Antiretroviral drug dolutegravir induces inflammation at the mouse brain barriers.

Integrase strand transfer inhibitors (INSTIs) based antiretroviral therapy (ART) is currently used as first-line regimen to treat HIV infection. Despite its high efficacy and barrier to resistance, ART-associated neuropsychiatric adverse effects remain a major concern. Recent studies have identified a potential interaction between the INSTI, dolutegravir (DTG), and folate transport pathways at the placental barrier. We hypothesized that such interactions could also occur at the two major blood-brain interfaces: blood-cerebrospinal fluid barrier (BCSFB) and blood-brain barrier (BBB). To address this question, we evaluated the effect of two INSTIs, DTG and bictegravir (BTG), on folate transporters and receptor expression at the mouse BCSFB and the BBB in vitro, ex vivo and in vivo. We demonstrated that DTG but not BTG significantly downregulated the mRNA and/or protein expression of folate transporters (RFC/SLC19A1, PCFT/SLC46A1) in human and mouse BBB models in vitro, and mouse brain capillaries ex vivo. Our in vivo study further revealed a significant downregulation in Slc19a1 and Slc46a1 mRNA expression at the BCSFB and the BBB following a 14-day DTG oral treatment in C57BL/6 mice. However, despite the observed downregulatory effect of DTG in folate transporters/receptor at both brain barriers, a 14-day oral treatment of DTG-based ART did not significantly alter the brain folate level in animals. Interestingly, DTG treatment robustly elevated the mRNA and/or protein expression of pro-inflammatory cytokines and chemokines (Cxcl1, Cxcl2, Cxcl3, Il6, Il23, Il12) in primary cultures of mouse brain microvascular endothelial cells (BBB). DTG oral treatment also significantly upregulated proinflammatory cytokines and chemokine (Il6, Il1ß, Tnfα, Ccl2) at the BCSFB in mice. We additionally observed a downregulated mRNA expression of drug efflux transporters (Abcc1, Abcc4, and Abcb1a) and tight junction protein (Cldn3) at the CP isolated from mice treated with DTG. Despite the structural similarities, BTG only elicited minor effects on the markers of interest at both the BBB and BCSFB. In summary, our current data demonstrates that DTG but not BTG strongly induced inflammatory responses in a rodent BBB and BCSFB model. Together, these data provide valuable insights into the mechanism of DTG-induced brain toxicity, which may contribute to the pathogenesis of DTG-associated neuropsychiatric adverse effect.

Safety and efficacy of baricitinib in steroid-resistant or relapsed immune thrombocytopenia: An open-label pilot study.

Patients with steroid-resistant or relapsed immune thrombocytopenia (ITP) suffer increased bleeding risk and impaired quality of life. Baricitinib, an oral Janus-associated kinases (JAK) inhibitor, could alleviate both innate and adaptive immune disorders without inducing thrombocytopenia in several autoimmune diseases. Accordingly, an open-label, single-arm, phase 2 trial (NCT05446831) was initiated to explore the safety and efficacy of baricitinib in ITP. Eligible patients were adults with primary ITP who were refractory to corticosteroids and at least one subsequent treatment, and had platelet counts below 30 × 109/L at enrolment. Participants received baricitinib 4 mg daily for 6 months. The primary endpoint was durable response at the 6-month follow-up. A total of 35 patients were enrolled. Durable response was achieved in 20 patients (57.1%, 95% confidence interval, 39.9 to 74.4), and initial response in 23 (65.7%) patients. For patients responding to baricitinib, the median time to response was 12 (IQR 6-20) days, and the median peak platelet count was 94 (IQR 72-128) × 109/L. Among the 27 patients undergoing extend observation, 12 (44.4%) remained responsive for a median duration of approximately 20 weeks after baricitinib discontinuation. Adverse events were reported in 11 (31.4%) patients, including infections in 6 (17.1%) patients during the treatment period. Treatment discontinuation due to an adverse event was reported in 2 (5.7%) patients. Evidence from this pilot study suggested that baricitinib might be a novel candidate for the armamentarium of ITP-modifying agents. Future studies are warranted to validate the safety, efficacy, and optimal dosing of baricitinib in patients with ITP.

Recent Advances in Materials, Devices and Algorithms Toward Wearable Continuous Blood Pressure Monitoring.

Continuous blood pressure (BP) tracking provides valuable insights into the health condition and functionality of the heart, arteries, and overall circulatory system of humans. The rapid development in flexible and wearable electronics has significantly accelerated the advancement of wearable BP monitoring technologies. However, several persistent challenges, including limited sensing capabilities and stability of flexible sensors, poor interfacial stability between sensors and skin, and low accuracy in BP estimation, have hindered the progress in wearable BP monitoring. To address these challenges, comprehensive innovations in materials design, device development, system optimization, and modeling have been pursued to improve the overall performance of wearable BP monitoring systems. In this review, we highlight the latest advancements in flexible and wearable systems toward continuous noninvasive BP tracking with a primary focus on materials development, device design, system integration, and theoretical algorithms. Existing challenges, potential solutions, and further research directions are also discussed to provide theoretical and technical guidance for the development of future wearable systems in continuous ambulatory BP measurement with enhanced sensing capability, robustness, and long-term accuracy.

High dimensional proteomic mapping of bone marrow immune characteristics in immune thrombocytopenia.

To investigate the role of co-stimulatory and co-inhibitory molecules on immune tolerance in immune thrombocytopenia (ITP), this study mapped the immune cell heterogeneity in the bone marrow of ITP at the single-cell level using Cytometry by Time of Flight (CyTOF). Thirty-six patients with ITP and nine healthy volunteers were enrolled in the study. As soluble immunomodulatory molecules, more sCD25 and sGalectin-9 were detected in ITP patients. On the cell surface, co-stimulatory molecules like ICOS and HVEM were observed to be upregulated in mainly central memory and effector T cells. In contrast, co-inhibitory molecules such as CTLA-4 were significantly reduced in Th1 and Th17 cell subsets. Taking a platelet count of 30×109 L-1 as the cutoff value, ITP patients with high and low platelet counts showed different T cell immune profiles. Antigen-presenting cells such as monocytes and B cells may regulate the activation of T cells through CTLA-4/CD86 and HVEM/BTLA interactions, respectively, and participate in the pathogenesis of ITP. In conclusion, the proteomic and soluble molecular profiles brought insight into the interaction and modulation of immune cells in the bone marrow of ITP. They may offer novel targets to develop personalized immunotherapies.

Corrigendum: Impact of drought on soil microbial biomass and extracellular enzyme activity.

[This corrects the article DOI: 10.3389/fpls.2023.1221288.].

Interface Engineering of PdPt Ultrafine Ethanol Electro-Oxidation Nanocatalysts by Bacterial Soluble Extracellular Polymeric Substances (s-EPS) to Break through Sabatier Principle.

Unsatisfactory performance of ethanol oxidation reaction (EOR) catalysts hinders the application of direct ethanol fuel cells (DEFCs), while traditional alloy catalysts (like PdPt) is cursed by Sabatier principle due to countable active site types. However, bacterial soluble extracellular polymeric substances (s-EPS) owning abundent functional groups may help breacking through it by contrusting different active sites on PdPt and inducing them to play synergy effect, which is called interface engineering. Using s-EPS to engineer catalysts is more green and consumes lower energy compared to chemical reagents. Herein, PdPt alloy nanoparticles (≈2.1 nm) are successfully in situ synthesized by/on s-EPS of Bacillus megaterium, an ex-holotype. Tryptophan residuals are proved as the main reductant. In EOR, PdPt@s-EPS shows higher activity (3.89 mA cm-2) than Pd@s-EPS, Pt@s-EPS, Pt/C and most reported akin catalysts. Its stability and durability are excellent, too. DFT modelling further demonstrates that, interface engineering by s-EPS breaks through Sabatier principle, by the synergy of diverse sites owning different degrees of d-p orbital hybridization. This work not only makes DEFCs closer to practice, but provides a facile and green strategy to design more catalysts.

Battery-free, wireless, and electricity-driven soft swimmer for water quality and virus monitoring.

Miniaturized mobile electronic system is an effective candidate for in situ exploration of confined spaces. However, realizing such system still faces challenges in powering issue, untethered mobility, wireless data acquisition, sensing versatility, and integration in small scales. Here, we report a battery-free, wireless, and miniaturized soft electromagnetic swimmer (SES) electronic system that achieves multiple monitoring capability in confined water environments. Through radio frequency powering, the battery-free SES system demonstrates untethered motions in confined spaces with considerable moving speed under resonance. This system adopts soft electronic technologies to integrate thin multifunctional bio/chemical sensors and wireless data acquisition module, and performs real-time water quality and virus contamination detection with demonstrated promising limits of detection and high sensitivity. All sensing data are transmitted synchronously and displayed on a smartphone graphical user interface via near-field communication. Overall, this wireless smart system demonstrates broad potential for confined space exploration, ranging from pathogen detection to pollution investigation.

Decitabine induces IRF7-mediated immune responses in p53-mutated triple-negative breast cancer: a clinical and translational study.

p53 is mutated in half of cancer cases. However, no p53-targeting drugs have been approved. Here, we reposition decitabine for triple-negative breast cancer (TNBC), a subtype with frequent p53 mutations and extremely poor prognosis. In a retrospective study on tissue microarrays with 132 TNBC cases, DNMT1 overexpression was associated with p53 mutations (P = 0.037) and poor overall survival (OS) (P = 0.010). In a prospective DEciTabinE and Carboplatin in TNBC (DETECT) trial (NCT03295552), decitabine with carboplatin produced an objective response rate (ORR) of 42% in 12 patients with stage IV TNBC. Among the 9 trialed patients with available TP53 sequencing results, the 6 patients with p53 mutations had higher ORR (3/6 vs. 0/3) and better OS (16.0 vs. 4.0 months) than the patients with wild-type p53. In a mechanistic study, isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53. In the DETECT trial, decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line (upregulation by 16-fold) and the most responsive patient with TNBC. Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.

Effectiveness and safety of regimens containing linezolid for treatment of Mycobacterium abscessus pulmonary Disease.

OBJECTIVE: To evaluate the effectiveness and safety of linezolid-containing regimens for treatment of M. abscessus pulmonary disease. METHODS: The records of 336 patients with M. abscessus pulmonary disease who were admitted to Shanghai Pulmonary Hospital from January 2018 to December 2020 were retrospectively analyzed. A total of 164 patients received a linezolid-containing regimen and 172 controls did not. The effectiveness, safety, antibiotic susceptibility profiles, outcomes, culture conversion, cavity closure, and adverse reactions were compared in these two groups. RESULTS: The two groups had similar treatment success (56.1% vs. 48.8%; P > 0.05), but treatment duration was shorter in the linezolid group (16.0 months [inter-quartile ranges, IQR: 15.0-17.0] vs. 18.0 months [IQR: 16.0-18.0]; P < 0.01). The rates of sputum culture conversion were similar (53.7% vs. 46.5%, P > 0.05), but time to conversion was shorter in the linezolid group (3.5 months [IQR: 2.5-4.4] vs. 5.5 months [IQR: 4.0-6.8]; P < 0.01). The linezolid group had a higher rate of cavity closure (55.2% vs. 28.6%, P < 0.05) and a shorter time to cavity closure (3.5 months [IQR: 2.5-4.4] vs. 5.5 months [IQR: 4.0-6.8]; P < 0.01). Anemia and peripheral neuropathy were more common in the linezolid group (17.7% vs. 1.7%, P < 0.01; 12.8% vs. 0.6%, P < 0.01). CONCLUSIONS: The linezolid and control groups had similar treatment success rates. The linezolid group had a shorter treatment duration, shorter time to sputum culture conversion, and higher rate and shorter time to lung cavity closure. More patients receiving linezolid developed anemia and peripheral neuropathy.

Protective effects of pyrroloquinoline quinone in brain folate deficiency.

BACKGROUND: Folates (Vitamin B9) are critical for normal neurodevelopment and function, with transport mediated by three major pathways: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Cerebral folate uptake primarily occurs at the blood-cerebrospinal fluid barrier (BCSFB) through concerted actions of FRα and PCFT, with impaired folate transport resulting in the neurological disorder cerebral folate deficiency (CFD). Increasing evidence suggests that disorders associated with CFD also present with neuroinflammation, oxidative stress, and mitochondrial dysfunction, however the role of brain folate deficiency in inducing these abnormalities is not well-understood. Our laboratory has identified the upregulation of RFC by nuclear respiratory factor 1 (NRF-1) at the blood-brain barrier (BBB) once indirectly activated by the natural compound pyrroloquinoline quinone (PQQ). PQQ is also of interest due to its anti-inflammatory, antioxidant, and mitochondrial biogenesis effects. In this study, we examined the effects of folate deficiency and PQQ treatment on inflammatory and oxidative stress responses, and changes in mitochondrial function. METHODS: Primary cultures of mouse mixed glial cells exposed to folate-deficient (FD) conditions and treated with PQQ were analyzed for changes in gene expression of the folate transporters, inflammatory markers, oxidative stress markers, and mitochondrial DNA (mtDNA) content through qPCR analysis. Changes in cellular reactive oxygen species (ROS) levels were analyzed in vitro through a DCFDA assay. Wildtype (C57BL6/N) mice exposed to FD (0 mg/kg folate), or control (2 mg/kg folate) diets underwent a 10-day (20 mg/kg/day) PQQ treatment regimen and brain tissues were collected and analyzed. RESULTS: Folate deficiency resulted in increased expression of inflammatory and oxidative stress markers in vitro and in vivo, with increased cellular ROS levels observed in mixed glial cells as well as a reduction of mitochondrial DNA (mtDNA) content observed in FD mixed glial cells. PQQ treatment was able to reverse these changes, while increasing RFC expression through activation of the PGC-1α/NRF-1 signaling pathway. CONCLUSION: These results demonstrate the effects of brain folate deficiency, which may contribute to the neurological deficits commonly seen in disorders of CFD. PQQ may represent a novel treatment strategy for disorders associated with CFD, as it can increase folate uptake, while in parallel reversing many abnormalities that arise with brain folate deficiency.

Positioning SUMO as an immunological facilitator of oncolytic viruses for high-grade glioma.

Oncolytic viral (OV) therapies are promising novel treatment modalities for cancers refractory to conventional treatment, such as glioblastoma, within the central nervous system (CNS). Although OVs have received regulatory approval for use in the CNS, efficacy is hampered by obstacles related to delivery, under-/over-active immune responses, and the "immune-cold" nature of most CNS malignancies. SUMO, the Small Ubiquitin-like Modifier, is a family of proteins that serve as a high-level regulator of a large variety of key physiologic processes including the host immune response. The SUMO pathway has also been implicated in the pathogenesis of both wild-type viruses and CNS malignancies. As such, the intersection of OV biology with the SUMO pathway makes SUMOtherapeutics particularly interesting as adjuvant therapies for the enhancement of OV efficacy alone and in concert with other immunotherapeutic agents. Accordingly, the authors herein provide: 1) an overview of the SUMO pathway and its role in CNS malignancies; 2) describe the current state of CNS-targeted OVs; and 3) describe the interplay between the SUMO pathway and the viral lifecycle and host immune response.

Upcycling spent palladium-based catalysts into high value-added catalysts via electronic regulation of Escherichia coli to high-efficiently reduce hexavalent chromium.

Upgrading and recycling Palladium (Pd) from spent catalysts may address Pd resource shortages and environmental problems. In this paper, Escherichia coli (E. coli) was used as an electron transfer intermediate to upcycle spent Pd-based catalysts into high-perform hexavalent chromium bio-catalysts. The results showed that Pd (0) nanoparticles (NPs) combined with the bacterial surface changed the electron transfer by enhancing the cell conductivity, thus promoting the removal rate of Pd(II). The recovery efficiency of Pd exceeded 98.6%. Notably, E. coli heightened the adsorption of H• and HCOO• via electron transfer of the Pd NPs electron-rich centre, resulting in a higher catalytic performance of the recycled spent catalysed the reduction of 20 ppm Cr(VI) under mild conditions within 18 min, in which maintained above 98% catalytic activity after recycling five times. This efficiency was found to be higher than that of the reported Pd-based catalysts. Hence, an electron transfer mechanism for E. coli recovery Pd-based catalyst under electron donor adjusting is proposed. These findings provide an important method for recovering Pd NPs from spent catalysts and are crucial to effectively reuse Pd resources.

EBUS-GS with the GeneXpert MTB/RIF assay for diagnosis of Mycobacterium tuberculosis infection of isolated pulmonary nodules.

OBJECTIVE: Investigate the use of endobronchial ultrasonography with a guide sheath (EBUS-GS) combined with Gene Xpert MTB/RIF (Xpert) for diagnosis of Mycobacterium tuberculosis (MTB) infection in isolated pulmonary nodules. METHODS: Patients who had isolated pulmonary nodules and unknown diagnoses at our institution from October 2020 to December 2021 were prospectively examined using EBUS-GS and Xpert. The diagnostic values of using EBUS-GS or bronchoalveolar lavage fluid (BALF) with acid-fast staining, MGIT 960 culture, pathological examination, and Xpert for isolated pulmonary nodules caused by MTB infection were compared using receiver operating characteristic (ROC) analysis. RESULTS: There were 135 patients, 64 with isolated pulmonary tuberculomas and 71 with non-tuberculous lesions. The sensitivity of EBUS-GS with Xpert was significantly higher than BALF with Xpert (57.81% vs. 34.78%, P = 0.017). Use of EBUS-GS with Xpert and MGIT 960 culture further increased the sensitivity to 62.50% (95%CI 50.64-74.36) and increased the specificity to 100%. The AUC values of BALF with MGIT 960 culture was 0.663(95%CI 0.543-0.783) and BALF with Xpert was 0.674 (95%CI 0.556-0.792). The AUC values of EBUS-GS with MGIT 960 culture was 0.680 (95%CI 0.554-0.743), with pathological examination was 0.713 (95%CI 0.573-0.760), and with Xpert was 0.789 (95%CI 0.655-0.829). CONCLUSION: Use of EBUS-GS with Xpert had high sensitivity and specificity in the diagnosis of isolated pulmonary tuberculoma. This method has significant potential for use in clinical practice.

Numerical Study of Step Drill Structure on Machining Damage in Drilling of CFRP/Ti Stacks.

The tool structure is an important factor affecting the damage of CFRP/Ti stacks machining. However, the impact of tool structure on the formation process of stacks hole damage cannot be fully revealed through experimental methods alone. In contrast, finite element simulation can effectively overcome the limitations of experiments. In this study, a numerical simulation model is established to investigate the relationship between step drill structure and formation process of CFRP/Ti stacks hole damage. Based on this, the research discusses the effect of step drill structure on the burr height of Ti layer, delamination of CFRP, aperture deviation, defects in hole surface. The results show that when the stacking sequence is CFRP to Ti, the burr height of Ti at hole exit decreases first and then increases with the rising of the ratio of primary drill bit diameter to secondary drill bit diameter (kd). When kd is 0.6, the burr height of Ti at hole exit is the lower. As kd increasing from 0.4 to 1.0, delamination factor of CFRP increases by 2.57%, which are affected little by the step drill structure due to the support of Ti. Besides, the aperture size deviation decreases first then increases with the rising of kd, and the minimum aperture size deviation is 2.09 µm when kd is 0.6. In addition, as kd is 0.6, the hole wall defect is fewer. In conclusion, step drill with kd of 0.6 is suitable for drilling of CFRP/Ti stacks.

Impact of drought on soil microbial biomass and extracellular enzyme activity.

Introduction: With the continuous changes in climate patterns due to global warming, drought has become an important limiting factor in the development of terrestrial ecosystems. However, a comprehensive understanding of the impact of drought on soil microbial activity at a global scale is lacking. Methods: In this study, we aimed to examine the effects of drought on soil microbial biomass (carbon [MBC], nitrogen [MBN], and phosphorus [MBP]) and enzyme activity (ß-1, 4-glucosidase [BG]; ß-D-cellobiosidase [CBH]; ß-1, 4-N-acetylglucosaminidase [NAG]; L-leucine aminopeptidase [LAP]; and acid phosphatase [AP]). Additionally, we conducted a meta-analysis to determine the degree to which these effects are regulated by vegetation type, drought intensity, drought duration, and mean annual temperature (MAT). Result and discussion: Our results showed that drought significantly decreased the MBC, MBN, and MBP and the activity levels of BG and AP by 22.7%, 21.2%, 21.6%, 26.8%, and 16.1%, respectively. In terms of vegetation type, drought mainly affected the MBC and MBN in croplands and grasslands. Furthermore, the response ratio of BG, CBH, NAG, and LAP were negatively correlated with drought intensity, whereas MBN and MBP and the activity levels of BG and CBH were negatively correlated with drought duration. Additionally, the response ratio of BG and NAG were negatively correlated with MAT. In conclusion, drought significantly reduced soil microbial biomass and enzyme activity on a global scale. Our results highlight the strong impact of drought on soil microbial biomass and carbon- and phosphorus-acquiring enzyme activity.

Global, Regional, and National Economic Consequences of Stroke.

BACKGROUND: An understanding of global, regional, and national macroeconomic losses caused by stroke is important for allocation of clinical and research resources. The authors investigated the macroeconomic consequences of stroke disease burden in the year 2019 in 173 countries. METHODS: Disability-adjusted life year data for overall stroke and its subtypes (ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage) were collected from the GBD study (Global Burden of Disease) 2019 database. Gross domestic product (GDP, adjusted for purchasing power parity [PPP]) data were collected from the World Bank; GDP and disability-adjusted life year data were combined to estimate macroeconomic losses using a value of lost welfare (VLW) approach. All results are presented in 2017 international US dollars adjusted for PPP. RESULTS: Globally, in 2019, VLW due to stroke was $2059.67 billion or 1.66% of the global GDP. Global VLW/GDP for stroke subtypes was 0.78% (VLW=$964.51 billion) for ischemic stroke, 0.71% (VLW=$882.81 billion) for intracerebral hemorrhage, and 0.17% (VLW=$212.36 billion) for subarachnoid hemorrhage. The Central European, Eastern European, and Central Asian GBD super-region reported the highest VLW/GDP for stroke overall (3.01%), ischemic stroke (1.86%), and for subarachnoid hemorrhage (0.26%). The Southeast Asian, East Asian, and Oceanian GBD super-region reported the highest VLW/GDP for intracerebral hemorrhage (1.48%). CONCLUSIONS: The global macroeconomic consequences related to stroke are vast even when considering stroke subtypes. The present quantification may be leveraged to help justify increased spending of finite resources on stroke in an effort to improve outcomes for patients with stroke globally.

MicroRNAs involved in the trans-kingdom gene regulation in the interaction of maize kernels and Fusarium verticillioides.

Maize ear rot is a widespread disease and the main pathogen is Fusarium verticillioides. Plant microRNAs (miRNAs) have great effects on disease resistance and it has been reported that maize miRNA participates in defense responses in maize ear rot. However, the trans-kingdom regulation of miRNAs between maize and F. verticillioides remains uncharacterized. In this study, the relationship between miRNA-like RNAs (milRNAs) of F. verticillioides and pathogenicity was investigated, followed by sRNA analysis and degradome sequencing of miRNA profiles and the target genes of maize and F. verticillioides after inoculation. It was found that the milRNA biogenesis positively regulated the pathogenicity of F. verticillioides by knocking out the gene FvDicer2-encoded Dicer-like protein in F. verticillioides. Following inoculation with F. verticillioides, 284 known and 6571 novel miRNAs were obtained in maize, including 28 miRNAs differentially expressed at multiple time points. The target genes of maize differentially expressed miRNAs in F. verticillioides mediated multiple pathways, including autophagy and MAPK signaling pathway. Fifty-one novel F. verticillioides milRNAs were predicted to target 333 genes in maize involved in MAPK signaling pathways, plant hormone signaling transduction and plant-pathogen interaction pathways. Additionally, the miR528b-5p in maize targeted the mRNA of FvTTP which encoded a twice transmembrane protein in F. verticillioides. The FvTTP-knockout mutants displayed decreased pathogenicity and reduced synthesis of fumonisins. Thus, by interfering with the translation of FvTTP, the miR528b-5p inhibited F. verticillioides infection. These findings suggested a novel function of miR528 in resisting F. verticillioides infection. The miRNAs identified in this research and their putative target genes can be used to further elucidate the trans-kingdom functions of microRNAs in plant pathogen interaction.

Single-Cell Enzymatic Screening for Epithelial Mesenchymal Transition with an Ultrasensitive Superwetting Droplet-Array Microchip.

The phenotypic changes of circulating tumor cells (CTCs) during the epithelial-mesenchymal transition (EMT) have been a hot topic in tumor biology and cancer therapeutic development. Here, an integrated platform of single-cell fluorescent enzymatic assays with superwetting droplet-array microchips (SDAM) for ultrasensitive functional screening of epithelial-mesenchymal sub-phenotypes of CTCs is reported. The SDAM can generate high-density, volume well-defined droplet (0.66 nL per droplet) arrays isolating single tumor cells via a discontinuous dewetting effect. It enables sensitive detection of MMP9 enzyme activities secreted by single tumor cells, correlating to their epithelial-mesenchymal sub-phenotypes. In the pilot clinical double-blind tests, the authors have demonstrated that SDAM assays allow for rapid identification and functional screening of CTCs with different epithelial-mesenchymal properties. The consistency with the clinical outcomes validates the usefulness of single-cell secreted MMP9 as a biomarker for selective CTC screening and tumor metastasis monitoring. Convenient addressing and recovery of individual CTCs from SDAM have been demonstrated for gene mutation sequencing, immunostaining, and transcriptome analysis, revealing new understandings of the signaling pathways between MMP9 secretion and the EMT regulation of CTCs. The SDAM approach combined with sequencing technologies promises to explore the dynamic EMT plasticity of tumors at the single-cell level.

Analysis of disease burden due to high body mass index in childhood asthma in China and the USA based on the Global Burden of Disease Study 2019.

BACKGROUND: Currently, there is a growing concern about the disease burden of child asthma particularly due to high body mass index (BMI). The prevalence and disease burden of asthma differ between developing and developed countries, with implications on disease intervention. Therefore, we provide a comparative analysis of childhood asthma between China and the United States of America (USA). METHODS: Using the Global Burden of Disease (GBD) 2019 data, we estimated and compared the age-standardized prevalence, disability-adjusted life years (DALYs), years of life lost (YLLs), years of lost due to disability (YLDs), DALYs due to high BMI of asthma in children aged 1-14 years in China and the USA. Joinpoint regression analysis was applied to assess changes in temporal trends. RESULTS: DALYs due to high BMI and the ratio of DALYs to DALYs due to high BMI in children with asthma showed a significant upward trend in both countries and were higher in males than in females. Almost all epidemiological indicators of asthma showed a hump of curve from 2014 to 2019, and peaked in 2017. There was a decreasing trend of YLLs for asthma in children both countries, while China has a saliently greater decreasing trend. CONCLUSION: The disease burden caused by high BMI of childhood asthma was on the rise in children with asthma in both China and the USA. High BMI needs to be taken more into account in the development of future policies for the prevention, control, and treatment of childhood asthma. However, the increasing trend of this disease burden in American children was significantly lower than that in Chinese children. We recommend learning from the American government to impose a high-calorie tax, increase physical exercise facilities, and provide better health care policies.

ß2-adrenergic receptor agonist corrects immune thrombocytopenia by reestablishing the homeostasis of T cell differentiation.

BACKGROUND: The sympathetic nerve is known to regulate immune responses in autoimmunity. Aberrant T cell immunity plays a vital role in immune thrombocytopenia (ITP) pathogenesis. The spleen is the primary site of platelet destruction. However, little is known whether and how splenic sympathetic innervation and neuroimmune modulation contribute to ITP pathogenesis. OBJECTIVES: To determine the sympathetic distribution in the spleen of ITP mice and the association between splenic sympathetic nerves and T cell immunity in ITP development, and to evaluate the treatment potential of ß2-adrenergic receptor (ß2-AR) in ITP. METHODS: Chemical sympathectomy was performed in an ITP mouse model with 6-hydroxydopamine and treated with ß2-AR agonists to evaluate the effects of sympathetic denervation and activation. RESULTS: Decreased sympathetic innervation in the spleen of ITP mice was observed. Significantly increased percentages of Th1 and Tc1 cells and reduced percentages of regulatory T cells (Tregs) were also observed in ITP mice with chemical sympathectomy (ITP-syx mice) relative to mice without sympathectomy (controls). Expression of genes associated with Th1, including IFN-γ and IRF8, was significantly upregulated, whereas genes associated with Tregs, including Foxp3 and CTLA4, were significantly downregulated in ITP-syx mice compared with controls. Furthermore, ß2-AR restored the percentage of Tregs and increased platelet counts at days 7 and 14 in ITP mice. CONCLUSION: Our findings indicate that decreased sympathetic distribution contributes to ITP pathogenesis by disturbing the homeostasis of T cells and that ß2-AR agonists have potential as a novel treatment for ITP.