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The healing of large skin defects remains a significant challenge in clinical settings. The lack of epidermal sources, such as autologous skin grafting, limits full-thickness skin defect repair and leads to excessive scar formation. Skin organoids have the potential to generate a complete skin layer, supporting in-situ skin regeneration in the defect area. In this study, skin organoid spheres, created with human keratinocytes, fibroblasts, and endothelial cells, showed a specific structure with a stromal core surrounded by surface keratinocytes. We selected an appropriate bioink and innovatively combined an extrusion-based bioprinting technique with dual-photo source cross-linking technology to ensure the overall mechanical properties of the 3D bioprinted skin organoid. Moreover, the 3D bioprinted skin organoid was customized to match the size and shape of the wound site, facilitating convenient implantation. When applied to full-thickness skin defects in immunodeficient mice, the 3D bioprinted human-derived skin organoid significantly accelerated wound healing through in-situ regeneration, epithelialization, vascularization, and inhibition of excessive inflammation. The combination of skin organoid and 3D bioprinting technology can overcome the limitations of current skin substitutes, offering a novel treatment strategy to address large-area skin defects.

Abstract Objective Chondrosarcoma (CHS) is resistant to conventional chemotherapy and radiotherapy and currently lacks effective treatment options when in advanced stages. Accordingly, this research investigated the mechanism of RNF2/CBX7 in CHS to drive the development of molecularly targeted drugs for CHS. Methods RNF2 and CBX7 levels were detected in CHS cells and tissues. RNF2 and CBX7 expression was modulated through cell transfection to examine their effects on cell proliferation, apoptosis, migration, and angiogenesis. The correlation between RNF2 and CBX7 levels was determined, and the ubiquitination level of CBX7 was tested. Protein synthesis was blocked in RNF2-knockdown/overexpressing cells with CHX to assess the effect of RNF2 on CBX7 stability. JJ012 cells transfected with LV-sh-RNF2 were subcutaneously injected into nu/nu nude mice to ascertain the action of RNF2 in the growth and metastasis of CHS. Results RNF2 was highly expressed in CHS cells and tissues. RNF2 knockdown curbed CHS cell proliferation, migration, and angiogenesis while promoting apoptosis. RNF2 knockdown in JJ012 cells upregulated CBX7 protein levels and reduced CBX7 ubiquitination, whilst RNF2 had no effect on CBX7 mRNA expression. CBX7 knockdown partially nullified the repressing effects of RNF2 knockdown on CHS cell proliferation, migration, and angiogenesis, and CBX7 overexpression partially abolished the promotional effects of RNF2 overexpression. LV-sh-RNF2 prominently restricted tumor growth and weight and declined lung metastatic nodules and Ki-67-positive cells in mice. Conclusion RNF2 fosters CHS progression by elevating CBX7 degradation via the ubiquitination pathway.

Mpox is a zoonotic disease caused by the monkeypox virus (MPXV). Diagnosing and treating the disease has become a global health concern requiring close attention to its spread to non-endemic regions. Clinical diagnosis is based on laboratory test results. Conventional detection techniques include real-time quantitative polymerase chain reaction (qPCR), genome sequencing, antigen and antibody identification, and virus isolation. Nevertheless, these methods fall short of rapidly and efficiently identifying MPXV, as they require specialized training, specific laboratory environments, and professional-grade equipment. Emerging technologies offer complementary advantages to meet diverse diagnostic needs, including various point-of-care testing (POCT) approaches and integrating biosensors with rapid detection techniques. This review discusses prospective future research avenues for MPXV detection, examining the advances and challenges of various detection techniques which may contribute to the ongoing elimination of mpox human-to-human transmission and serves as a reference for developing effective prevention and control strategies.

Abstract Background Ischemia/reperfusion (I/R) injury is a severe brain disorder with currently limited effective treatments. This study aims to explore the role of N6-methyladenosine (m6A) modification and associated regulatory factors in I/R to identify potential therapeutic targets. Methods We utilized a middle cerebral artery occlusion (MCAO) rat model and SH-SY5Y cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to assess m6A levels and investigate the impact of METTL3 overexpression on long non-coding RNA (lncRNA) CRNDE expression. The effects of silencing lncRNA CRNDE on the interaction between YTHDC1 and ATG10 mRNA, as well as the stability of ATG10 mRNA, were evaluated. Additionally, apoptosis rates, pro-inflammatory and anti-inflammatory factor levels, ATG10 expression, and autophagic activity were analyzed to determine the effects of METTL3. The reverse effects of YTHDC1 overexpression were also examined. Results MCAO rats and OGD/R-treated SH-SY5Y cells exhibited reduced m6A levels. METTL3 overexpression significantly inhibited lncRNA CRNDE expression. Silencing lncRNA CRNDE mitigated OGD/R-induced apoptosis and inflammation in SH-SY5Y cells, while enhancing autophagy and stabilizing ATG10 mRNA. METTL3 overexpression decreased cell apoptosis, reduced the levels of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and increased IL-10 secretion. Furthermore, METTL3 overexpression upregulated ATG10 expression and promoted autophagy. Conversely, lncRNA CRNDE overexpression negated these effects. Conclusion The inhibition of lncRNA CRNDE affects the interaction between YTHDC1 and ATG10 mRNA and stabilizes ATG10 mRNA, mediated by METTL3 overexpression. These findings suggest that targeting lncRNA CRNDE to reduce apoptosis, inhibit inflammation, increase ATG10 expression, and enhance autophagy could offer new therapeutic strategies for I/R injury.

Abstract Background Child and adolescent mental health is a major public health concern worldwide. The development of children’s social and emotional skills helps to improve mental health and wellbeing, and prevent anxiety and depression. The school-based social emotional learning (SEL) programmes have proved effective in a number of countries. But in Mainland China, there has been no empirical research of the effectiveness on children’s mental health. The study conducted a SEL programme in China during the COVID-19 pandemic and aimed to determine whether: (1) a SEL programme can reduce anxiety and depression, (2) the intervention effect is influenced by sociodemographic characteristics, (3) the programme effects change children’s emotion management and communication. Methods Participants were 230 children aged 8–12 years in the intervention school and 325 in the control school in two poor villages in central China. The study was a quasi-experimental trial, comprising 16 weekly 90-minute sessions. It used a mixed-methods design, with a quantitative survey administered at baseline, post-intervention, and 5-month follow-up, and qualitative interviews. Linear mixed effects regression modeling was used to analyse the intervention effectiveness, linear models were conducted to examine the moderation effect of sociodemographic variables, and the inductive thematic analysis approach was used for interview data. Results The intervention had no significant effect on anxiety or depression, except that intervention school children who lived with neither parent (left behind children) reported lower depression scores than control school at post-intervention and 5-month follow-up. Qualitative interviews showed after intervention children were more able to control tempers and better communicated their thoughts and feelings, improving their relationships with family and friends. Conclusions The programme was cheap, easy to implement, and warmly welcomed by children, schools and caregivers, suggesting it was feasible and potentially sustainable. More research is needed on the adaptation of the SEL programme in the Chinese context.

Liquid metal, as a novel material, has become ideal for the fabrication of flexible conductive fibers and has shown great potential in the field of biomedical sensing. This paper presents a comprehensive review of the unique properties of liquid metals such as gallium-based alloys, including their excellent electrical conductivity, mobility, and biocompatibility. These properties make liquid metals ideal for the fabrication of flexible and malleable biosensors. The article explores common preparation methods for liquid metal conductive fibers, such as internal liquid metal filling, surface printing with liquid metal, and liquid metal coating techniques, and their applications in health monitoring, neural interfaces, and wearable devices. By summarizing and analyzing the current research, this paper aims to reveal the current status and challenges of liquid metal conductive fibers in the field of biosensors and to look forward to their development in the future, which will provide valuable references and insights for researchers in the field of biomedical engineering.

Summary: Previous studies have indicated the neuroprotective effect of olfactory mucosa mesenchymal stem cells (OM-MSCs) on brain injury. Intracerebral hemorrhage (ICH) models were established in rats by injecting autologous blood. SENP1 expression was enhanced in neurons but decreased in astrocytes compared to that in OM-MSCs. Overexpression of SENP1 promoted the proliferation and neuronal differentiation, while inhibiting the astrocytic differentiation of OM-MSCs. Conversely, its knockdown had the opposite effect. Moreover, OM-MSCs reduced neurological dysfunction in rats after ICH, and the neuroprotective effect of OM-MSCs could be further enhanced by SENP1 overexpression. In addition, SENP1 promoted mitophagy, which might be related to SENP1-mediated OPTN deSUMOylation. Furthermore, SENP1 promoted neuronal differentiation of OM-MSCs through mitophagy mediated by OPTN. Similar to SENP1, OPTN transfection further enhanced the remission effect of OM-MSC on ICH rats. SENP1 promoted neuronal differentiation of OM-MSCs through OPTN-mediated mitophagy to improve neurological deficits in ICH rats.

Abstract In this article, we study the quasilinear Schrödinger equation − △ ( u ) + V ( x ) u − △ ( u 2 ) u = g ( x , u ) , x ∈ R N , $$ -\triangle (u)+V(x)u-\triangle \bigl(u^{2}\bigr)u=g(x,u), \quad x\in \mathbb{R}^{N}, $$ where the potential V ( x ) $V(x)$ and the primitive of g ( x , u ) $g(x,u)$ are allowed to be sign-changing. Under more general superlinear conditions on g, we obtain the existence of infinitely many nontrivial solutions by using the mountain pass theorem. Recent results in the literature are significantly improved.

Numerous studies have established that the hypoxic conditions within ovarian follicles induce apoptosis in granulosa cells (GCs), a pivotal hallmark of follicular atresia. Melatonin (N-acetyl-5-methoxytryptamine, MT), a versatile antioxidant naturally present in follicular fluid, acts as a safeguard for maintaining GCs’ survival during stress exposure. In this study, we unveil an innovative protective mechanism of melatonin against hypoxia-triggered GC apoptosis by selectively inhibiting mitochondrial ROS (mtROS) generation. Specifically, under hypoxic conditions, a gradual accumulation of mitochondrial ROS occurred, consequently activating the JNK-FOXO1 pathway, and driving GCs toward apoptosis. The blocking of JNK or FOXO1 diminished hypoxia-induced GC apoptosis, but this effect was nullified in the presence of GSH, indicating that mtROS instigates apoptosis through the JNK-FOXO1 pathway. Consistent with this, hypoxic GCs treated with melatonin exhibited decreased levels of mtROS, reduced JNK-FOXO1 activation, and mitigated apoptosis. However, the protective capabilities of melatonin were attenuated upon inhibiting its receptor MTNR1B, accompanied by the decreased expression of antioxidant genes. Notably, SOD2, a key mitochondrial antioxidant gene modulated by the melatonin–MTNR1B axis, effectively inhibited the activation of mtROS-JNK-FOXO1 and subsequent apoptosis, whereas SOD2 knockdown abrogated the protective role of melatonin in hypoxic GCs. In conclusion, our study elucidates that melatonin, through MTNR1B activation, fosters SOD2 expression, effectively quelling mtROS-JNK-FOXO1-mediated apoptosis in follicular GCs under hypoxic stress.

Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with progressive motor system impairment, and recent evidence has identified the extra-motor involvement. Small fiber neuropathy reflecting by sensory and autonomic disturbances in ALS has been reported to accompany the motor damage. However, non-invasive assessment of this impairment and its application in disease evaluation of ALS is scarce. We aim to evaluate the use of corneal confocal microscopy (CCM) to non-invasively quantify the corneal small fiber neuropathy in ALS and explore its clinical value in assessing disease severity of ALS. Methods Sixty-six patients with ALS and 64 healthy controls were included in this cross-sectional study. Participants underwent detailed clinical assessments and corneal imaging with in vivo CCM. Using ImageJ, the following parameters were quantified: corneal nerve length (IWL) and dendritic cell density (IWDC) in the inferior whorl region and corneal nerve fiber length (CNFL), nerve fiber density (CNFD), nerve branch density (CNBD), and dendritic cell density (CDC) in the peripheral region. Disease severity was evaluated using recognized scales. Results Corneal nerve lengths (IWL and CNFL) were lower while dendritic cell densities (IWDC and CDC) were higher in patients with ALS than controls in peripheral and inferior whorl regions (p

Cellular behaviors and functions can be regulated by mechanical cues from microenvironments, which are transmitted to nucleus through the physical connections of cytoskeletons in the cells. How these physical connections determine transcriptional activity were not clearly known. The actomyosin, which generates intracellular traction force, has been recognized to control the nuclear morphology. Here, we have revealed that microtubule, the stiffest cytoskeleton, is also involved in the process of nuclear morphology alteration. The microtubule negatively regulates the actomyosin-induced nuclear invaginations but not the nuclear wrinkles. Moreover, these nuclear shape changes are proven to mediate the chromatin remodeling, which essentially mediates cell gene expression and phenotype determination. The actomyosin disruption leads to the loss of chromatin accessibility, which can be partly recovered by microtubule interference through nuclear shape control. This finding answers the question of how mechanical cues regulate chromatin accessibility and cell behaviors. It also provides new insights into cell mechanotransduction and nuclear mechanics.

Background: Acute kidney injury is a highly common and multifactorial renal disease resulting in significant morbidity and mortality, especially sepsis-induced acute kidney injury. There is no effective therapy available to treat or prevent sepsis-induced acute kidney injury. One of the specialized pro-resolving mediators, Resolvin D1 exhibits special anti-inflammatory effects in several inflammatory disease models, but there is little evidence about the effect and mechanism of Resolvin D1 in sepsis-induced acute kidney injury. Methods: We conducted experiments to explore the effect and mechanism of Resolvin D1 in sepsis-induced acute kidney injury. In vitro, human proximal tubular epithelial cells were used to test the apoptosis ratio, cell viability and reactive oxygen species level. In vivo, C57BL/6 mice were injected with lipopolysaccharide to establish a sepsis-induced acute kidney injury model. Renal function and structure, apoptosis ratio of kidney cells, mitochondrial structure and function and related protein and gene levels were assessed. Results: In vitro, the resolvin D1-treated group showed higher cell viability and lower reactive oxygen species levels and apoptosis ratios than the LPS group. In vivo, Resolvin D1 can not only improve renal function and mitochondrial function but also reduce the apoptosis ratio, while mediating mitochondrial dynamics and inhibiting NF-κB pathway. Conclusions: Resolvin D1 has a good renoprotective effect by maintaining mitochondrial dynamics and inhibiting the NF-κB pathway.

BackgroundAlthough many studies have proven the beneficial effects of caffeine on human health, the association between caffeine intake and the risk of kidney stones is limited in large epidemiologic studies.ObjectivesWe aimed to investigate the association between caffeine intake and the risk of kidney stones.MethodsA total of 30,716 participants (with weight numbers of 204, 189, and 886) with a history of kidney stone were included in this analysis. All data were survey-weighted, and corresponding logistic regression models were performed to examine the associations between caffeine intake and the risk of kidney stones.ResultsIn a fully adjusted model, a per-quartile increase in caffeine intake was associated with a 5.32% decreased risk of kidney stones. In the subgroup analysis, the multivariate-adjusted odds ratios (95% confidence intervals) of the risk of kidney stones for per-quartile increments in caffeine intake were 0.9650 (0.9643, 0.9656) for men, 0.9320 (0.9313, 0.9327) for women, 0.9384 (0.9378, 0.9389) for white race individuals, 1.0281 (1.0270, 1.0292) for nonwhite race individuals, 0.9460 (0.9455, 0.9465) for overweight/obese individuals, and 0.9314 (0.9303, 0.9324) for non-overweight individuals, 0.9100 (0.9094, 0.9105) for caffeine from coffee, and 1.0021 (1.0013, 1.0029) for caffeine from non-coffee sources.ConclusionCaffeine intake was negatively associated with the risk of kidney stones. In subgroup analyses, the negative association of caffeine with kidney stone risk was only found in white individuals. In addition, the decreased risk was found higher in women and non-overweight individuals. Especially for women, white individuals and non-overweight individuals. The protective effect of caffeine intake from coffee on stone formation was more significant than that of caffeine from non-coffee sources.

BackgroundAlthough many molecular studies have tried to explore the relationship between vitamin D metabolism and kidney function, the association between 25-hydroxyvitamin D [25(OH)D] and kidney function is still controversial. Previous studies reported that low vitamin D status and decreased kidney function were associated with insulin resistance (IR). However, neither of them was confirmed by large population-based studies. This study evaluated the associations between 25(OH)D and kidney function and the associations between both of them and IR among adults in the United States of America (USA).MethodsWe analyzed 36,523 adults from the National Health and Nutrition Examination Survey (NHANES) (2001–2014). Kidney function was assessed by the estimated glomerular filtration rate (eGFR), and IR was assessed by homeostasis model assessment (HOMA-IR). All data were survey-weighted, and corresponding linear regression models were performed to examine the associations.ResultsThe mean serum 25(OH)D levels were found to be increased in participants with decreased kidney function (eGFR

Sepsis-associated acute kidney injury (S-AKI) is a common complication in hospitalized and critically ill patients, which increases the risk of multiple comorbidities and is associated with extremely high mortality. Maresin 1 (MaR1), a lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid has been reported to protect against inflammation and promote the regression of acute inflammation. This study proposed to systematically investigate the renoprotective effects and potential molecular mechanism of MaR1 in septic acute kidney injury. We established a S-AKI animal model by a single intraperitoneal injection of lipopolysaccharide (LPS), 10 mg/kg, on male C57BL/6J mice. LPS-stimulated (100 μg/ml) mouse kidney tubular epithelium cells (TCMK-1) were used to simulate septic AKI in vitro. The results showed that pretreatment with MaR1 significantly reduced serum creatinine and blood urea nitrogen levels as well as tubular damage scores and injury marker neutrophil gelatinase-associated lipocalin in septic AKI mice. Meanwhile, MaR1 administration obviously diminished pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, and MCP-1), downregulated BAX and cleaved caspase-3 expression, and upregulated BCL-2 expression in the injured kidney tissues and TCMK-1 cells. In addition, MaR1 reduced malondialdehyde production and improved the superoxide dismutase activity of renal tissues while inhibiting reactive oxygen species (ROS) production and protecting the mitochondria. Mechanistically, LPS stimulated the expression of the NOX4/ROS/NF-κB p65 signaling pathway in S-AKI kidneys, while MaR1 effectively suppressed the activation of the corresponding pathway. In conclusion, MaR1 attenuated kidney inflammation, apoptosis, oxidative stress, and mitochondrial dysfunction to protect against LPS-induced septic AKI via inhibiting the NOX4/ROS/NF-κB p65 signaling pathway.

Aims: This study aimed to evaluate the association between blood lead level (BLL) and abdominal aortic calcification (AAC) in US adults aged ≥40 years.Methods: We obtained data from 2013 to 2014 National Health and Nutrition Examination Survey (NHANES). Participants missing the data of BLL and AAC scores were excluded. BLL was measured using inductively coupled plasma mass spectrometry directly. AAC scores were quantified by Kauppila score system, and severe AAC was defined as AAC score >6. Weighted multivariable regression analysis and subgroup analysis were conducted to explore the independent relationship between BLL with AAC score and severe AAC.Results: A total of 1,530 participants were included with the mean BLL of 1.45 ± 1.31 ng/dl and mean AAC score of 1.40 ± 3.13. The prevalence of severe AAC was 7.98% overall, and participants in higher BLL quartile showed higher prevalence of severe AAC (Quartile 1: 3.55%, Quartile 2: 7.28%, Quartile 3: 9.88%, Quartile 4: 12.58%, P < 0.0001). BLL was positively associated with higher AAC score (β = 0.15, 95% CI: 0.02, 0.27, P = 0.021) and increased risk of severe AAC (OR = 1.11; 95% CI: 1.00–1.22; P = 0.047). Subgroup analysis and interaction test indicated that the association between BLL and AAC was similar in different population settings.Conclusions: Higher BLL was associated with higher AAC score and increased risk of severe AAC. Lead burden should be considered for people with AAC in clinical settings.

The mitigation of aerosol pollution is a great challenge in many cities in China, due to the complex sources and formation mechanism of particulate matter (PM) in different seasons. To understand the particular features of pollution in China and formulate different targeted policies, aerosol samples of PM2.5 were collected from January to October of 2018 in Longyou. The temporal profile of the meteorological parameters and the concentrations of water-soluble inorganic ions (WSIs) and organic matter (OM) were characterized. An Aerodyne High-Resolution Time-of-Flight Aerosol Mass Spectrometer (HR-TOF-AMS) was also applied to further analyze the composition of water-soluble organic carbon (WSOC). The sources of WSOC were resolved by positive matrix factorization (PMF) analysis. The origin of air parcels and potential sources of WSOC were analyzed using a backward trajectory and potential source contribution function (PSCF). Winds from the northeast dominated each sampling period, and the relative humidity did not show a significant difference. The results showed that the proportion of OM in PM2.5 was the highest in summer and decreased in spring, autumn, and winter in turn. Four organic aerosol (OA) factors, including a hydrocarbon-like factor, a coal combustion factor, and two oxygenated OA factors, were identified in the WSOC by means of PMF analysis. The hydrocarbon-like OA (HOA) contributed the majority of the WSOC in summer, while the contribution of the coal-combustion OA (CCOA) increased significantly in winter, suggesting the presence of different sources of WSOC in different seasons. The air parcels from the north of China and Zhejiang province contributed to the CCOA in winter, while those from the marine regions in the south and southeast of China mainly contributed to the HOA during spring and summer. The weighted PSCF (WPSCF) analysis showed that the regions of east Zhejiang province were the main contributors, which means that local and regional emissions were the most probable source areas of WSOC. It implied that not only were the emissions control of both local and regional emissions important but also that the transport of pollutants needed to be sufficiently well accounted for to ensure the successful implementation of air pollution mitigation in Longyou.

The prevalence of traditional bullying and cyberbullying is high among Chinese adolescents. The aims of this study are to explore: (1) characteristics of children who are targets or perpetrators of traditional bullying or cyberbullying; (2) causes of bullying in middle school; (3) reactions and coping strategies of bullying victims; and (4) impacts of bullying on victims' psychosocial well-being. Students were selected based on the findings of previous quantitative research at schools in Zhejiang, Henan, and Chongqing. Snowball sampling led to identification of more informants. Semi-structured interviews were conducted with students involved in traditional bullying and cyberbullying as perpetrators, victims, and bystanders. Forty-one students aged 12–16 years (21 boys and 20 girls) from 16 schools in three provinces participated. Data collection and analysis followed a grounded theory approach. Among these students traditional bullying was much more common than cyberbullying, but there was a large overlap between the two types. The results informed a conceptual framework which identified the main causes of bullying in these settings: these included lack of education about bullying, inadequate classroom and dormitory management, and teachers' failure to recognize and punish bullying. Children with specific characteristics (such as being unattractive or low-achieving), were more likely to be bullied. Most victims lacked support of parents and teachers even when requested, leading to poor psychosocial well-being, difficulties with socialization, and poor academic performance. Our findings suggest that schools need to address bullying culture, through multi-faceted locally-appropriate approaches, based on zero tolerance. It is crucial to ensure that students, teachers and parents recognize the importance of such interventions.

Streptococcus suis serotype 2 (SS2) is an important zoonotic pathogen causing serious disease and even death in pigs and humans. Public health events and economic losses caused by SS2 have prompted widespread concern. Because of the unavailability of vaccines, the development of rapid detection methods for timely diagnosis of SS2 infection or contaminated products, and monitoring of its prevalence in susceptible animals and populations, is required to aid in the prevention and control of SS2 infections. Several sets of primers and one probe for a recombinase polymerase amplification (RPA) assay targeting the cpsJ2 gene were designed and synthesized. Lateral flow (LF) tests in combination with RPA were used to provide visual results. Primers with high amplification efficiency were screened, and the reaction system was optimized. Indicators of detection effectiveness were evaluated. The established method had a detection limit of 100 copies/reaction for recognizing SS2 rather than other organisms. The sensitivity was 100%, as evaluated in infected animal samples. The detection could be completed within 20 min and required only constant temperature equipment. The established rapid, visual, sensitive and specific RPA-LF assay showed superior detection performance and is expected to be widely applied to fight SS2 infection in resource-limited areas.

Phillyrin, a well-known bisepoxylignan, has been shown to have many critical pharmacological activities. In this study, a novel strategy for the extensive acquisition and use of data was established based on UHPLC-Q-Exactive mass spectrometry to analyze and identify the in vivo metabolites of phillyrin and to elucidate the in vivo metabolic pathways of phillyrin. Among them, the generation of data sets was mainly due to multichannel data mining methods, such as high extracted ion chromatogram (HEIC), diagnostic product ion (DPI), and neutral loss filtering (NLF). A total of 60 metabolites (including the prototype compound) were identified in positive and negative ion modes based on intuitive and useful data such as the standard’s cleavage rule, accurate molecular mass, and chromatographic retention time. The results showed that a series of biological reactions of phillyrin in vivo mainly included methylation, hydroxylation, hydrogenation, sulfonation, glucuronidation, demethylation, and dehydrogenation and their composite reactions. In summary, this study not only comprehensively explained the in vivo metabolism of phillyrin, but also proposed an effective strategy to quickly analyze and identify the metabolites of natural pharmaceutical ingredients in nature.

Kidney failure is associated with high morbidity and mortality. Hemodialysis, the most prevalent modality of renal replacement therapy, uses the principle of semipermeable membranes to remove solutes and water in the plasma of patients with kidney failure. With the evolution of hemodialysis technology over the last half century, the clearance of small water-soluble molecules in such patients is adequate. However, middle molecules uremic toxins are still retained in the plasma and cause cardiovascular events, anemia, and malnutrition, which significantly contribute to poor quality of life and high mortality in maintenance hemodialysis patients. A new class of membrane, defined as a medium cut-off (MCO) membrane, has emerged in recent years. Expanded hemodialysis with MCO membranes is now recognized as the artificial kidney model closest to natural kidney physiology. This review summarizes the unique morphological characteristics and internal filtration–backfiltration mechanism of MCO membranes, and describes their effects on removing uremic toxins, alleviating inflammation and cardiovascular risk, and improving quality of life in maintenance hemodialysis patients.

Background/Aims: Blood pressure variability (BPV) is a novel cardiovascular risk factor for the population undergoing hemodialysis (HD). Methods: We conducted a retrospective cohort study of 526 HD patients. Four short-term peridialysis BPV metrics were analyzed: systolic blood pressure (SBP) change, SBP coefficient of variation (CV), SBP intradialytic average real variability (ARV), and absolute SBP residual. Multi variate analysis with Cox regression models were used to account for the potential confounders. Results: Short-term BPV is found to be affected by age, pre-dialysis SBP, antihypertensive drugs, dialysis time, and vascular access. Calcium-channel blockers (CCBs) were found to be associated with lower BPV than those on non-CCB therapy or no antihypertensive drugs. Patients dialyzed in the morning had a greater absolute SBP change than those dialyzed in the afternoon or evening. Patients using fistulas had a lower BPV than catheters. Higher BPV metrics including SBP CV (unadjusted hazard ratio [HR]: 1.37, 95% confidence interval [CI] 1.14-1.66, p=0.001), SBP intradialytic ARV (unadjusted HR: 1.46, 95% CI: 1.20-1.77, p< 0.001), and SBP residual (unadjusted HR: 1.47, 95% CI: 1.21-1.79, p< 0.001) were associated with a greater risk of cardiovascular events. After complete multivariate adjustment for other potential confounders, the HR remained statistically significant for SBP intradialytic ARV (HR 1.31, 95% CI: 1.04-1.66, p=0.024). Conclusion: Peridialytic BPV may be a potential target for improved blood pressure (BP) management in HD patients. Each short-term BPV metric has different advantages and disadvantages and should be applied according to the clinical context and purpose.

Objectives: Orientia tsutsugamushi is an obligate intracellular pathogen that causes scrub typhus. Diagnosing scrub typhus remains a challenge, and a sensitive, specific, simple, and rapid diagnostic test is still needed. Methods: A recombinase polymerase amplification (RPA) assay combined with a lateral flow (LF) test targeting the 56-kDa gene of a Karp-like strain of O. tsutsugamushi was developed and optimized. The detection limits, sensitivity, specificity, and simulative clinical performance were evaluated. Results: Primers and probe were screened to establish the RPA assay, and the reaction conditions were optimized. The detection limit was 10 copies/reaction in detecting plasmid DNA and 12 copies/reaction in detecting genomic DNA. The RPA–LF method could differentiate O. tsutsugamushi from other phylogenetically related bacteria. The sensitivity was 100% and specificity was over 90%, when evaluated using infected animal samples or simulative clinical samples. Furthermore, the method was completed in 20 min at 37 °C followed by a 3–5 min incubation at room temperature for the development of an immunochromatographic strip, and the results could be determined visually. Conclusions: This method is promising for wide-ranging use in basic medical units considering that it requires minimal instruments and infrastructure and is highly time-efficient, sensitive, and specific for diagnosing scrub typhus. Keywords: Orientia tsutsugamushi, Scrub typhus, Recombinase polymerase amplification, Diagnosis, Lateral flow test

En medio de los supermercados de propiedad china en Argentina, hay problemas de la extorsión ejercida por grupos criminales chinos. Un gran número de empresarios chinos han sido afligidos por tales actividades de extorsión y algunos incluso han sufrido de violencia relacionada con extorsión, con cuarenta tenderos chinos asesinados. Esto no solo supone un reto a las autoridades argentinas que se encuentran bajo presión para luchar contra el crimen, sino también puede tener implicaciones preocupantes para las relaciones argentino-chinas. El artículo tiene como objetivo explorar cómo dicha extorsión se lleva a cabo en Argentina, y también las razones detrás de este crimen organizado. Primero, se analiza la historia de la migración china a la Argentina. Después se examina el hecho de tal extorsión a través del marco de Extortion Racket Systems, incluyendo quiénes son los delincuentes y la forma en que operan dentro de la comunidad china en Argentina. La última parte se ocupa de los factores que conducen a la extorsión mediante el uso de la teoría del Estado en la sociedad. A través del análisis, podemos ver que tal extorsión puede ser visto como una consecuencia de la interacción entre la debilidad del Estado de Argentina y la falta de integración de la comunidad china, así como algunas cuestiones culturales.

Snake venoms contain components selected to immobilize prey. The venoms from Elapidae mainly contain neurotoxins, which are critical for rapid prey paralysis, while the venoms from Viperidae and Colubridae may contain fewer neurotoxins but are likely to induce circulatory disorders. Here, we show that the venoms from Protobothrops mucrosquamatus and Trimeresurus stejnegeri are comparable to those of Naja atra in prey immobilization. Further studies indicate that snake C-type lectin-like proteins (snaclecs), which are one of the main nonenzymatic components in viper venoms, are responsible for rapid prey immobilization. Snaclecs (mucetin and stejnulxin) from the venoms of P. mucrosquamatus and T. stejnegeri induce the aggregation of both mammalian platelets and avian thrombocytes, leading to acute cerebral ischemia, and reduced animal locomotor activity and exploration in the open field test. Viper venoms in the absence of snaclecs fail to aggregate platelets and thrombocytes, and thus show an attenuated ability to cause cerebral ischemia and immobilization of their prey. This work provides novel insights into the prey immobilization mechanism of Viperidae snakes and the understanding of viper envenomation-induced cerebral infarction.

OBJECTIVES:Rickettsia rickettsii is the causative agent of Rocky Mountain spotted fever, which is the most severe spotted fever group (SFG) rickettsiosis. Developing a simple and reliable detection method is required. METHODS:A detection method for R. rickettsii was established based on a recombinase polymerase amplification (RPA) assay and the lateral flow (LF) test. A specific target sequence was screened, and corresponding primers and probes were designed, synthesized, and screened for establishing an RPA assay with high amplification efficiency. Reagent concentrations, amplification time, and loading volume for strip development were optimized. The detection limit, analytic sensitivity and specificity were evaluated. RESULTS:A rapid, visual, sensitive and specific method for the detection of R. rickettsii based on RPA and the LF test was successfully established. The novel method had a limit of detection of 10 to 50 copies/reaction without recognizing other organisms. Analytical sensitivity and specificity were ≥90% and 100%, respectively, as evaluated by animal and simulative human samples. CONCLUSIONS:Using the established method, detection could be completed in 30 min with visually detectable results by the naked eye, without requirement of any instrument except a constant temperature equipment. The technique shows superior detection performance and is promising for wide use in the field as well as resource-limited areas for R. rickettsii detection.

It was recently discovered that Ssm Spooky Toxin (SsTx) with 53 residues serves as a key killer factor in red-headed centipede’s venom arsenal, due to its potent blockage of the widely expressed KCNQ channels to simultaneously and efficiently disrupt cardiovascular, respiratory, muscular, and nervous systems, suggesting that SsTx is a basic compound for centipedes’ defense and predation. Here, we show that SsTx also inhibits KV1.3 channel, which would amplify the broad-spectrum disruptive effect of blocking KV7 channels. Interestingly, residue R12 in SsTx extends into the selectivity filter to block KV7.4, however, residue K11 in SsTx replaces this ploy when toxin binds on KV1.3. Both SsTx and its mutant SsTx_R12A inhibit cytokines production in T cells without affecting the level of KV1.3 expression. The results further suggest that SsTx is a key molecule for defense and predation in the centipedes’ venoms and it evolves efficient strategy to disturb multiple physiological targets.