Single-cell transcriptome profiling reveals neutrophil heterogeneity in homeostasis and infection.

The full neutrophil heterogeneity and differentiation landscape remains incompletely characterized. Here, we profiled >25,000 differentiating and mature mouse neutrophils using single-cell RNA sequencing to provide a comprehensive transcriptional landscape of neutrophil maturation, function and fate decision in their steady state and during bacterial infection. Eight neutrophil populations were defined by distinct molecular signatures. The three mature peripheral blood neutrophil subsets arise from distinct maturing bone marrow neutrophil subsets. Driven by both known and uncharacterized transcription factors, neutrophils gradually acquire microbicidal capability as they traverse the transcriptional landscape, representing an evolved mechanism for fine-tuned regulation of an effective but balanced neutrophil response. Bacterial infection reprograms the genetic architecture of neutrophil populations, alters dynamic transitions between subpopulations and primes neutrophils for augmented functionality without affecting overall heterogeneity. In summary, these data establish a reference model and general framework for studying neutrophil-related disease mechanisms, biomarkers and therapeutic targets at single-cell resolution.

Auto-inhibition and activation of a short Argonaute-associated TIR-APAZ defense system.

Short prokaryotic Ago accounts for most prokaryotic Argonaute proteins (pAgos) and is involved in defending bacteria against invading nucleic acids. Short pAgo associated with TIR-APAZ (SPARTA) has been shown to oligomerize and deplete NAD+ upon guide-mediated target DNA recognition. However, the molecular basis of SPARTA inhibition and activation remains unknown. In this study, we determined the cryogenic electron microscopy structures of Crenotalea thermophila SPARTA in its inhibited, transient and activated states. The SPARTA monomer is auto-inhibited by its acidic tail, which occupies the guide-target binding channel. Guide-mediated target binding expels this acidic tail and triggers substantial conformational changes to expose the Ago-Ago dimerization interface. As a result, SPARTA assembles into an active tetramer, where the four TIR domains are rearranged and packed to form NADase active sites. Together with biochemical evidence, our results provide a panoramic vision explaining SPARTA auto-inhibition and activation and expand understanding of pAgo-mediated bacterial defense systems.

Imaging viscous flow of the Dirac fluid in graphene.

The electron-hole plasma in charge-neutral graphene is predicted to realize a quantum critical system in which electrical transport features a universal hydrodynamic description, even at room temperature1,2. This quantum critical 'Dirac fluid' is expected to have a shear viscosity close to a minimum bound3,4, with an interparticle scattering rate saturating1 at the Planckian time, the shortest possible timescale for particles to relax. Although electrical transport measurements at finite carrier density are consistent with hydrodynamic electron flow in graphene5-8, a clear demonstration of viscous flow at the charge-neutrality point remains elusive. Here we directly image viscous Dirac fluid flow in graphene at room temperature by measuring the associated stray magnetic field. Nanoscale magnetic imaging is performed using quantum spin magnetometers realized with nitrogen vacancy centres in diamond. Scanning single-spin and wide-field magnetometry reveal a parabolic Poiseuille profile for electron flow in a high-mobility graphene channel near the charge-neutrality point, establishing the viscous transport of the Dirac fluid. This measurement is in contrast to the conventional uniform flow profile imaged in a metallic conductor and also in a low-mobility graphene channel. Via combined imaging and transport measurements, we obtain viscosity and scattering rates, and observe that these quantities are comparable to the universal values expected at quantum criticality. This finding establishes a nearly ideal electron fluid in charge-neutral, high-mobility graphene at room temperature4. Our results will enable the study of hydrodynamic transport in quantum critical fluids relevant to strongly correlated electrons in high-temperature superconductors9. This work also highlights the capability of quantum spin magnetometers to probe correlated electronic phenomena at the nanoscale.

c-MET-positive circulating tumor cells and cell-free DNA as independent prognostic factors in hormone receptor-positive/HER2-negative metastatic breast cancer.

BACKGROUND: Endocrine therapy resistance in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) is a significant clinical challenge that poses several unmet needs in the management of the disease. This study aimed to investigate the prognostic value of c-MET-positive circulating tumor cells (cMET+ CTCs), ESR1/PIK3CA mutations, and cell-free DNA (cfDNA) concentrations in patients with hormone receptor-positive (HR+) metastatic breast cancer (mBC). METHODS: Ninety-seven patients with HR+ mBC were prospectively enrolled during standard treatment at Samsung Medical Center. CTCs were isolated from blood using GenoCTC® and EpCAM or c-MET CTC isolation kits. PIK3CA and ESR1 hotspot mutations were analyzed using droplet digital PCR. CfDNA concentrations were calculated using internal control copies from the ESR1 mutation test. Immunocytochemistry was performed to compare c-MET overexpression between primary and metastatic sites. RESULTS: The proportion of c-MET overexpression was significantly higher in metastatic sites than in primary sites (p = 0.00002). Survival analysis showed that c-MET+ CTC, cfDNA concentration, and ESR1 mutations were significantly associated with poor prognosis (p = 0.0026, 0.0021, and 0.0064, respectively) in HR+/HER2- mBC. By contrast, EpCAM-positive CTC (EpCAM+ CTC) and PIK3CA mutations were not associated with progression-free survival (PFS) in HR+/HER2- mBC. Multivariate analyses revealed that c-MET+ CTCs and cfDNA concentration were independent predictors of PFS in HR+/HER2- mBC. CONCLUSIONS: Monitoring c-MET+ CTC, rather than assessing c-MET expression in the primary BC site, could provide valuable information for predicting disease progression, as c-MET expression can change during treatment. The c-MET+ CTC count and cfDNA concentration could provide complementary information on disease progression in HR+ /HER2- mBC, highlighting the importance of integrated liquid biopsy.

Assessing Glaucoma Severity and Progression in Individuals with Asymmetric Axial Length: An Intrapatient Comparative Study.

PURPOSE: To investigate whether a difference exists in intereye glaucoma severity and progression in patients with asymmetric axial length. DESIGN: Long-term observational study. PARTICIPANTS: Patients older than 20 years with a diagnosis of glaucoma at Seoul National University Hospital, Seoul, Korea, between 2010 and 2020. METHODS: Patients with a diagnosis of glaucoma in both eyes with an axial length difference of more than 1.0 mm were included. Each individual's eyes were classified into longer eye and shorter eye, and the baseline and follow-up clinical data were analyzed using the paired T-test and McNemar test. MAIN OUTCOME MEASURES: Differences in clinical characteristics in patients with asymmetric axial length. RESULTS: A total of 190 eyes of 95 patients with glaucoma with asymmetric axial length were included in the study. The patients' mean age was 51.2 ± 12.3 years, and the mean follow-up period was 10.1 ± 3.9 years. No difference was found in baseline intraocular pressure (IOP) or central corneal thickness between longer eyes and shorter eyes. Among the baseline disc parameters, ovality index, ß-zone and γ-zone parapapillary atrophy (PPA) area were larger (P < 0.001) in the longer eyes. In the baseline OCT data, the retinal nerve fiber layer (RNFL) thickness (P = 0.009) and ganglion cell-inner plexiform layer (GCIPL) thickness (P < 0.001) were thinner in the longer eyes. According to a baseline visual field (VF) test, the mean deviation and VF index (VFI) values were significantly lower (P < 0.001, P = 0.034) in the longer eyes. Based on an analysis of glaucoma progression, the rate of change of superior GCIPL (longer eyes, -0.65 µm/year; shorter eyes, -0.40 µm/year), mean deviation (longer eyes, -0.40 dB/year; shorter eyes, -0.21 dB/year), and VFI (longer eyes, -0.92%/year; shorter eyes, -0.46%/year) were larger (P = 0.006, P = 0.005, P < 0.001) in the longer eyes. Additionally, the greater the difference in IOP fluctuation, the greater the difference in the rate of change between mean deviation and VFI. CONCLUSIONS: When an axial length difference of more than 1.0 mm was present, glaucoma tended to be more severe and to progress faster in the longer eyes. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Nonclinical Pharmacokinetics Study of OLX702A-075-16, N-Acetylgalactosamine Conjugated Asymmetric Small Interfering RNA (GalNAc-asiRNA).

In this study, the nonclinical pharmacokinetics of OLX702A-075-16, an RNA interference (RNAi) therapeutic currently in development, were investigated. OLX702A-075-16 is a novel N-acetylgalactosamine conjugated asymmetric small-interfering RNA (GalNAc-asiRNA) used for the treatment of an undisclosed liver disease. Its unique 16/21-mer asymmetric structure reduces nonspecific off-target effects without compromising efficacy. We investigated the plasma concentration, tissue distribution, metabolism, and renal excretion of OLX702A-075-16 following a subcutaneous administration in mice and rats. For bioanalysis, high-performance liquid chromatography with fluorescence detection (HPLC-FD) was used. The results showed rapid clearance from plasma (0.5 to 1.5 h of half-life) and predominant distribution to the liver, and/or kidney. Less than 1% of the liver concentration of OLX702A-075-16 was detected in the other tissues. Metabolite profiling using liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) revealed that the intact duplex OLX702A-075-16 was the major compound in plasma. The GalNAc moiety was predominantly metabolized from the sense strand in the liver, with the unconjugated sense strand of OLX702A-075-16 accounting for more than 95% of the total exposure in the rat liver. Meanwhile, the antisense strand was metabolized by the sequential loss of nucleotides from the 3'-terminus by exonuclease, with the rat liver samples yielding the most diverse truncated forms of metabolites. Urinary excretion over 96 h was less than 1% of the administered dose in rats. High plasma protein binding of OLX702A-075-16 likely inhibited its clearance through renal filtration. Significance Statement This study presents the first comprehensive characterization of the in vivo pharmacokinetics of GalNAc-asiRNA. The pharmacokinetic insights gained from this research will aid in understanding toxicology and efficacy, optimizing delivery platforms, and improving the predictive power of preclinical species data for human applications.

Effect of RANKL on Lower Depressive Symptoms In Hemodialysis Patients.

Depression and osteoporosis are common diseases in dialysis patients. In addition, patients with osteoporosis are more susceptible to depression. Contrary to previous anti-osteoporosis agents, denosumab and romosozumab could be used in dialysis patients and have similar action mechanisms for blocking RANKL. RANKL causes bone resorption after binding RANKL, but binding with OPG leads to suppress of bone resorption. In recent mice study, inhibition of RANKL with denosumab improved depressive-like phenotype. Besides, it was found that OPG was associated with depression. Therefore, this study aimed to investigate the association of depressive symptoms with RANKL and OPG in hemodialysis patients. We conducted a cross-sectional study with a total of 172 hemodialysis patients. The participants were measured for plasma RANKL, OPG, MMP-2, and MMP-9 levels. Logistic regression analysis was performed to evaluate the effect of RANKL and OPG on the presence of depressive symptoms. The depressive symptoms were observed in 90 (52.3%) subjects. RANKL tertile 3 had negative association with BDI score (ß - 4.527, 95% CI - 8.310 to - 0.743) in univariate analysis, and this association persisted even after multivariate adjustments (ß - 5.603, 95% CI - 9.715 to -1.491) in linear regression. In logistic regression between RANKL tertiles and depressive symptoms, RANKL tertile 3 had significantly lower unadjusted OR (0.40, 95% CI 0.19-0.86), and multivariate-adjusted OR (0.31, 95% CI 0.12-0.82) for depressive symptoms. OPG was not significantly associated with depressive symptoms. Higher plasma RANKL concentrations were significantly associated with lower depressive symptoms in HD patients.Trial registration WHO registry, No. KCT0003281, date: January 12, 2017.

Myeloid cell-derived reactive oxygen species externally regulate the proliferation of myeloid progenitors in emergency granulopoiesis.

The cellular mechanisms controlling infection-induced emergency granulopoiesis are poorly defined. Here we found that reactive oxygen species (ROS) concentrations in the bone marrow (BM) were elevated during acute infection in a phagocytic NADPH oxidase-dependent manner in myeloid cells. Gr1(+) myeloid cells were uniformly distributed in the BM, and all c-kit(+) progenitor cells were adjacent to Gr1(+) myeloid cells. Inflammation-induced ROS production in the BM played a critical role in myeloid progenitor expansion during emergency granulopoiesis. ROS elicited oxidation and deactivation of phosphatase and tensin homolog (PTEN), resulting in upregulation of PtdIns(3,4,5)P3 signaling in BM myeloid progenitors. We further revealed that BM myeloid cell-produced ROS stimulated proliferation of myeloid progenitors via a paracrine mechanism. Taken together, our results establish that phagocytic NADPH oxidase-mediated ROS production by BM myeloid cells plays a critical role in mediating emergency granulopoiesis during acute infection.

Understanding the Korean Dialysis Cohort for Mineral, Vascular Calcification, and Fracture (ORCHESTRA) Study: Design, Method, and Baseline Characteristics.

INTRODUCTION: End-stage renal disease (ESRD) is a growing disease worldwide, including Korea. This is an important condition that affects patient outcome. To provide optimal management for mineral disturbance, vascular calcification, and bone disease in ESRD patients, the Korean dialysis cohort for mineral, vascular calcification, and fracture (ORCHESTRA) study was conducted by enrolling Korean dialysis patients. METHODS: Sixteen university-affiliated hospitals and one Veterans' Health Service Medical Center participated in this study. This prospective cohort study enrolled approximately 900 consecutive patients on dialysis between May 2019 and January 2021. Enrolled subjects were evaluated at baseline for demographic information, laboratory tests, radiologic imaging, and bone mineral densitometry (BMD) scans. After enrollment, regular assessments of the patients were performed, and their biospecimens were collected according to the study protocol. The primary outcomes were the occurrence of major adverse cardiovascular events, invasive treatment for peripheral artery disease, and osteoporotic fractures. The secondary outcomes were hospitalization for cerebrovascular disease or progression of abdominal aortic calcification. Participants will be assessed for up to 3 years to determine whether primary or secondary outcomes occur. RESULTS: Between May 2019 and January 2021, all participating centers recruited 900 consecutive dialysis patients, including 786 undergoing hemodialysis (HD) and 114 undergoing peritoneal dialysis (PD). The mean age of the subjects was 60.4 ± 12.3 years. Males accounted for 57.7% of the total population. The mean dialysis vintage was 6.1 ± 6.0 years. The HD group was significantly older, had a longer dialysis vintage, and more comorbidities. Overall, the severity of vascular calcification was higher and the level of BMD was lower in the HD group than in the PD group. CONCLUSION: This nationwide, multicenter, prospective cohort study focused on chronic kidney disease-mineral and bone disorder and aimed to provide clinical evidence to establish optimal treatment guidelines for Asian dialysis patients.

Management of Immunosuppressive Therapy in Kidney Transplant Recipients with Sepsis: A Multicenter Retrospective Study.

BACKGROUND: Up to 6% of kidney transplant recipients (KTRs) experience life-threatening complications requiring intensive care unit (ICU) admission, and one of the most common medical complications requiring ICU admission is infection. This study aimed to evaluate the effect of immunosuppressive therapy (IST) modification on prognosis of KTRs with sepsis. METHODS: We conducted a multicenter retrospective study in 4 university-affiliated hospitals to evaluate the effect of adjusting the IST in KTRs with sepsis. Only patients who either maintained IST after ICU admission or those who underwent immediate (within 24 h of ICU admission) reduction or withdrawal of IST following ICU admission were included in this study. "Any reduction" was defined as a dosage reduction of any IST or discontinuation of at least 1 IST. "Complete withdrawal of IST" was defined as concomitant discontinuation of all ISTs, except steroids. RESULTS: During the study period, 1596 of the KTRs were admitted to the ICU, and 112 episodes of sepsis or septic shock were identified. The overall in-hospital mortality rate was 35.7%. In-hospital mortality was associated with higher sequential organ failure assessment score, simplified acute physiology score 3, non-identical human leukocyte antigen relation, presence of septic shock, and complete withdrawal of IST. After adjusting for potential confounding factors, complete withdrawal of IST remained significantly associated with in-hospital mortality (adjusted coefficient, 1.029; 95% confidence interval, 0.024-2.035) and graft failure (adjusted coefficient, 2.001; 95% confidence interval, 0.961-3.058). CONCLUSIONS: Complete IST withdrawal was common and associated with worse outcomes in critically ill KTRs with sepsis.

High-salt diet suppresses autoimmune demyelination by regulating the blood-brain barrier permeability.

Sodium chloride, "salt," is an essential component of daily food and vitally contributes to the body's homeostasis. However, excessive salt intake has often been held responsible for numerous health risks associated with the cardiovascular system and kidney. Recent reports linked a high-salt diet (HSD) to the exacerbation of artificially induced central nervous system (CNS) autoimmune pathology through changes in microbiota and enhanced TH17 cell differentiation [M. Kleinewietfeld et al., Nature 496, 518-522 (2013); C. Wu et al., Nature 496, 513-517 (2013); N. Wilck et al., Nature 551, 585-589 (2017)]. However, there is no evidence that dietary salt promotes or worsens a spontaneous autoimmune disease. Here we show that HSD suppresses autoimmune disease development in a mouse model of spontaneous CNS autoimmunity. We found that HSD consumption increased the circulating serum levels of the glucocorticoid hormone corticosterone. Corticosterone enhanced the expression of tight junction molecules on the brain endothelial cells and promoted the tightening of the blood-brain barrier (BBB) thereby controlling the entry of inflammatory T cells into the CNS. Our results demonstrate the multifaceted and potentially beneficial effects of moderately increased salt consumption in CNS autoimmunity.

Psychological Distress Trends and Effect of Media Exposure Among Community Residents After the Seoul Halloween Crowd Crush.

BACKGROUND: It is unclear how exposure to and perception of community trauma creates a mental health burden. This study aimed to examine the psychological distress trends among community residents in acute stress reaction, acute stress disorder, and post-traumatic stress disorder phases following the Seoul Halloween crowd crush. METHODS: A three-wave repeated cross-sectional survey was conducted with participants after the incident. Analysis of covariance (ANCOVA) with post hoc Bonferroni test was adopted to examine temporal changes in psychological distress and psychological outcomes resulting from media impacts. A two-way ANCOVA was adopted to examine the interaction effects of time and relevance to victims on psychological distress. RESULTS: A total of 807, 1,703, and 2,220 individuals participated in the three waves. Anxiety (estimated mean [standard error of the mean]: 2.28 [0.03] vs. 2.12 [0.02] vs. 2.03 [0.02]; P < 0.001), depression (2.22 [0.03] vs. 2.01 [0.02] vs. 1.90 [0.02]; P < 0.001), and anger (2.70 [0.03] vs. 2.66 [0.02] vs. 2.49 [0.02]; P < 0.001) gradually improved. However, sense of safety initially worsened and did not recover well (2.96 [0.03] vs. 2.75 [0.02] vs. 2.77 [0.02]; P < 0.001). The interaction effect of time and relevance to the victim were significant in depression (P for interaction = 0.049), anger (P for interaction = 0.016), and sense of safety (P for interaction = 0.004). Among participants unrelated to the victim, those exposed to graphics exhibited higher levels of anxiety (2.09 [0.02] vs. 1.87 [0.07]; P = 0.002), depression (1.99 [0.02] vs. 1.83 [0.07]; P = 0.020), and anger (2.71 [0.03] vs. 2.47 [0.08]; P = 0.003) at W2 and higher anger (2.49 [0.02] vs. 2.31 [0.06]; P = 0.005) at W3. CONCLUSION: Community residents indirectly exposed to trauma also experienced psychological distress in the early stages after the incident. A significant impact of media which might have served as a conduit for unfiltered graphics and rumors was also indicated.

The Impact of Obesity on Kidney Disease: Observational Cohort Study Analyzing 14,492 Kidney Biopsy Cases.

BACKGROUND: The obesity epidemic is associated with the emergence of new kidney diseases including obesity-related glomerulopathy (ORG) and metabolic syndrome-associated disorders. However, the effects of obesity on prevalence and outcome of biopsy-proven kidney disease are not well known. METHODS: We analyzed 14,492 kidney biopsies in 18 hospitals from 1979 to 2018 in Korea. Obesity was defined as a body mass index value of ≥ 30 kg/m². RESULTS: The most common disease was IgA nephropathy (IgAN) in both obese and non-obese participants (33.7% vs. 38.9%). Obesity was associated with a higher risk of focal segmental glomerulosclerosis (FSGS) and hypertensive nephropathy (HT-N) (odds ratio [OR], 1.72, 95% confidence interval [CI], 1.37-2.17; OR, 1.96, 95% CI, 1.21-3.19) and a lower risk of IgAN (OR, 0.74, 95% CI, 0.62-0.88). During the median follow up of 93.1 ± 88.7 months, obesity increased the risk of end-stage kidney disease (ESKD) in patients with IgAN (relative risk [RR], 1.49, 95% CI, 1.01-2.20) and lupus nephritis (LN) (RR, 3.43, 95% CI, 1.36-8.67). Of 947 obese individuals, ORG was detected in 298 (31.5%), and 230 participants had other kidney diseases, most commonly, IgAN (40.9%) followed by diabetic nephropathy (15.2%). Participants with ORG, when combined with other renal diseases, showed higher risks for developing ESKD compared to those with ORG alone (RR, 2.48, 95% CI, 1.09-5.64). CONCLUSION: Obesity is associated with an increased risk of FSGS and HT-N, and also increase the ESKD risk in IgAN and LN patients. ORG in obese participants may have favorable renal outcomes if it occurs alone without any other renal disease.

A Network Meta-Analysis of Randomized Controlled Trials Assessing Intraoperative Anesthetic Therapies for Analgesic Efficacy and Morphine Consumption Following Total Knee Arthroplasty.

BACKGROUND: The purpose of this study was to compare intraoperative anesthetic therapies for total knee arthroplasty (TKA) regarding postoperative analgesic efficacy and morphine consumption by conducting a systematic literature search. METHODS: Randomized controlled trials of TKA using various anesthetic therapies were identified from various databases from conception through December 31, 2021. A network meta-analysis of relevant literature was performed to investigate which treatment showed better outcomes. In total, 40 trials were included in this study. RESULTS: Surface under the cumulative ranking curve showed local infiltration anesthesia (LIA) with saphenous nerve block (SNB) to produce the best pain relief on postoperative days (PODs) 1 and 2 and the best reduction of morphine consumption on PODs 1 and 3. However, femoral nerve block showed the largest effect on pain relief on POD 3, and liposomal bupivacaine showed the largest effect on reduction of morphine consumption on POD 2. CONCLUSIONS: According to this network meta-analysis, surface under the cumulative ranking curve percentage showed that LIA with SNB provided the best analgesic effect after TKA. Furthermore, patients receiving LIA with SNB had the lowest consumption of morphine. Although femoral nerve block resulted in better pain relief on POD 3, LIA with SNB could be selected first when trying to reduce morphine consumption or increase early ambulation.

PHA-665752's Antigrowth and Proapoptotic Effects on HSC-3 Human Oral Cancer Cells.

c-Met is a tyrosine-kinase receptor, and its aberrant activation plays critical roles in tumorigenesis, invasion, and metastatic spread in many human tumors. PHA-665752 (PHA) is an inhibitor of c-Met and has antitumor effects on many hematological malignancies and solid cancers. However, the activation and expression of c-Met and its role and the antitumor effect of PHA on human oral squamous cell carcinoma (OSCC) cells remain unclear. Here, we investigated the activation and expression of c-Met and the effects of PHA on the growth of a highly tumorigenic HSC-3 human OSCC cell line with high c-Met phosphorylation and expression. Of note, c-Met was highly expressed and phosphorylated on Y1234/1235 in HSC-3 cells, and PHA treatment significantly suppressed the growth and induced apoptosis of these cells. Moreover, PHA that inhibited the phosphorylation (activation) of c-Met further caused the reduced phosphorylation and expression levels of Src, protein kinase B (PKB), mammalian target of rapamycin (mTtor), and myeloid cell leukemia-1 (Mcl-1) in HSC-3 cells. In addition, the antiangiogenic property of PHA in HSC-3 cells was shown, as evidenced by the drug's suppressive effect on the expression of hypoxia-inducible factor-1α (HIF-1α), a critical tumor angiogenic transcription factor. Importantly, genetic ablation of c-Met caused the reduced growth of HSC-3 cells and decreased Src phosphorylation and HIF-1α expression. Together, these results demonstrate that c-Met is highly activated in HSC-3 human oral cancer cells, and PHA exhibits strong antigrowth, proapoptotic, and antiangiogenic effects on these cells, which are mediated through regulation of the phosphorylation and expression of multiple targets, including c-Met, Src, PKB, mTOR, Mcl-1, and HIF-1α.

Characterizing Glomerular Barrier Dysfunction with Patient-Derived Serum in Glomerulus-on-a-Chip Models: Unveiling New Insights into Glomerulonephritis.

Glomerulonephritis (GN) is characterized by podocyte injury or glomerular filtration dysfunction, which results in proteinuria and eventual loss of kidney function. Progress in studying the mechanism of GN, and developing an effective therapy, has been limited by the absence of suitable in vitro models that can closely recapitulate human physiological responses. We developed a microfluidic glomerulus-on-a-chip device that can recapitulate the physiological environment to construct a functional filtration barrier, with which we investigated biological changes in podocytes and dynamic alterations in the permeability of the glomerular filtration barrier (GFB) on a chip. We also evaluated the potential of GN-mimicking devices as a model for predicting responses to human GN. Glomerular endothelial cells and podocytes successfully formed intact monolayers on opposite sides of the membrane in our chip device. Permselectivity analysis confirmed that the chip was constituted by a functional GFB that could accurately perform differential clearance of albumin and dextran. Reduction in cell viability resulting from damage was observed in all serum-induced GN models. The expression of podocyte-specific marker WT1 was also decreased. Albumin permeability was increased in most models of serum-induced IgA nephropathy (IgAN) and membranous nephropathy (MN). However, sera from patients with minimal change disease (MCD) or lupus nephritis (LN) did not induce a loss of permeability. This glomerulus-on-a-chip system may provide a platform of glomerular cell culture for in vitro GFB in formation of a functional three-dimensional glomerular structure. Establishing a disease model of GN on a chip could accelerate our understanding of pathophysiological mechanisms of glomerulopathy.

Comprehensive analysis of predominant pathogenic bacteria and viruses in seafood products.

Given the growing global demand for seafood, it is imperative to conduct a comprehensive study on the prevalence and persistence patterns of pathogenic bacteria and viruses associated with specific seafood varieties. This assessment thoroughly examines the safety of seafood products, considering the diverse processing methods employed in the industry. The importance of understanding the behavior of foodborne pathogens, such as Salmonella typhimurium, Vibrio parahaemolyticus, Clostridium botulinum, Listeria monocytogenes, human norovirus, and hepatitis A virus, is emphasized by recent cases of gastroenteritis outbreaks linked to contaminated seafood. This analysis examines outbreaks linked to seafood in the United States and globally, with a particular emphasis on the health concerns posed by pathogenic bacteria and viruses to consumers. Ensuring the safety of seafood is crucial since it directly relates to consumer preferences on sustainability, food safety, provenance, and availability. The review focuses on assessing the frequency, growth, and durability of infections that arise during the processing of seafood. It utilizes next-generation sequencing to identify the bacteria responsible for these illnesses. Additionally, it analyzes methods for preventing and intervening of infections while also considering the forthcoming challenges in ensuring the microbiological safety of seafood products. This evaluation emphasizes the significance of the seafood processing industry in promptly responding to evolving consumer preferences by offering current information on seafood hazards and future consumption patterns. To ensure the continuous safety and sustainable future of seafood products, it is crucial to identify and address possible threats.

The effect of lung-recruitment maneuver on postoperative shoulder pain in patients undergoing laparoscopic cholecystectomy: a randomized controlled trial.

PURPOSE: Lung-recruitment maneuvers (LRM) have been shown to reduce postoperative pain after laparoscopic surgery. This study aimed to investigate the association of LRM with the incidence of shoulder pain after laparoscopic cholecystectomy. METHODS: A randomized controlled study was conducted with 110 patients undergoing elective laparoscopic cholecystectomy from July 2022 to March 2023. Participants were randomized to receive either routine exsufflation or LRM at pneumoperitoneum release. The postoperative shoulder pain and abdominal pain were assessed at 1, 4, 6, 12, and 24 h after surgery using a numeric rating scale. Analgesic consumption and postoperative nausea or vomiting (PONV) were evaluated during the first 24 h after surgery. RESULTS: The incidence of shoulder pain during the first 24 h after surgery was significantly lower in the LRM group compared to the control group (26.9 vs. 59.3%; P = 0.001). The median [interquartile range] score of worst shoulder pain was significantly lower compared to the control group (3 [2-3] vs 4 [3-5.5]; P = 0.003). Participants in the LRM group showed reduced abdominal pain at rest at 4 and 24 h after surgery, and experienced significantly lower intensities of abdominal pain during mobilization at all time points over 24 h after surgery. There were no significant differences in opioid consumption or the incidence of PONV between the groups. CONCLUSIONS: LRM reduces both the incidence and intensity of shoulder pain during 24 h after laparoscopic cholecystectomy. Additionally, LRM was associated with reduced intensity of abdominal pain during mobilization over the study period.

Association between toothbrushing and cardiovascular risk factors: a cross-sectional study using Korean National Health and Nutrition Examination Survey 2015-2017.

BACKGROUND: Previous studies have suggested that frequent toothbrushing is associated with a lower risk of future cardiovascular events. We sought to investigate further the relationship between toothbrushing, cardiovascular risk factors, and lifestyle behaviours. METHODS: We analysed a cross-sectional survey including 13,761 adults aged 30 years or older without a history of cardiovascular diseases from the Korean National Health and Nutritional Examination Survey. Conventional cardiovascular risk factors (blood pressure, lipid profiles, and fasting glucose), and inflammatory markers (high-sensitivity C-reactive protein [hsCRP], and white blood cell counts [WBC]) were investigated in relation to the frequency of toothbrushing. RESULTS: The estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk, calculated using the pooled cohort equations was 13.7%, 9.1%, and 7.3% for participants who reported toothbrushing 0-1, 2, and ≥ 3 times a day, respectively. Both conventional risk factors and inflammatory markers were significantly associated with frequent toothbrushing. However, after adjusting potential confounding factors such as age, sex, comorbidities, and lifestyle behaviours, only inflammatory markers were remained as significant factors. CONCLUSIONS: Oral hygiene behaviours are closely linked to cardiovascular risk factors. This study suggests that reduced systemic inflammatory burden may explain the benefit of improved oral hygiene in terms of cardiovascular risk.