment. Dexmedetomidine (DEX) is an alpha 2 adrenal receptor agonist with antioxidant and anti-apoptotic effects. This study aimed to investigate the therapeutic effects of DEX on sepsis-associated AKI and to elucidate the role of mitochondrial dynamics during this process. METHODS: A lipopolysaccharide (LPS)-induced AKI rat model and an NRK-52E cell model were used in the study. This study investigated the effects of DEX on sepsis-associated AKI and the molecular mechanisms using histologic assessment, biochemical analyses, ultrastructural observation, western blotting, immunofluorescence, immunohistochemistry, qRT-PCR, flow cytometry, and si-mRNA transfection. RESULTS: In rats, the results showed that administration of DEX protected kidney structure and function from LPS-induced septic AKI. In addition, we found that DEX upregulated the α2-AR/SIRT1/PGC-1α pathway, protected mitochondrial structure and function, and decreased oxidative stress and apoptosis compared to the LPS group. In NRK-52E cells, DEX regulated the mitochondrial dynamic balance by preventing intracellular Ca2+ overloading and activating CaMKII. CONCLUSIONS: DEX ameliorated septic AKI by reducing oxidative stress and apoptosis in addition to modulating mitochondrial dynamics via upregulation of the α2-AR/SIRT1/PGC-1α pathway. This is a confirmatory study about DEX pre-treatment to ameliorate septic AKI. Our research reveals a novel mechanistic molecular pathway by which DEX provides nephroprotection.

Comparison of focusing property and radiation force between autofocusing Bessel beams and focused Gaussian beams.

As abruptly autofocusing beams, autofocusing Bessel beams (ABBs) have been proven to be a class solution for the Helmholtz equation [Opt. Express31, 33228 (2023)10.1364/OE.500383]. In this paper, we use the Fresnel number as the basic parameter and accurately compare the focusing property and radiation force of ABBs versus focused Gaussian beams (FGBs) under the same Fresnel number. Unlike FGBs, ABBs can achieve autofocusing without the need for an initial focusing phase. Our analysis of the beam width defined by power in the bucket, revealed that FGBs exhibit uniform focusing along the straight line, whereas ABBs demonstrate accelerated focusing along the elliptic curve. At the same Fresnel number, FGBs exhibit a higher peak intensity in the focal plane, yet ABBs excel in gradient force on particles. In comparison to FGBs, ABBs exhibit smaller potential well widths, allowing for stable and precise trapping of high refractive index particles at the focal point. While FGBs are considered suitable for laser processing and ablation due to their high peak power density, ABBs possess significant advantages in optical manipulation due to their great gradient force. Furthermore, we conduct a comparative analysis between ABBs and circular Airy beams (CABs). The peak intensity and gradient force exhibited by CABs are slightly lesser than those of ABBs. CABs are appropriate for multi-point trapping along the axis, whereas ABBs are more suited for precise single-point trapping.

Agreement of lymphocyte subsets detection permits reference intervals transference between flow cytometry systems: direct validation using established reference intervals.

OBJECTIVES: With the increasing demand and application of lymphocyte subsets detection in clinical laboratories, different single-platform flow cytometer (FCM) systems have been developed. There is an urgent need to establish the reference intervals (RIs) for different single-platform FCMs and transferring them from one FCM system to another provides a much more feasible and convenient approach. This study aimed to explore the transferability of RIs for lymphocyte subsets across different flow cytometry platforms. METHODS: We first conducted the pairwise method comparison across four FCM platforms, including NovoCyte, BriCyteE6, DxFLEX, and FACSCantoII systems. Next, the transferability of RIs of lymphocyte subsets was evaluated. Furthermore, we conducted the RIs transference based on the FACSCantoII system, BriCyteE6 system and DxFLEX system, except for NK cells. The transferred RIs were further verified by calculating the bias (CV) between the established ones. RESULTS: The results of lymphocyte subsets detection based on the NovoCyte, BriCyteE6, DxFLEX, and FACSCantoII systems were comparable and it was feasible to transfer the RIs of lymphocyte subsets detected by the four FCM systems. The RIs of lymphocyte subsets detection using FACSCantoII, DxFLEX, and BriCyteE6 systems were established. Upon transferring the RIs of lymphocyte subsets from the FACSCantoII system to the BriCyteE6 system, and DxFLEX system except for NK cells, the CV between the transferred RIs and the established ones was below 20 % for all parameters. CONCLUSIONS: The present study illustrated that the RIs of lymphocyte subsets could be transferred across different flow cytometry systems except for NK cells with different definition strategies.

Enhancing malignancy prediction in thyroid nodules: A multimodal ultrasound radiomics approach in TI-RADS category 4 lesions.

PURPOSE: To explore the diagnostic value of intralesional and perilesional radiomics based on multimodal ultrasound (US) images in predicting the malignant ACR TIRADS 4 thyroid nodules (TNs). METHODS: A total of 297 cases of TNs in patients who underwent preoperative thyroid grayscale US and shear wave elastography (STE) were enrolled (training cohort: n = 150, internal validation cohort: n = 77, external validation cohort: n = 70). Regions of interests (ROIs) were delineated on grayscale US images and STE images, and then an isotropic expansion of 1.0, 1.5, 2.0, 2.5, and 3.0 mm was applied. Predictive models were established using recursive feature elimination-support vector machines (RFE-SVM) based on radiomics features calculated by random forest. RESULTS: The perilesional ROI1.5mm expansion achieved the highest area under curve (AUC) (AUC: 0.753 for grayscale US, 0.728 for STE; 95% confidence interval (CI): 0.664-0.743, 0.684-0.739, respectively). The joint model had the highest AUC values of 0.936 in the training dataset, 0.926 in internal dataset, and 0.893 in external dataset. The calibration curve showed good consistency and the decision curve indicated a greater clinical net benefit of the joint model. CONCLUSION: Joint model containing perilesional radiomics (1.5 mm) had significant value in predicting the malignant ACR TIRADS 4 TNs.

Melatonin Delays Arthritis Inflammation and Reduces Cartilage Matrix Degradation through the SIRT1-Mediated NF-κB/Nrf2/TGF-ß/BMPs Pathway.

Cartilage, a flexible and smooth connective tissue that envelops the surfaces of synovial joints, relies on chondrocytes for extracellular matrix (ECM) production and the maintenance of its structural and functional integrity. Melatonin (MT), renowned for its anti-inflammatory and antioxidant properties, holds the potential to modulate cartilage regeneration and degradation. Therefore, the present study was devoted to elucidating the mechanism of MT on chondrocytes. The in vivo experiment consisted of three groups: Sham (only the skin tissue was incised), Model (using the anterior cruciate ligament transection (ACLT) method), and MT (30 mg/kg), with sample extraction following 12 weeks of administration. Pathological alterations in articular cartilage, synovium, and subchondral bone were evaluated using Safranin O-fast green staining. Immunohistochemistry (ICH) analysis was employed to assess the expression of matrix degradation-related markers. The levels of serum cytokines were quantified via Enzyme-linked immunosorbent assay (ELISA) assays. In in vitro experiments, primary chondrocytes were divided into Control, Model, MT, negative control, and inhibitor groups. Western blotting (WB) and Quantitative RT-PCR (q-PCR) were used to detect Silent information regulator transcript-1 (SIRT1)/Nuclear factor kappa-B (NF-κB)/Nuclear factor erythroid-2-related factor 2 (Nrf2)/Transforming growth factor-beta (TGF-ß)/Bone morphogenetic proteins (BMPs)-related indicators. Immunofluorescence (IF) analysis was employed to examine the status of type II collagen (COL2A1), SIRT1, phosphorylated NF-κB p65 (p-p65), and phosphorylated mothers against decapentaplegic homolog 2 (p-Smad2). In vivo results revealed that the MT group exhibited a relatively smooth cartilage surface, modest chondrocyte loss, mild synovial hyperplasia, and increased subchondral bone thickness. ICH results showed that MT downregulated the expression of components related to matrix degradation. ELISA results showed that MT reduced serum inflammatory cytokine levels. In vitro experiments confirmed that MT upregulated the expression of SIRT1/Nrf2/TGF-ß/BMPs while inhibiting the NF-κB pathway and matrix degradation-related components. The introduction of the SIRT1 inhibitor Selisistat (EX527) reversed the effects of MT. Together, these findings suggest that MT has the potential to ameliorate inflammation, inhibit the release of matrix-degrading enzymes, and improve the cartilage condition. This study provides a new theoretical basis for understanding the role of MT in decelerating cartilage degradation and promoting chondrocyte repair in in vivo and in vitro cultured chondrocytes.

Early Detection of Severe Acute Respiratory Syndrome Coronavirus 2 Variants Using Traveler-based Genomic Surveillance at 4 US Airports, September 2021-January 2022.

We enrolled arriving international air travelers in a severe acute respiratory syndrome coronavirus 2 genomic surveillance program. We used molecular testing of pooled nasal swabs and sequenced positive samples for sublineage. Traveler-based surveillance provided early-warning variant detection, reporting the first US Omicron BA.2 and BA.3 in North America.

Fibroblast Growth Factor 2 Is Produced By Renal Tubular Cells to Act as a Paracrine Factor in Maladaptive Kidney Repair After Cisplatin Nephrotoxicity.

Kidney repair after injury involves the cross-talk of injured kidney tubules with interstitial fibroblasts and immune cells. Although tubular cells produce multiple cytokines, the role and regulation of specific cytokines in kidney repair are largely undefined. In this study, we detected the induction of fibroblast growth factor 2 (FGF2) in mouse kidneys after repeated low-dose cisplatin (RLDC) treatment and in RLDC-treated renal proximal tubule cells in vitro. We further detected FGF2 in the culture medium of RLDC-treated renal tubular cells but not in the medium of control cells, indicating that RLDC induces FGF2 expression and secretion. Compared with the medium of control cells, the medium of RLDC-treated renal tubular cells was twice as effective in promoting fibroblast proliferation. Remarkably, the proliferative effect of the RLDC-treated cell medium was diminished by FGF2-neutralizing antibodies. In addition, the RLDC-treated cell medium induced the expression of fibrosis-related proteins, which was partially suppressed by FGF2-neutralizing antibodies. In mice, FGF2 deficiency partially prevented RLDC-induced decline in kidney function, loss of kidney weight, renal fibrosis, and inflammation. Together, these results indicate that FGF2 is produced by renal tubular cells after kidney injury and acts as an important paracrine factor in maladaptive kidney repair and disease progression.

Focusing property of autofocusing Bessel beams.

We introduce what we believe to be a new family of abruptly autofocusing waves named autofocusing Bessel beams (ABBs). Since the beams only strongly influence the area near the focus, it holds promise for medical laser treatment and optical tweezers. By the angular spectrum method, ABBs are proved to be a class solution for the Helmholtz equation. The focal length is well-defined and easily tuned in our mathematical description. Under the finite energy limitation, the abruptly autofocusing and vortex characteristics of Gaussian-modulated ABBs are studied. Interestingly, we found a kind of abruptly autofocusing waves focusing twice on the propagation axis, which is formed by an ABB passing through a focusing lens. Dual-focus ABBs make it possible for a single laser to manipulate two particles on the propagation axis simultaneously. In the experiment, the autofocusing of ABBs and the dual focus of ABBs passing through a focusing lens are observed. This article provides a theoretical model and experimental protocol for studying abruptly autofocusing waves.

Effect of Predeparture Testing on Postarrival SARS-CoV-2-Positive Test Results Among International Travelers - CDC Traveler-Based Genomic Surveillance Program, Four U.S. Airports, March-September 2022.

Beginning December 6, 2021, all international air passengers boarding flights to the United States were required to show either a negative result from a SARS-CoV-2 viral test taken ≤1 day before departure or proof of recovery from COVID-19 within the preceding 90 days (1). As of June 12, 2022, predeparture testing was no longer mandatory but remained recommended by CDC (2,3). Various modeling studies have estimated that predeparture testing the day before or the day of air travel reduces transmission or importation of SARS-CoV-2 by 31%-76% (4-7). Postarrival SARS-CoV-2 pooled testing data from CDC's Traveler-based Genomic Surveillance program were used to compare SARS-CoV-2 test results among volunteer travelers arriving at four U.S. airports during two 12-week periods: March 20-June 11, 2022, when predeparture testing was required, and June 12-September 3, 2022, when predeparture testing was not required. In a multivariable logistic regression model, pooled nasal swab specimens collected during March 20-June 11 were 52% less likely to be positive for SARS-CoV-2 than were those collected during June 12-September 3, after adjusting for COVID-19 incidence in the flight's country of origin, sample pool size, and collection airport (adjusted odds ratio [aOR] = 0.48, 95% CI = 0.39-0.58) (p<0.001). These findings support predeparture testing as a tool for reducing travel-associated SARS-CoV-2 transmission and provide important real-world evidence that can guide decisions for future outbreaks and pandemics.

Reactive membranes for groundwater remediation of chlorinated aliphatic hydrocarbons: competitive dechlorination and cost aspects.

A nanocomposite membrane incorporating reactive Pd-Fe nanoparticles (NPs) was developed to remediate chlorinated aliphatic hydrocarbons (CAHs) from groundwater. Other than recapturing the produced Fen+ for in-situ regeneration, the functionalized polyanions prevented NPs agglomeration and resulting in a spherical Fe0 core (55 nm, O/Fe = 0.05) and an oxidized shell (4 nm, O/Fe = 1.38). The reactive membranes degraded 92% of target CAHs with a residence time of 1.7 seconds. After long-term treatment and regeneration, reusability was confirmed through recovered reactivity, recurrence of Fe0 in X-ray photoelectron spectroscopy, and >96% remaining of Fe and Pd. The total cost (adjusted present value for 20 years) was estimated to be 13.9% lower than the granular activated carbon system, following an EPA work breakdown structure-based cost model. However, non-target CAHs from groundwater can compete for active sites, leading to decreased surface-area normalized dechlorination rate (ksa) by 28.2-79.9%. A hybrid nanofiltration (NF)/reactive membrane was proposed to selectively intercept larger competitors, leading to 54% increased dechlorination efficiency and 1.3 to 1.9-fold enlarged ksa. Overall, the practical viability of the developed reactive membranes was demonstrated by the stability, reusability, and cost advantages, while the optional NF strategy could alleviate competitive degradation towards complex water chemistry.

The association between dietary inflammation index and bone mineral density: results from the United States National Health and nutrition examination surveys.

OBJECTIVE: To investigate the associations of dietary inflammation index (DII) with bone density and osteoporosis in different femoral areas. METHODS: The study population was selected from the National Health and Nutrition Examination Survey (NHANES) with the exclusion criteria of age 18, pregnancy, or missing information on DII, femoral bone marrow density (BMD), estimated glomerular filtration rate (eGFR), and urine albumin-to-creatinine ratio (UACR), or had diseases which may influence systemic inflammation. DII was calculated based on the questionnaire interview of dietary recall within 24 h. Subjects' baseline characteristics were collected. The associations between DII and different femoral areas were analyzed. RESULTS: After applying exclusion criteria, 10,312 participants were included in the study. Significant differences among DII tertiles were found in BMD or T scores (p < .001) of the femoral neck, the trochanter, the intertrochanter, and the total femur. High DII was associated with low BMDs and T scores in all the femoral areas (all p < .01). Compared to low DII (tertile1, DII < 0.380 as reference), in the femoral neck, the intertrochanter, and the total femur, increased DII is independently associated with increased the possibility of the presence of osteoporosis (OR, 95% CI: 1.88, 1.11-3.20; 2.10, 1.05-4.20; 1.94, 1.02-3.69, respectively). However, this positive association was only observed in the trochanteric area of the non-Hispanic White population after full adjustment (OR, 95% CI: 3.22 (1.18, 8.79)). No significant difference in the association of DII and the presence of osteoporosis were found in subjects with or without impaired kidney function (eGFR < 60 ml/min/1.73 m2). CONCLUSION: High DII is independently related to declined femoral BMD of femoral areas.

Multimodal radiomics and nomogram-based prediction of axillary lymph node metastasis in breast cancer: An analysis considering optimal peritumoral region.

PURPOSE: To explore the optimal peri-tumoral regions on ultrasound (US) images and investigate the performance of multimodal radiomics for predicting axillary lymph node metastasis (ALNM). METHODS: This retrospective study included 326 patients (training cohort: n = 162, internal validation cohort: n = 74, external validation cohort: n = 90). Intra-tumoral region of interests (ROIs) were delineated on US and digital mammography (DM) images. Peri-tumoral ROI (PTR) on US images were gained by dilating actual 0.5, 1.0, 1.5, 2.0, 2.5, 3.0 and 3.5 mm radius surrounding the tumor. Support vector machine (SVM) method was used to calculate the importance of radiomics features and to pick the 10 most important. Recursive feature elimination-SVM was used to evaluate the efficacy of models with different feature numbers used. RESULTS: The PTR0.5mm yielded a maximum AUC of 0.802 (95% confidence interval (CI): 0.676-0.901) within the validation cohort using SVM classifier. The multimodal radiomics (intra-tumoral US and DM and US-based PTR0.5mm radiomics model) achieved the highest predictive ability (AUC = 0.888/0.844/0.835 and 95% CI = 0.829-0.936/0.741-0.929/0.752-0.896 for training/internal validation/external validation cohort, respectively). CONCLUSION: The PTR0.5mm could be the optimal area for predicting ALNM. A favorable predictive accuracy for predicting ALNM was achieved using multimodal radiomics and its based nomogram.

Value of clinical features combined with multimodal ultrasound in predicting lymph node metastasis in cervical central area of papillary thyroid carcinoma.

OBJECTIVE: To explore the clinical features, multimodal ultrasound features and multimodal ultrasound imaging features in predicting lymph node metastasis in the central cervical region of papillary thyroid carcinoma. METHODS: A total of 129 patients with papillary thyroid carcinoma (PTC) confirmed by pathology were selected from our hospital from September 2020 to December 2022. According to the pathological results of cervical central lymph nodes, these patients were divided into metastatic group and non-metastatic group. Patients were randomly sampled and divided into training group (n = 90) and verification group (n = 39) according to the ratio of 7:3. The independent risk factors for central lymph node metastasis (CLNM) were determined by least absolute shrinkage and selection operator and multivariate logistic regression. Based on independent risk factors to build a prediction model, select the best diagnostic effectiveness of the prediction model sketch line chart, and finally, the line chart calibration and clinical benefits were evaluated. RESULTS: A total of 8, 11 and 17 features were selected from conventional ultrasound images, shear wave elastography (SWE) images and contrast-enhanced ultrasound (CEUS) images to construct the Radscore of conventional ultrasound, SWE and CEUS, respectively. After univariate and multivariate logistic regression analysis, male, multifocal, encapsulation, iso-high enhancement and multimodal ultrasound imaging score were independent risk factors for cervical CLNM in PTC patients (p < 0.05). Based on independent risk factors, a clinical combined with multimodal ultrasound feature model was constructed, and multimodal ultrasound Radscore were added to the clinical combined with multimodal ultrasound feature model to form a joint prediction model. In the training group, the diagnostic efficacy of combined model (AUC = 0.934) was better than that of clinical combined with multimodal ultrasound feature model (AUC = 0.841) and multimodal ultrasound radiomics model (AUC = 0.829). In training group and validation group, calibration curves show that the joint model has good predictive ability for cervical CLNM of PTC patients; The decision curve shows that most of the net benefits of the nematic chart are higher than those of clinical + multimodal ultrasound feature model and multimodal ultrasound radiomics model within a reasonable risk threshold range. CONCLUSION: Male, multifocal, capsular invasion and iso-high enhancement are independent risk factors of CLNM in PTC patients, and the clinical plus multimodal ultrasound model based on these four factors has good diagnostic efficiency. The joint prediction model after adding multimodal ultrasound Radscore to clinical and multimodal ultrasound features has the best diagnostic efficiency, high sensitivity and specificity, which is expected to provide objective basis for accurately formulating individualized treatment plans and evaluating prognosis.

Crystallizing Self-Standing Covalent Organic Framework Membranes for Ultrafast Proton Transport in Flow Batteries.

Covalent organic frameworks (COFs) display great potential to be assembled into proton conductive membranes for their uniform and controllable pore structure, yet constructing self-standing COF membrane with high crystallinity to fully exploit their ordered crystalline channels for efficient ionic conduction remains a great challenge. Here, a macromolecular-mediated crystallization strategy is designed to manipulate the crystallization of self-standing COF membrane, where the -SO3 H groups in introduced sulfonated macromolecule chains function as the sites to interact with the precursors of COF and thus offer long-range ordered template for membrane crystallization. The optimized self-standing COF membrane composed of highly-ordered nanopores exhibits high proton conductivity (75 mS cm-1 at 100 % relative humidity and 20 °C) and excellent flow battery performance, outperforming Nafion 212 and reported membranes. Meanwhile, the long-term run of membrane is achieved with the help of the anchoring effect of flexible macromolecule chains. Our work provides inspiration to design self-standing COF membranes with ordered channels for permselective application.

Formation and characterization of noncovalent ternary complexes based on whey protein concentrate, high methoxyl pectin, and phenolic acid.

Protein-polysaccharide-polyphenol noncovalent ternary complexes possess unique physicochemical, structural, and functional properties. In the present study, ternary complexes based on whey protein concentrate (WPC; 2%, wt/vol) and high methoxyl pectin (HMP; 0.5%, wt/vol) complexes and 0.2 to 0.6% (wt/vol) chlorogenic acid (CA) or rosmarinic acid (RA) were formed and characterized at 3 pH values (4, 4.5, and 5). The pH conditions were decided according to phase diagram of WPC and HMP during acidification. Fluorescence quenching experiments indicated that WPC-HMP complexes bound RA stronger than CA and the binding constant increased with increasing pH for both phenolic acids. Particle size of ternary complexes decreased and absolute ζ-potential increased with pH values changing from 4 to 5, and RA influenced the particle size of WPC-HMP complexes greater than CA. The CA and RA in ternary complexes showed good stability against UV light with pH order of pH 5 > pH 4.5 > pH 4. Fourier-transform infrared spectroscopy spectra indicated the involvement of hydrogen bonding between WPC-HMP and CA or RA. Antibacterial tests showed that ternary complexes had good antibacterial activity against Staphylococcus aureus and Escherichia coli at concentrations of 6.2 mg/mL and the ability increased with decreasing pH values. All ternary complexes possessed strong scavenging radical capacities with median inhibitory concentration (IC50) values ranging from 2.71 ± 0.05 to 6.20 ± 0.41 µg/mL. Antioxidative ability of ternary complexes increased as pH went up and WPC-HMP-RA showed significantly higher antioxidative property compared with WPC-HMP-CA. Data may provide useful information for rational design of ternary complexes and applications of the formed complexes in food matrices such as beverages and emulsions.

Downregulation of the NLRP3/Caspse-1 Pathway Ameliorates Ketamine-Induced Liver Injury and Inflammation in Developing Rats.

Ketamine is an anesthetic drug that is widely used in human and veterinary medicine. In the developmental stage, long-term exposure to ketamine may cause serious side effects. MCC950 and VX765 play protective roles in many disease models by regulating the NLRP3/Caspase-1 pathway. This study aims to explore the potential protective effect of MCC950 and VX765 on ketamine-induced liver injury in neonatal rats and clarify its underlying mechanism. After administration of MCC950 and VX765 in a ketamine-induced liver injury rat model, liver function and inflammatory factors were determined, and immunohistochemistry and western blotting were performed. We found that ketamine caused liver injury in 7-day-old SD rats, decreased liver function indexes, and increased inflammation. MCC950 and VX765 effectively alleviated liver damage and inflammation, and downregulated the expression of proteins such as NLRP3, Caspase-1, and GSDMD-N. In summary, these results indicated that MCC950 and VX765 could have potential protective effects on ketamine-induced liver injury through inhibiting the NLRP3/Caspase-1 pathway.

Leptin relieves ischemia/reperfusion induced acute kidney injury through inhibiting apoptosis and autophagy. / ç˜¦ç´ é€šè¿‡æŠ‘åˆ¶ç»†èƒžå‡‹äº¡å’Œè‡ªå™¬å‡è½»æ€¥æ€§ç¼ºè¡€å†çŒæ³¨å¼•èµ·çš„è‚¾æŸä¼¤.

OBJECTIVES: Acute kidney injury (AKI) can be caused by ischemia/reperfusion (I/R), nephrotoxin, and sepsis, with poor prognosis and high mortality. Leptin is a protein molecule that regulates the body's energy metabolism and reproductive activities via binding to its specific receptor. Leptin can inhibit cardiomyocyte apoptosis caused by I/R, but its effect on I/R kidney injury and the underlying mechanisms are still unclear. This study aims to investigate the effect and mechanisms of leptin on renal function, renal histopathology, apoptosis, and autophagy during acute I/R kidney injury. METHODS: Healthy adult male mice were randomly divided into 4 groups: a sham+wild-type mice (ob/+) group, a sham+leptin gene-deficient mice (ob/ob) group, an I/R+ob/+ group, and an I/R+ob/ob group (n=8 per group). For sham operation, a longitudinal incision was made on the back of the mice to expose and separate the bilateral kidneys and renal arteries, and no subsequent treatment was performed. I/R treatment was ischemia for 30 min and reperfusion for 48 h. The levels of BUN and SCr were detected to evaluate renal function; HE staining was used to observe the pathological changes of renal tissue; TUNEL staining was used to observe cell apoptosis, and apoptosis-positive cells were counted; Western blotting was used to detect levels of apoptosis-related proteins (caspase 3, caspase 9), autophagy-related proteins [mammalian target of rapamycin (mTOR), phosphorylated mTOR (p-mTOR), LC3 I, LC3 II], mTOR-dependent signaling pathway proteins [phosphate and tension homology (PTEN), adenosine monophosphate-activated protein kinase (AMPK), protein kinase B (AKT), extracellular regulated protein kinase (ERK), phosphorylated PTEN (p-PTEN), phosphorylated AMPK (p-AMPK), phosphorylated AKT (p-AKT), phosphorylated ERK (p-ERK)]. RESULTS: There was no significant difference in the levels of BUN and SCr between the sham+ob/+ group and the sham+ob/ob group (both P>0.05). The levels of BUN and SCr in the I/R+ob/+ group were significantly higher than those in the sham+ob/+ group (both P<0.05). Compared with the mice in the sham+ob/ob group or the I/R+ob/+ group, the levels of BUN and SCr in the I/R+ob/ob group were significantly increased (all P<0.05). There was no obvious damage to the renal tubules in the sham+ob/+ group and the sham+ob/ob group. Compared with sham+ob/+ group and sham+ob/ob group, both the I/R+ob/+ group and the I/R+ob/ob group had cell damage such as brush border shedding, vacuolar degeneration, and cast formation. Compared with the I/R+ob/+ group, the renal tubules of the mice in the I/R+ob/ob group were more severely damaged. The pathological score of renal tubular injury showed that the renal tubular injury was the most serious in the I/R+ob/ob group (P<0.05). Compared with the sham+ob/+ group, the protein levels of caspase 3, caspase 9, PTEN, and LC3 II were significantly up-regulated, the ratio of LC3 II to LC3 I was significantly increased, and the protein levels of p-mTOR, p-PTEN, p-AMPK, p-AKT, and p-ERK were significantly down-regulated in the I/R+ob/+ group (all P<0.05). Compared with the sham+ob/ob group, the protein levels of caspase 3, caspase 9, PTEN, and LC3 II were significantly up-regulated, and the ratio of LC3 II to LC3 I was significantly increased, while the protein levels of p-mTOR, p-PTEN, p-AMPK, p-AKT, and p-ERK were significantly down-regulated in the I/R+ob/ob group (all P<0.05). Compared with the I/R+ob/+ group, the levels of p-mTOR, p-PTEN, p-AMPK, p-AKT were more significantly down-regulated, while the levels of caspase 3, caspase 9, PTEN, and LC3 II were more significantly up-regulated, and the ratio of LC3 II to LC3 I was more significantly increase in the I/R+ob/ob group (all P<0.05). CONCLUSIONS: Renal function and tubular damage, and elevated levels of apoptosis and autophagy are observed in mice kidneys after acute I/R. Leptin might relieve I/R induced AKI by inhibiting apoptosis and autophagy that through a complex network of interactions between mTOR-dependent signaling pathways.

Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal rats.

BACKGROUND: Multiple studies have revealed that repeated or long-term exposure to ketamine causes neurodegeneration and cognitive dysfunction. Pyroptosis is an inflammatory form of programmed cell death that has been linked to various neurological diseases. However, the role of NLRP3/caspase-1 axis-related pyroptosis in ketamine-induced neurotoxicity and cognitive dysfunction remains uncertain. METHODS: To evaluate whether ketamine caused NLRP3/caspase1-dependent pyroptosis, flow cytometry analysis, western blotting, ELISA test, histopathological analysis, Morris water maze (MWM) test, cell viability assay, and lactate dehydrogenase release (LDH) assay were carried out on PC12 cells, HAPI cells, and 7-day-old rats. In addition, the NLRP3 inhibitor MCC950 or the caspase-1 inhibitor VX-765 was used to investigate the role of the NLRP3/caspase-1 axis in ketamine-induced neurotoxicity and cognitive dysfunction. RESULTS: Our findings demonstrated that ketamine exposure caused cell damage and increased the levels of pyroptosis in PC12 cells, HAPI cells, and the hippocampus of neonatal rats. After continuous exposure to ketamine, targeting NLRP3 and caspase-1 with MCC950 or VX765 improved pyroptosis, reduced neuropathological damages, and alleviated cognitive dysfunction. CONCLUSION: NLRP3/Caspase-1 axis-dependent pyroptosis is involved in ketamine-induced neuroinflammation and cognitive dysfunction, and it provides a promising strategy to treat ketamine-related neurotoxicity.

Transcriptional insights into the CD8+ T cell response in mono-HIV and HCV infection.

BACKGROUND: Disease progression in the absence of therapy varies significantly in mono-HIV and HCV infected individuals. Virus-specific CD8+ T cells play an important role in restricting lentiviral replication and determining the rate of disease progression during HIV and HCV mono- and co-infection. Thus, understanding the similarities in the characteristics of CD8+ T cells in mono-HIV and HCV infection at the transcriptomic level contributes to the development of antiviral therapy. In this study, a meta-analysis of CD8+ T cell gene expression profiles derived from mono-HIV and HCV infected individuals at different stages of disease progression, was conducted to understand the common changes experienced by CD8+ T cells. METHODS: Five microarray datasets, reporting CD8+ T cell mRNA expression of the mono-HIV and HCV infected patients, were retrieved from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified via integrative meta-analysis of expression data (INMEX) program. Network analysis methods were used to assess protein-protein interaction (PPI) networks, Gene Ontology (GO) terms and pathway enrichment for DEGs. MirDIP and miRDB online prediction tools were used to predict potential microRNAs (miRNAs) targeting hub genes. RESULTS: First, we identified 625 and 154 DEGs in the CD8+ T cells originating from mono-HIV and HCV chronic progressor patients, respectively, compared to healthy individuals. Among them, interferon-stimulated genes (ISGs) including ISG15, IFIT3, ILI44L, CXCL8, FPR1 and TLR2, were upregulated after mono-HIV and HCV infection. Pathway enrichment analysis of DEGs showed that the "cytokine-cytokine receptor interaction" and "NF-kappa B" signaling pathways were upregulated after mono-HIV and HCV infection. In addition, we identified 92 and 50 DEGs in the CD8+ T cells of HIV non-progressor and HCV resolver patients, respectively, compared with corresponding chronic progressors. We observed attenuated mitosis and reduced ISG expression in HIV non-progressors and HCV resolvers compared with the corresponding chronic progressors. Finally, we identified miRNA-143-3p, predicted to target both IFIT3 in HIV and STAT5A in HCV infection. CONCLUSIONS: We identified DEGs and transcriptional patterns in mono-HIV and HCV infected individuals at different stages of disease progression and identified miRNA-143-3p with potential to intervene disease progression, which provides a new strategy for developing targeted therapies.