Improving human cardiac organoid design using transcriptomics.

Cardiovascular disease (CVD) is the leading cause of death worldwide. To this end, human cardiac organoids (hCOs) have been developed for improved organotypic CVD modeling over conventional in vivo animal models. Utilizing human cells, hCOs hold great promise to bridge key gaps in CVD research pertaining to human-specific conditions. hCOs are multicellular 3D models which resemble heart structure and function. Varying hCOs fabrication techniques leads to functional and phenotypic differences. To investigate heterogeneity across hCO platforms, we performed a transcriptomic analysis utilizing bulk RNA-sequencing from four previously published unique hCO studies. We further compared selected hCOs to 2D and 3D hiPSC-derived cardiomyocytes (hiPSC-CMs), as well as fetal and adult human myocardium bulk RNA-sequencing samples. Upon investigation utilizing Principal Component Analysis, K-means clustering analysis of key genes, and further downstream analyses such as Gene Set Enrichment (GSEA), Gene Set Variation (GSVA), and GO term enrichment, we found that hCO fabrication method influences maturity and cellular heterogeneity across models. Thus, we propose that adjustment of fabrication method will result in an hCO with a defined maturity and transcriptomic profile to facilitate its specified applications, in turn maximizing its modeling potential.

Spatial Dynamics of Chickenpox Outbreaks in Rapidly Developing Regions: Implications for Global Public Health.

Objective: The occurrence of chickenpox in rapidly developing areas poses substantial seasonal risk to children. However, certain factors influencing local chickenpox outbreaks have not been studied. Here, we examined the relationship between spatial clustering, heterogeneity of chickenpox outbreaks, and socioeconomic factors in Southern China. Methods: We assessed chickenpox outbreak data from Southern China between 2006 and 2021, comprising both relatively fast-growing parts and slower sub-regions, and provides a representative sample of many developing regions. We analyzed the spatial clustering attributes associated with chickenpox outbreaks using Moran's I and local indicators of spatial association and quantified their socioeconomic determinants using Geodetector q statistics. Results: There were significant spatial heterogeneity in the risk of chickenpox outbreaks, with strong correlations between chickenpox risk and various factors, particularly demographics and living environment. Furthermore, interactive effects among specific are factors, such as population density and per capita residential building area, percentage of households with toilets, percentage of rental housing, exhibited q statistics of 0.28, 0.25, and 0.24, respectively. Conclusion: This study provides valuable insights into the spatial dynamics of chickenpox outbreaks in rapidly developing regions, revealing the socioeconomic factors affecting disease transmission. These implications extend the formulation of effective public health strategies and interventions to prevent and control chickenpox outbreaks in similar global contexts.

De novo design of miniprotein antagonists of cytokine storm inducers.

Cytokine release syndrome (CRS), commonly known as cytokine storm, is an acute systemic inflammatory response that is a significant global health threat. Interleukin-6 (IL-6) and interleukin-1 (IL-1) are key pro-inflammatory cytokines involved in CRS and are hence critical therapeutic targets. Current antagonists, such as tocilizumab and anakinra, target IL-6R/IL-1R but have limitations due to their long half-life and systemic anti-inflammatory effects, making them less suitable for acute or localized treatments. Here we present the de novo design of small protein antagonists that prevent IL-1 and IL-6 from interacting with their receptors to activate signaling. The designed proteins bind to the IL-6R, GP130 (an IL-6 co-receptor), and IL-1R1 receptor subunits with binding affinities in the picomolar to low-nanomolar range. X-ray crystallography studies reveal that the structures of these antagonists closely match their computational design models. In a human cardiac organoid disease model, the IL-1R antagonists demonstrated protective effects against inflammation and cardiac damage induced by IL-1ß. These minibinders show promise for administration via subcutaneous injection or intranasal/inhaled routes to mitigate acute cytokine storm effects.

Protecting stable biological nomenclatural systems enables universal communication: A collective international appeal.

The fundamental value of universal nomenclatural systems in biology is that they enable unambiguous scientific communication. However, the stability of these systems is threatened by recent discussions asking for a fairer nomenclature, raising the possibility of bulk revision processes for "inappropriate" names. It is evident that such proposals come from very deep feelings, but we show how they can irreparably damage the foundation of biological communication and, in turn, the sciences that depend on it. There are four essential consequences of objective codes of nomenclature: universality, stability, neutrality, and transculturality. These codes provide fair and impartial guides to the principles governing biological nomenclature and allow unambiguous universal communication in biology. Accordingly, no subjective proposals should be allowed to undermine them.

Impact of pre-delivery medication treatment on delivery outcome in patients with primary immune thrombocytopenia: a cohort study.

BACKGROUND: Clinical research data showed a series of adverse events in the delivery period of primary immune thrombocytopenia (ITP) patients, including high cesarean section rate. Consensus report proposed that for patients with platelet count below 50 × 109/L, prednisone or intravenous immunoglobulins (IVIg) can be given to raise the platelet count in third trimester in preparation for labor. OBJECTIVES: To evaluate the effect of low-dose prednisone or IVIg therapy on delivery outcomes in patients with ITP. STUDY DESIGN: This was a cohort study that included pregnant women with ITP from January 2017 to December 2022. Patients with platelet counts of (20-50) ×109/L at the time of delivery (≥34 weeks) and who had not received any medication before were enrolled in the study. Patients were divided into the pre-delivery medication group (oral prednisone or IVIg) and untreated group according to their preferences. The differences in vaginal delivery rate, postpartum bleeding rate, and platelet transfusion volume between the two groups were compared using t-test, Wilcoxon rank-sum test, and χ2 test. Logistic regression analysis was used to identify the factors affecting vaginal delivery rate and postpartum bleeding rate, and multiple linear regression analysis was used to identify the factors affecting platelet transfusion volume. RESULTS: During the study period, a total of 96 patients with ITP were enrolled, including 70 in the pre-delivery medication group and 26 in the untreated group. The platelet count of pre-delivery medication group was 54.8 ± 34.5 × 109/L, which was significantly higher than that of untreated group 34.4 ± 9.0 × 109/L (p = .004). The vaginal delivery rate of the medication group was higher than the untreated group [60.0% (42/70) vs. 30.8% (8/26), χ2 = 6.49, p = .013]. After adjusting for the proportion of multiparous women and gestational weeks, the results showed that medication therapy during the peripartum period was associated with vaginal delivery (OR = 4.937, 95% CI: 1.511-16.136, p = .008). The postpartum bleeding rates were 22.9% (16/70) and 26.9% (7/26) in the medication group and untreated group, respectively, with no significant difference between the two groups (χ2 = 0.17, p = .789), while the platelet transfusion volume was lower in the medication group than untreated group [(1.1 ± 1.0) vs. (1.6 ± 0.8) U]. CONCLUSION: Pre-delivery medication therapy can increase vaginal delivery rate, reduce platelet transfusion volume, but does not decrease the incidence of postpartum hemorrhage.

What is the context?The high cesarean section rate has always been a prominent pregnancy issue in ITP patients. The data shows that the reason for cesarean section in most ITP patients may be related to early induced labor due to thrombocytopenia or patients' concerns of bleeding events during delivery. The study of treatment during the perinatal period is expected to further increase platelet count and prepare for safer delivery.What is new?To date, no study has focused on pre-delivery treatment for pregnant ITP patients. In this study, patients with a platelet count<50 × 109/L after 34 weeks can experience a significant increase in platelet count after receiving immunoglobulin or prednisone therapy. The results of this study preliminarily demonstrate IVIg or prednisone is a promising pre-delivery treatment for pregnant ITP patients in preparation for labor. The pre-delivery medication therapy can improve the rate of successful vaginal delivery and reduce the consumption of blood products.What is the impact?This study provides further evidence that the target threshold for platelets should be raised in late third trimester, with a platelet count above 50 × 109/L as the standard for delivery, in order to further reduce the cesarean section rate and blood product infusion in ITP patients.

The first large scale rDNA amplicon database of soil microbiomes from Pamir Plateau, China.

The Eastern Pamir, distinguished with high altitude, extremely arid and cold climate, limited nutrients and sparse vegetation, is a unique ecological reservoir. Microbial communities play a central role in maintaining Eastern Pamir's ecosystem functioning. Despite the ecological significance, due to the difficulty of sample collection and microbial isolation, the microbial diversity and its functionality at the Pamir Plateau have been rarely documented. To fill this gap, 80 soil samples from 17 sites across different elevations were collected, performed the rDNA amplicon sequencing to present the first large-scale overview of bacterial, archaeal, and fungal communities in the Eastern Pamir. Microbiome analysis revealed that the bacteria Actinobacteria, Alphaproteobacteria and Bacteroidia, alongside such as archaea Nitrososphaeria and Halobacteria, and fungi including Dothideomycetes, Sordariomycetes and Eurotiomycetes were dominant lineages at class level in soil microbial communities. The community structure and biodiversity of soil microorganisms provided by this dataset would be pivotal for future studies aimed at understanding the biogeographical distribution, ecological functions and environmental responses of microbial communities of the Pamir Plateau.

Genome-Wide Mendelian Randomization Study Reveals Druggable Genes for Cerebral Small Vessel Disease.

BACKGROUND: Cerebral small vessel disease (CSVD) is a group of neurological disorders that affect the small blood vessels within the brain, for which no effective treatments are currently available. We conducted a Mendelian randomization (MR) study to identify candidate therapeutic genes for CSVD. METHODS: We retrieved genome-wide association study data from 6 recently conducted, extensive investigations focusing on CSVD magnetic resonance imaging markers and performed a 2-sample MR analysis to assess the potential causal effects of gene expression and protein level within druggable genes on CSVD in blood and brain tissues. Colocalization analyses and repeat studies were undertaken to verify the relationship. Additionally, mediation analysis was conducted to explore the potential mechanisms involving druggable genes and known risk factors for CSVD. Finally, phenome-wide MR analyses were applied to evaluate the potential adverse effects related to the identified druggable genes for CSVD treatment. RESULTS: Overall, 5 druggable genes consistently showed associations with CSVD in MR analyses across both the discovery and validation cohorts. Notably, the ALDH2 and KLHL24 genes were identified as associated with CSVD in both blood and brain tissues, whereas the genes ADRB1, BTN3A2, and EFEMP1 were exclusively detected in brain tissue. Moreover, mediation analysis elucidated the proportion of the total effects mediated by CSVD risk factors through candidate druggable genes, which ranged from 5.5% to 18.5%, and offered potential explanations for the observed results. A comprehensive phenome-wide MR analysis further emphasized both the therapeutic benefits and potential side effects of targeting these candidate druggable genes. CONCLUSIONS: This study provides genetic evidence supporting the potential therapeutic benefits of targeting druggable genes for treating CSVD, which will be useful for prioritizing CSVD drug development.

[A quality improvement project on reducing antibiotic use duration in very low birth weight preterm infants in the neonatal intensive care unit]. / é™ä½Žæ–°ç”Ÿå„¿é‡ç—‡ç›‘æŠ¤å®¤æžä½Žå‡ºç”Ÿä½“é‡æ—©äº§å„¿æŠ—ç”Ÿç´ ä½¿ç”¨æ—¶é—´çš„è´¨é‡æ”¹è¿›ç ”ç©¶.

OBJECTIVES: To develop effective measures to reduce antibiotic use duration in very low birth weight (VLBW) preterm infants in the neonatal intensive care unit through quality improvement methods. METHODS: The study population consisted of hospitalized VLBW preterm infants, with the percentage of hospitalization time during which antibiotics were used from November 2020 to June 2021 serving as the baseline. The specific quality improvement goal was to reduce the duration of antibiotic use. Factors affecting antibiotic use duration in preterm infants were analyzed using Pareto charts. Key drivers were identified, and specific interventions were formulated based on the stages of antibiotic use. Changes in the percentage of antibiotic use duration were monitored with run charts until the quality improvement target was achieved. RESULTS: From November 2020 to June 2021, the baseline antibiotic use duration percentage was 49%, with a quality improvement target to reduce this by 10% within 12 months. The Pareto analysis indicated that major factors influencing antibiotic duration included non-standard antibiotic use; delayed cessation of antibiotics when no infection evidence was present; prolonged central venous catheter placement; insufficient application of kangaroo care; and delayed progress in enteral nutrition. The interventions implemented included: (1) establishing sepsis evaluation and management standards; (2) educating medical staff on the rational use of antibiotics for preterm infants; (3) supervising the enforcement of antibiotic use standards during ward rounds; (4) for those without clear signs of infection and with negative blood cultures, discontinued the use of antibiotics 36 hours after initiation; (5) reducing the duration of central venous catheterization and parenteral nutrition to lower the risk of infection in preterm infants. The control chart showed that with continuous implementation of interventions, the percentage of antibiotic use duration was reduced from 49% to 32%, a statistically significant decrease. CONCLUSIONS: The application of quality improvement tools based on statistical principles and process control may significantly reduce the antibiotic use duration in VLBW preterm infants. Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(7): 736-742.

Does using a bioptic telescope improve visual recognition of the on-road environment?

SIGNIFICANCE: Individuals with reduced visual acuity (VA) may drive with bioptic telescopes in some jurisdictions. The effect of bioptic telescope use on on-road recognition distances is important for driving safety, as increased recognition distances increase the time available to react to road signs or driving events. PURPOSE: This study aimed to investigate the impact of bioptic telescope use on visual recognition of road signs, traffic lights, and hazards in an on-road driving environment in individuals with reduced VA. METHODS: Ten individuals (mean ± standard deviation age, 39.1 ± 19.1 years) with reduced VA (trained to use bioptic telescopes) participated in a repeated-measures on-road experiment for two viewing conditions, with and without a bioptic telescope (randomized order). Participants underwent a clinical low vision assessment, including high-contrast VA with and without the bioptic telescope aligned, visual fields, and contrast sensitivity testing. For the driving component, participants seated in the front passenger seat of a moving car reported all road signs, traffic lights, and hazards (unpredictable road events that represent a risk to driving safety including other vehicles, cyclists, pedestrians) seen along a route that included suburban roads and highways. Video cameras captured participants' viewing behavior, verbal commentary, and the distance at which three pre-selected road signs were reported. RESULTS: In the eye with the bioptic telescope, high-contrast VA improved from 0.75 ± 0.17 (without) to 0.25 ± 0.1 logMAR with the bioptic telescope. Bioptic telescope use did not affect the percentage of road signs, traffic lights, or hazards correctly recognized but did result in 2.6 times longer recognition distances (49 ± 23 vs. 19 ± 11 m, t9 = 5.02, p<0.001). CONCLUSIONS: Road signs were recognized at significantly longer distances when using a bioptic telescope, confirming their positive impact on timely visual recognition of objects within the driving scene. Future work should explore whether this effect generalizes to individuals using bioptic telescopes when driving a vehicle.

Challenges, experiences, and potential supports for East and Southeast Asian mothers in the workforce: a systematic review.

OBJECTIVE: To examine the challenges faced by Asian working mothers with a focus on re-entry to the workplace. In addition, we highlight potential supports that retain women in the workforce. DESIGN: A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations and registered with PROSPERO database (CRD42022341130). METHODS: Three independent reviewers were involved in the study selection to screen the search results sequentially by title, abstract, and full text using predefined inclusion and exclusion criteria. The methodological quality of each article was assessed via the Critical Appraisal Skills Programme (CASP) tool. RESULTS: We analysed a total of 36 studies conducted across different regions: 30 from the East and 6 from Southeast Asia. Among these studies, 20 were quantitative in nature, 15 were qualitative, and one intervention. The 36 studies cover five themes: 1) policies, 2) external support sources, 3) external pressure, 4) breastfeeding and 5) health status. Within each theme the same factor can have a positive or negative impact on the mother depending on her having a pro-career or pro-family mindset. Companies can take various initiatives to support working mothers, such as providing facilities for expressing breast milk at the workplace, educating staff to promote breastfeeding and accommodate childcare needs, and extending maternity leaves. However, there is a lack of literature that directly addresses the barriers and concrete support available to working mothers in Asia, beyond the scope of breastfeeding. CONCLUSIONS: Our findings underscore several obstacles that can impede a woman's seamless return to work. Pro-family and pro-career mothers have differing needs that cannot be addressed at the same time. There is a lack of comprehensive understanding regarding effective strategies or interventions that can support a positive reintegration into the workforce.

Rhopaloic acid A triggers mitochondria damage-induced apoptosis in oral cancer by JNK/BNIP3/Nix-mediated mitophagy.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a frequently occurring type of head and neck cancer with a high mortality and morbidity rate. Rhopaloic acid A (RA), a terpenoid derived from sponges, has demonstrated a promising anti-tumor activity, but its effectiveness for treating OSCC remains unknown. PURPOSE: The aim of this study was to investigate whether RA inhibits the growth of OSCC. METHODS: Cell viability was evaluated using CCK-8 assays in OSCC cells (Ca9-22, HSC-3 and SAS) and in normal cells (HGF-1) treated with RA. DAPI staining, AO staining, JC-1 staining and immunofluorescence were used to determine apoptosis, mitochondrial membrane potential and autophagy in RA-treated OSCC cells. Protein expression levels were determined by western blotting. Furthermore, the anti-tumor effect of RA was confirmed in vivo using a zebrafish oral cancer xenotransplantation model. RESULTS: OSCC cells had a significantly reduced viability after RA treatment, but normal cells were not affected. Treatment with RA caused chromatin condensation in OSCC cells, which increased their expression of autophagy- and apoptosis-related proteins. Furthermore, RA caused mitochondrial damage and increased autophagosome formation. Mitophagy was also induced by RA through the JNK/BNIP3/Nix/LC3B pathway. The JNK inhibitor SP600125 prevented both RA-mediated cell death and mitophagy of OSCC cells. A zebrafish xenograft model demonstrated that RA inhibits OSCC growth. CONCLUSION: In conclusion, RA showed a potent anticancer activity in in vitro and in in vivo oral cancer models by promoting mitochondrial damage-induced apoptosis and mitophagy, which suggests that RA may be useful as a novel and effective treatment for OSCC.

Dysrhythmic saliva microbiota in mobile phone addicts with sleep disorders and restored by acupuncture.

Background: Mobile phone addiction (MPA) greatly affects the biological clock and sleep quality and is emerging as a behavioral disorder. The saliva microbiota has been linked to circadian rhythms, and our previous research revealed dysrhythmic saliva metabolites in MPA subjects with sleep disorders (MPASD). In addition, acupuncture had positive effects. However, the dysbiotic saliva microbiota in MPASD patients and the restorative effects of acupuncture are unclear. Objectives: To probe the circadian dysrhythmic characteristics of the saliva microbiota and acupunctural restoration in MPASD patients. Methods: MPASD patients and healthy volunteers were recruited by the Mobile Phone Addiction Tendency Scale (MPATS) and the Pittsburgh Sleep Quality Index (PSQI). Saliva samples were collected every 4 h for 72 h. After saliva sampling, six MPDSD subjects (group M) were acupuncturally treated (group T), and subsequent saliva sampling was conducted posttreatment. Finally, all the samples were subjected to 16S rRNA gene sequencing and bioinformatic analysis. Results: Significantly increased MPATS and PSQI scores were observed in MPDSD patients (p< 0.01), but these scores decreased (p<0.001) after acupuncture intervention. Compared with those in healthy controls, the diversity and structure of the saliva microbiota in MPASD patients were markedly disrupted. Six genera with circadian rhythms were detected in all groups, including Sulfurovum, Peptostreptococcus, Porphyromonas and Prevotella. There were five genera with circadian rhythmicity in healthy people, of which the rhythmicities of the genera Rothia and Lautropia disappeared in MPASD patients but effectively resumed after acupuncture intervention. Conclusions: This work revealed dysrhythmic salivary microbes in MPASD patients, and acupuncture, as a potential intervention, could be effective in mitigating this ever-rising behavioral epidemic.

Composition and distribution of bacterial communities and potential radiation-resistant bacteria at different elevations in the eastern Pamirs.

Altitude and ultraviolet (UV) radiation may affect the community composition and distribution of microorganisms in soil ecosystems. In this study, 49 soil samples from 10 locations were collected from different elevations on the eastern Pamir Plateau and analyzed for soil microbial community structure and function using high-throughput sequencing. The results showed that soil samples from different elevations of the eastern Pamir Plateau contained 6834 OTUs in 26 phyla and 399 genera. The dominant phyla common to different elevations were Actinobacteria, Proteobacteria, Bacteroidota, Acidobacteriota, and Gemmatimonadota. The dominant genera were Rubrobacter, Sphingomonas, Nocardioides, and Solirubrobacter. Species richness increased slightly with elevation, and there were significant differences in community composition between the elevations. Elevation and UV exposure are important factors that drive changes in bacterial communities. The results of the KEGG pathway showed that drug resistance, antineoplastic, aging, replication, and repair were enhanced and then slightly decreased with increasing elevation. Bacterial communities at different elevations were rich in radiation-resistant microorganisms, and the main genera were Rubrobacter, Sphingomonas, Nocardioides, Pontibacter, and Streptomyces. The findings have shown the composition and distribution of bacterial communities at different elevations on the Eastern Pamir Plateau. Potentially radiation tolerant microbial species were also examined. The results are of considerable importance for the succession of bacterial microorganisms in the plateau region, the study of radiation tolerant bacterial germplasm resources, and the application of biofunctionality.

The development of meridional anisotropies in neurotypical children with and without astigmatism: Electrophysiological and psychophysical findings.

It is important to understand the development of meridional anisotropies in neurotypical children since those with poor visual development, such as amblyopia, can have different patterns of meridional anisotropies. While the oblique effect is usually observed in adults, neurotypical children who have normal 20/20 visual acuity tend to demonstrate a horizontal effect electrophysiologically. In this longitudinal study, orientation-specific visual evoked potentials (osVEPs) and psychophysical grating acuity were used to investigate the changes in the meridional anisotropies in children aged 3.8 to 9.2 years over two visits averaging four months apart. While it was hypothesized that the electrophysiological horizontal effect may shift towards an oblique effect, it was found that the electrophysiological horizontal effect persisted to be present in response to the suprathreshold moderate contrast 4 cycles-per-degree grating stimuli. Psychophysical grating acuity, however, demonstrated an oblique effect when assessed binocularly. In addition, a significant effect of visit, representing an increase in the average age over this period, was observed in the average osVEP C3 amplitudes (4.5 µV) and psychophysical grating acuity (0.28 octaves or approximately 1-line on the logMAR chart). These findings are relevant when evaluating amblyopia treatments and interventions, as it confirms the necessity to take into account of the effect of normal maturation and learning effects when evaluating young children. Special attention should also be given to children with early-onset myopia and high astigmatism even when their visual acuity is 20/20 as the electrophysiological findings are suggestive of poor visual development, which warrants further investigation.

Structural investigations on the mitochondrial uncouplers niclosamide and FCCP.

There has been renewed interest in using mitochondrial uncoupler compounds such as niclosamide and carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) for the treatment of obesity, hepatosteatosis and diseases where oxidative stress plays a role. However, both FCCP and niclosamide have undesirable effects that are not due to mitochondrial uncoupling, such as inhibition of mitochondrial oxygen consumption by FCCP and induction of DNA damage by niclosamide. Through structure-activity analysis, we identified FCCP analogues that do not inhibit mitochondrial oxygen consumption but still provided good, although less potent, uncoupling activity. We also characterized the functional role of the niclosamide 4'-nitro group, the phenolic hydroxy group and the anilide amino group in mediating uncoupling activity. Our structural investigations provide important information that will aid further drug development.

[A multicenter study of neonatal stroke in Shenzhen, China]. / 深圳市新生儿脑卒中多中心现况调查.

OBJECTIVES: To investigate the incidence rate, clinical characteristics, and prognosis of neonatal stroke in Shenzhen, China. METHODS: Led by Shenzhen Children's Hospital, the Shenzhen Neonatal Data Collaboration Network organized 21 institutions to collect 36 cases of neonatal stroke from January 2020 to December 2022. The incidence, clinical characteristics, treatment, and prognosis of neonatal stroke in Shenzhen were analyzed. RESULTS: The incidence rate of neonatal stroke in 21 hospitals from 2020 to 2022 was 1/15 137, 1/6 060, and 1/7 704, respectively. Ischemic stroke accounted for 75% (27/36); boys accounted for 64% (23/36). Among the 36 neonates, 31 (86%) had disease onset within 3 days after birth, and 19 (53%) had convulsion as the initial presentation. Cerebral MRI showed that 22 neonates (61%) had left cerebral infarction and 13 (36%) had basal ganglia infarction. Magnetic resonance angiography was performed for 12 neonates, among whom 9 (75%) had involvement of the middle cerebral artery. Electroencephalography was performed for 29 neonates, with sharp waves in 21 neonates (72%) and seizures in 10 neonates (34%). Symptomatic/supportive treatment varied across different hospitals. Neonatal Behavioral Neurological Assessment was performed for 12 neonates (33%, 12/36), with a mean score of (32±4) points. The prognosis of 27 neonates was followed up to around 12 months of age, with 44% (12/27) of the neonates having a good prognosis. CONCLUSIONS: Ischemic stroke is the main type of neonatal stroke, often with convulsions as the initial presentation, involvement of the middle cerebral artery, sharp waves on electroencephalography, and a relatively low neurodevelopment score. Symptomatic/supportive treatment is the main treatment method, and some neonates tend to have a poor prognosis.

Nobiletin derivative, 5-acetoxy-6,7,8,3',4'-pentamethoxyflavone, inhibits neuroinflammation through the inhibition of TLR4/MyD88/MAPK signaling pathways and STAT3 in microglia.

OBJECTIVE: Microglia in the central nervous system regulate neuroinflammation that leads to a wide range of neuropathological alterations. The present study investigated the anti-neuroinflammatory properties of nobiletin (Nob) derivative, 5-acetoxy-6,7,8,3',4'-pentamethoxyflavone (5-Ac-Nob), in lipopolysaccharide (LPS)-activated BV2 microglia. MATERIALS AND METHODS: By using the MTT assay, Griess method, flow cytometry, and enzyme-linked immunosorbent assay (ELISA), we determined the cell viability, the levels of nitric oxide (NO), reactive oxygen species (ROS), and pro-inflammatory factors (interleukin 1 beta; IL-1ß, interleukin 6; IL-6, tumor necrosis factor alpha; TNF-α and prostaglandin E2; PGE2) in LPS-stimulated BV2 microglia. Toll-like receptor 4 (TLR4)-mediated myeloid differentiation primary response gene 88 (MyD88)/nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) signaling pathway and signal transducer and activator of transcription 3 (STAT3) were measured by western blotting. Analysis of NO generation and mRNA of pro-inflammatory cytokines was confirmed in the zebrafish model. RESULTS: 5-Ac-Nob reduced cell death, the levels of NO, ROS, inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and pro-inflammatory factors in LPS-activated BV-2 microglial cells. TLR4-mediated MyD88/NF-κB and MAPK pathway (p38, ERK and JNK) after exposure to 5-Ac-Nob was also suppressed. Moreover, 5-Ac-Nob inhibited phosphorylated STAT3 proteins expression in LPS-induced BV-2 microglial cells. Furthermore, we confirmed that 5-Ac-Nob decreased LPS-induced NO generation and mRNA of pro-inflammatory cytokines in the zebrafish model. CONCLUSIONS: Our findings suggest that 5-Ac-Nob represses neuroinflammatory responses by inhibiting TLR4-mediated signaling pathway and STAT3. As a result of these findings, 5-Ac-Nob has potential as an anti-inflammatory agent against microglia-mediated neuroinflammatory disorders.

Mesenchymal stem cells and their derived exosomes for the treatment of COVID-19.

Coronavirus disease 2019 (COVID-19) is an acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 infection typically presents with fever and respiratory symptoms, which can progress to severe respiratory distress syndrome and multiple organ failure. In severe cases, these complications may even lead to death. One of the causes of COVID-19 deaths is the cytokine storm caused by an overactive immune response. Therefore, suppressing the overactive immune response may be an effective strategy for treating COVID-19. Mesenchymal stem cells (MSCs) and their derived exosomes (MSCs-Exo) have potent homing abilities, immunomodulatory functions, regenerative repair, and antifibrotic effects, promising an effective tool in treating COVID-19. In this paper, we review the main mechanisms and potential roles of MSCs and MSCs-Exo in treating COVID-19. We also summarize relevant recent clinical trials, including the source of cells, the dosage and the efficacy, and the clinical value and problems in this field, providing more theoretical references for the clinical use of MSCs and MSCs-Exo in the treatment of COVID-19.

The Antimicrobial Peptide Tilapia Piscidin 4 Induced the Apoptosis of Bladder Cancer Through ERK/SIRT1/PGC-1α Signaling Pathway.

Marine antimicrobial peptides have been demonstrated in numerous studies to possess anti-cancer properties. This research investigation aimed to explore the fundamental molecular mechanisms underlying the antitumor activity of Tilapia piscidin 4 (TP4), an antimicrobial peptide, in human bladder cancer. TP4 exhibited a remarkable inhibitory effect on the proliferation of bladder cancer cells through cell cycle arrest at the G2/M phase. Additionally, TP4 upregulated the expression of cleaved caspase-3, caspase-9, and PARP, leading to the activation of apoptotic pathways in bladder cancer cells. TP4 exhibit a marked rise in mitochondria reactive oxygen species, leading to the subsequent loss of potential for the mitochondrial membrane. Furthermore, the inhibition of mitochondrial oxidative phosphorylation resulted in a decrease in downstream ATP production. Meanwhile, TP4-treated bladder cancer cells showed an increase in Bax and ERK but a decrease in SIRT1, PGC-1α, and Bcl2. ERK activation, SIRT1/PGC-1α-axis, and TP4-induced apoptosis were all significantly reversed by the ERK inhibitor SCH772984. Finally, the inhibitory effect of TP4 on tumor growth has been confirmed in a zebrafish bladder cancer xenotransplantation model. These findings suggest that TP4 may be a potential agents for human bladder cancer through apoptosis induction, ERK activation, and the promotion of SIRT1-mediated signaling pathways.

Exaggerated sensitivity to threat and reduced medial prefrontal engagement during threat generalization in reactive aggressive adolescents.

Aggressive adolescents tend to exhibit abnormal fear acquisition and extinction, and reactive aggressive adolescents are often more anxious. However, the relationship between fear generalization and reactive aggression (RA) remains unknown. According to Reactive-Proactive Aggression Questionnaire (RPQ) scores, 61 adolescents were divided into two groups, namely, a high RA group (N = 30) and a low aggression (LA) group (N = 31). All participants underwent three consecutive phases of the Pavlovian conditioning paradigm (i.e., habituation, acquisition, and generalization), and neural activation of the medial prefrontal cortex (mPFC) was assessed by functional near-infrared spectroscopy (fNIRS). The stimuli were ten circles with varying sizes, including two conditioned stimuli (CSs) and eight generalization stimuli (GSs). A scream at 85 dB served as the auditory unconditioned stimulus (US). The US expectancy ratings of both CSs and GSs were higher in the RA group than in the LA group. The fNIRS results showed that CSs and GSs evoked lower mPFC activation in the RA group compared to the LA group during fear generalization. These findings suggest that abnormalities in fear acquisition and generalization are prototypical dysregulations in adolescents with RA. They provide neurocognitive evidence for dysregulated fear learning in the mechanisms underlying adolescents with RA, highlighting the need to develop emotional regulation interventions for these individuals.