PRL1 and PRL3 promote macropinocytosis via its lipid phosphatase activity.

PRL1 and PRL3, members of the protein tyrosine phosphatase family, have been associated with cancer metastasis and poor prognosis. Despite extensive research on their protein phosphatase activity, their potential role as lipid phosphatases remains elusive. Methods: We conducted comprehensive investigations to elucidate the lipid phosphatase activity of PRL1 and PRL3 using a combination of cellular assays, biochemical analyses, and protein interactome profiling. Functional studies were performed to delineate the impact of PRL1/3 on macropinocytosis and its implications in cancer biology. Results: Our study has identified PRL1 and PRL3 as lipid phosphatases that interact with phosphoinositide (PIP) lipids, converting PI(3,4)P2 and PI(3,5)P2 into PI(3)P on the cellular membranes. These enzymatic activities of PRLs promote the formation of membrane ruffles, membrane blebbing and subsequent macropinocytosis, facilitating nutrient extraction, cell migration, and invasion, thereby contributing to tumor development. These enzymatic activities of PRLs promote the formation of membrane ruffles, membrane blebbing and subsequent macropinocytosis. Additionally, we found a correlation between PRL1/3 expression and glioma development, suggesting their involvement in glioma progression. Conclusions: Combining with the knowledge that PRLs have been identified to be involved in mTOR, EGFR and autophagy, here we concluded the physiological role of PRL1/3 in orchestrating the nutrient sensing, absorbing and recycling via regulating macropinocytosis through its lipid phosphatase activity. This mechanism could be exploited by tumor cells facing a nutrient-depleted microenvironment, highlighting the potential therapeutic significance of targeting PRL1/3-mediated macropinocytosis in cancer treatment.

Association of random glucose to albumin ratio with post-contrast acute kidney injury and clinical outcomes in patients with ST-elevation myocardial infarction.

Purpose: Both glucose and albumin are associated with chronic inflammation, which plays a vital role in post-contrast acute kidney injury (PC-AKI). To explore the relationship between random glucose to albumin ratio (RAR) and the incidence of PC-AKI after percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI). Patients and methods: STEMI patients who underwent PCI were consecutively enrolled from January, 01, 2010 to February, 28, 2020. All patients were categorized into T1, T2, and T3 groups, respectively, based on RAR value (RAR < 3.377; 3.377 ≤ RAR ≤ 4.579; RAR > 4.579). The primary outcome was the incidence of PC-AKI, and the incidence of major adverse clinical events (MACE) was the second endpoint. The association between RAR and PC-AKI was assessed by multivariable logistic regression analysis. Results: A total of 2,924 patients with STEMI undergoing PCI were finally included. The incidence of PC-AKI increased with the increasing tertile of RAR (3.2% vs 4.8% vs 10.6%, P<0.001). Multivariable regression analysis demonstrated that RAR (as a continuous variable) was associated with the incidence of PC-AKI (adjusted odds ratio (OR) =1.10, 95% confidence interval (CI) =1.04 - 1.16, P<0.001) and in-hospital MACE (OR=1.07, 95% CI=1.02 - 1.14, P=0.012); RAR, as a categorical variable, was significantly associated with PC-AKI (T3 vs. T1, OR=1.70, 95% CI=1.08 - 2.67, P=0.021) and in-hospital MACE (T3 vs. T1, OR=1.63, 95% CI=1.02 - 2.60, P=0.041) in multivariable regression analyses. Receiver operating characteristic curve analysis showed that RAR exhibited a predictive value for PC-AKI (area under the curve (AUC)=0.666, 95% CI=0.625 - 0.708), and in-hospital MACE (AUC= 0.662, 95% CI =0.619 - 0.706). Conclusions: The high value of RAR was significantly associated with the increasing risk of PC-AKI and in-hospital MACE after PCI in STEMI patients, and RAR offers a good predictive value for those outcomes.

Terpinen-4-ol Improves Lipopolysaccharide-Induced Macrophage Inflammation by Regulating Glutamine Metabolism.

Terpinen-4-ol (T-4-O) is an important component of tea tree oil and has anti-inflammatory effects. Currently, there are very few studies on the mechanisms by which T-4-O improves lipopolysaccharide (LPS)-induced macrophage inflammation. In this study, LPS-stimulated mouse RAW264.7 macrophages were used as a model to analyze the effects of T-4-O on macrophage inflammatory factors and related metabolic pathways in an inflammatory environment. The results showed that T-4-O significantly decreased the expression levels of inflammatory cytokines induced by LPS. Cellular metabolism results showed that T-4-O significantly decreased the ratio of the extracellular acidification rate and oxygen consumption rate. Non-targeted metabolomics results showed that T-4-O mainly affected glutamine and glutamate metabolism and glycine, serine, and threonine metabolic pathways. qPCR results showed that T-4-O increased the transcript levels of GLS and GDH and promoted glutamine catabolism. Western blotting results showed that T-4-O inhibited the mTOR and IκB, thereby decreasing NF-κB activity. The overall results showed that T-4-O inhibited mTOR phosphorylation to promote glutamine metabolism and increased cell oxidative phosphorylation levels, thereby inhibiting the expression of LPS-induced inflammatory cytokines.

Alterations in dynamic regional homogeneity within default mode network in patients with thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is a significant autoimmune eye disease known for causing exophthalmos and substantial optic nerve damage. Prior investigations have solely focused on static functional MRI (fMRI) scans of the brain in TAO patients, neglecting the assessment of temporal variations in local brain activity. This study aimed to characterize alterations in dynamic regional homogeneity (dReHo) in TAO patients and differentiate between TAO patients and healthy controls using support vector machine (SVM) classification. Thirty-two patients with TAO and 32 healthy controls underwent resting-state fMRI scans. We calculated dReHo using sliding-window methods to evaluate changes in regional brain activity and compared these findings between the two groups. Subsequently, we employed SVM, a machine learning algorithm, to investigate the potential use of dReHo maps as diagnostic markers for TAO. Compared to healthy controls, individuals with active TAO demonstrated significantly higher dReHo values in the right angular gyrus, left precuneus, right inferior parietal as well as the left superior parietal gyrus. The SVM model demonstrated an accuracy ranging from 65.62 to 68.75% in distinguishing between TAO patients and healthy controls based on dReHo variability in these identified brain regions, with an area under the curve of 0.70 to 0.76. TAO patients showed increased dReHo in default mode network-related brain regions. The accuracy of classifying TAO patients and healthy controls based on dReHo was notably high. These results offer new insights for investigating the pathogenesis and clinical diagnostic classification of individuals with TAO.

Digital Image Comparison of Cellular Yield in Bronchial Brushing: Pre- and Post-Biopsy Lavage Cytology.

INTRODUCTION: Bronchoscopy is a useful diagnostic tool capable of performing core biopsy, forceps biopsy, bronchoalveolar lavage, and bronchial brushing. This study compares the cellularity of bronchial cytology including pre- and post-biopsy lavage by digital image analysis, aiming to increase diagnostic and tumor yield by optimizing the sequence and combination of bronchial biopsy and cytology. METHODS: Alveolar macrophage, bronchial epithelium, and tumor cell cellularity from liquid-based cytology preparations of bronchial brushing and pre-biopsy and post-biopsy bronchoalveolar lavage were annotated on digitized whole-slide images and compared. Secondary analysis on the relationship of tumor cell and non-lesional cell yield was performed. RESULTS: Overall, 118 cytology specimens from 43 patients were retrieved in total. Bronchial epithelium count was higher in pre-biopsy than post-biopsy lavage (p < 0.01) but not for alveolar macrophages nor tumor cell (p > 0.05). Tumor cell count was higher for bronchial brushing cytology samples than lavage (p = 0.018). The alveolar macrophage count was higher in post-biopsy lavage than bronchial brushing (p = 0.033); otherwise, brushing showed consistently higher bronchial epithelium and tumor cell counts. There were 33 false negative (tumor cell absent) specimens, and the combination of bronchial brushing and pre-biopsy lavage yielded the lowest false negative cases. Correlation between bronchial epithelium and alveolar macrophage counts with tumor cell count was weak (correlation coefficient = -0.168-0.203) except for post-biopsy lavage (correlation coefficient = 0.412-0.479, p < 0.05). CONCLUSION: Bronchial brushing yields a greater amount of tumor cell than lavage, and timing lavage before or after core biopsy does not affect tumor cell yield. Combining bronchial brushing and pre-biopsy lavage results in the lowest false negative rate.

The glutathione S-transferase Gstt1 drives survival and dissemination in metastases.

Identifying the adaptive mechanisms of metastatic cancer cells remains an elusive question in the treatment of metastatic disease, particularly in pancreatic cancer (pancreatic adenocarcinoma, PDA). A loss-of-function shRNA targeted screen in metastatic-derived cells identified Gstt1, a member of the glutathione S-transferase superfamily, as uniquely required for dissemination and metastasis, but dispensable for primary tumour growth. Gstt1 is expressed in latent disseminated tumour cells (DTCs), is retained within a subpopulation of slow-cycling cells within existing metastases, and its inhibition leads to complete regression of macrometastatic tumours. This distinct Gstt1high population is highly metastatic and retains slow-cycling phenotypes, epithelial-mesenchymal transition features and DTC characteristics compared to the Gstt1low population. Mechanistic studies indicate that in this subset of cancer cells, Gstt1 maintains metastases by binding and glutathione-modifying intracellular fibronectin, in turn promoting its secretion and deposition into the metastatic microenvironment. We identified Gstt1 as a mediator of metastasis, highlighting the importance of heterogeneity and its influence on the metastatic tumour microenvironment.

Key Transdermal Patch Using Cannabidiol-Loaded Nanocarriers with Better Pharmacokinetics in vivo.

Purpose: Cannabidiol (CBD) is a promising therapeutic drug with low addictive potential and a favorable safety profile. However, CBD did face certain challenges, including poor solubility in water and low oral bioavailability. To harness the potential of CBD by combining it with a transdermal drug delivery system (TDDS). This innovative approach sought to develop a transdermal patch dosage form with micellar vesicular nanocarriers to enhance the bioavailability of CBD, leading to improved therapeutic outcomes. Methods: A skin-penetrating micellar vesicular nanocarriers, prepared using nano emulsion method, cannabidiol loaded transdermal nanocarriers-12 (CTD-12) was presented with a small particle size, high encapsulation efficiency, and a drug-loaded ratio for CBD. The skin permeation ability used Strat-M™ membrane with a transdermal diffusion system to evaluate the CTD and patch of CTD-12 (PCTD-12) within 24 hrs. PCTD-12 was used in a preliminary pharmacokinetic study in rats to demonstrate the potential of the developed transdermal nanocarrier drug patch for future applications. Results: In the transdermal application of CTD-12, the relative bioavailability of the formulation was 3.68 ± 0.17-fold greater than in the free CBD application. Moreover, PCTD-12 indicated 2.46 ± 0.18-fold higher relative bioavailability comparing with free CBD patch in the ex vivo evaluation. Most importantly, in the pharmacokinetics of PCTD-12, the relative bioavailability of PCTD-12 was 9.47 ± 0.88-fold higher than in the oral application. Conclusion: CTD-12, a transdermal nanocarrier, represents a promising approach for CBD delivery, suggesting its potential as an effective transdermal dosage form.

Mecp2 fine-tunes quiescence exit by targeting nuclear receptors.

Quiescence (G0) maintenance and exit are crucial for tissue homeostasis and regeneration in mammals. Here, we show that methyl-CpG binding protein 2 (Mecp2) expression is cell cycle-dependent and negatively regulates quiescence exit in cultured cells and in an injury-induced liver regeneration mouse model. Specifically, acute reduction of Mecp2 is required for efficient quiescence exit as deletion of Mecp2 accelerates, while overexpression of Mecp2 delays quiescence exit, and forced expression of Mecp2 after Mecp2 conditional knockout rescues cell cycle reentry. The E3 ligase Nedd4 mediates the ubiquitination and degradation of Mecp2, and thus facilitates quiescence exit. A genome-wide study uncovered the dual role of Mecp2 in preventing quiescence exit by transcriptionally activating metabolic genes while repressing proliferation-associated genes. Particularly disruption of two nuclear receptors, Rara or Nr1h3, accelerates quiescence exit, mimicking the Mecp2 depletion phenotype. Our studies unravel a previously unrecognized role for Mecp2 as an essential regulator of quiescence exit and tissue regeneration.

Interhemispheric functional in age-related macular degeneration patient: a resting-state functional MRI study.

Age-related macular degeneration (AMD) is a prevalent disease leading to severe visual impairment in the elderly population. Despite this, the pathogenesis of AMD remains largely unexplored. The application of resting-state functional MRI (rs-fMRI) allows for the detection of coherent intrinsic brain activities along with the interactions taking place between the two hemispheres. In the frame of our study, we utilize voxel-mirrored homotopic connectivity (VMHC) as an rs-fMRI method to carry out a comparative analysis of functional homotopy between the two hemispheres with the aim of further understanding the pathogenesis of AMD patients. In our study, we utilized the VMHC method to explore levels of brain activity in individuals diagnosed with AMD, planning to investigate potential links with their clinical characteristics. We extended our invitation to 20 AMD patients and 20 healthy controls from Jiangxi Provincial People's Hospital to participate in this research. rs-fMRIs were captured for each participant, and associated neural activity levels were examined using the VMHC method. Remarkably, our comparative examination with the healthy control group revealed significantly reduced VMHC in the cuneus, superior occipital lobe, precentral gyrus, and superior parietal lobule in the patient cohort. Utilizing the VMHC method allows us to identify discrepancies in the visual pathways of AMD patients compared with standard controls, potentially explaining the common challenges among AMD patients with object recognition, face recognition, and reading.

Macrophage-Capturing Self-Assembly Photosensitizer Nanoparticles Induces Immune Microenvironment Re-Programming and Golgi-Responsive Immunogenic Cell Death in Head and Neck Carcinoma.

Head and neck carcinoma treatment is shifted toward the combination of therapy causing immune checkpoint blockade (ICB) and immunogenic cell death. In this study, a CSFRi-chimeric TAMCSFR+-targeting extracellular vesicle (EV@CSFRi) platform is developed and designed an intracellular protoporphyrin conjugated with RVRR peptide sequence for furin-cleavage to perform Golgi-targeting and generating ROS (GT-RG). The graphical abstract illustrates the self-assembly of GT-RG nanoparticles into nanofiber through the hydrophily of RVRR and hydrophobicity of RG, and the red line indicates the site of furin cleavage. As is shown in the Graphical abstract, the Golgi-targeting Protoporphyrin-RVRR platform is composed with CSFRi-chimeric extracellular vesicles and forms the tumor-responsive TAM-reprogramming bilayers (GT-RGEV@CSFRi). The GT-RGEV@CSFRi acted as a multifunctional theranostic platform, which can induce immunogenic cell death and further help modulate TAM, thus suppressing the HNC xenograft model by combination therapy with anti-PD-1.

The impact of icodextrin on the outcomes of incident peritoneal dialysis patients.

OBJECTIVE: The aim of the study is to investigate the effects of icodextrin on the risks of death, technique failure and the first episode of peritonitis in peritoneal dialysis (PD) patients. METHODS: From medical records of a medical center in Taiwan, a total of 725 newly diagnosed end-stage kidney disease patients receiving PD for at least 90 days from January 1, 2007 to December 31, 2018 were identified. These patients were grouped as 190 icodextrin users and 535 non-users. Users were defined as utilization of icodextrin for ≥ 50% of their PD duration. The use of icodextrin was considered a time-varying exposure in the Cox proportional hazard model. The risks of death, technique failure and the first episode of peritonitis were compared between two cohorts by the end of 2018. RESULTS: Compared to the non-users, the icodextrin users had significant lower risks of mortality (6.5 vs.7.2 per 100 person-years; adjusted HR = 0.62, 95% CI = 0.42-0.91) and technique failure (12.7 vs. 15.2 per 100 person-years; adjusted HR = 0.61, 95% CI = 0.47-0.81), and the first peritonitis episode (5.0 vs. 17.0 per 100 person-years; adjusted HR = 0.22, 95% CI = 0.14-0.35). The risk of peritonitis reduced further in icodextrin users with diabetes and with cardiovascular disease. CONCLUSION: Icodextrin was associated with lower risks of mortality, technique failure, and the first episode of peritonitis.

Severe chemical pneumonitis by vanadium pentoxide responded well to aggressive steroid therapy.

The optimal treatment of acute chemical pneumonitis remains controversial. Here we report a healthy man with severe chemical pneumonitis caused by accidental inhalation of vanadium pentoxide. He presented with acute respiratory distress and received aggressive steroid therapy on arrival. Pulmonary symptoms and chest X-ray were improved dramatically the next day. The beneficial effect of steroid therapy for such a critical patient may outweigh the infection risk following inhalation of relative sterile material. We suggest early and aggressive steroid therapy may help shorten the disease course.

Retinoic acid receptor activation reprograms senescence response and enhances anti-tumor activity of natural killer cells.

Cellular senescence can exert dual effects in tumors, either suppressing or promoting tumor progression. The senescence-associated secretory phenotype (SASP), released by senescent cells, plays a crucial role in this dichotomy. Consequently, the clinical challenge lies in developing therapies that safely enhance senescence in cancer, favoring tumor-suppressive SASP factors over tumor-promoting ones. Here, we identify the retinoic-acid-receptor (RAR) agonist adapalene as an effective pro-senescence compound in prostate cancer (PCa). Reactivation of RARs triggers a robust senescence response and a tumor-suppressive SASP. In preclinical mouse models of PCa, the combination of adapalene and docetaxel promotes a tumor-suppressive SASP that enhances natural killer (NK) cell-mediated tumor clearance more effectively than either agent alone. This approach increases the efficacy of the allogenic infusion of human NK cells in mice injected with human PCa cells, suggesting an alternative therapeutic strategy to stimulate the anti-tumor immune response in "immunologically cold" tumors.

Remodelling of cAMP dynamics within the SERCA2a microdomain in heart failure with preserved ejection fraction caused by obesity and type 2 diabetes.

AIMS: Despite massive efforts, we remain far behind in our attempts to identify effective therapies to treat heart failure with preserved ejection fraction (HFpEF). Diastolic function is critically regulated by sarcoplasmic/endoplasmic reticulum (SR) calcium ATPase 2a (SERCA2a), which forms a functional cardiomyocyte (CM) microdomain where 3',5'-cyclic adenosine monophosphate (cAMP) produced upon ß-adrenergic receptor (ß-AR) stimulation leads to phospholamban (PLN) phosphorylation and facilitated Ca2+ re-uptake. METHODS AND RESULTS: To visualize real-time cAMP dynamics in the direct vicinity of SERCA2a in healthy and diseased myocytes, we generated a novel mouse model on the leprdb background that stably expresses the Epac1-PLN Förster resonance energy transfer biosensor. Mice homozygous for the leprdb mutation (db/db) developed obesity and type 2 diabetes and presented with a HFpEF phenotype, evident by mild left ventricular hypertrophy and elevated left atria filling pressures. Live cell imaging uncovered a substantial ß2-AR subtype stimulated cAMP response within the PLN/SERCA2a microdomain of db/db but not healthy control (db/+) CMs, which was accompanied by increased PLN phosphorylation and accelerated calcium re-uptake. Importantly, db/db CMs also exhibited a desensitization of ß1-AR stimulated cAMP pools within the PLN/SERCA2a microdomain, which was accompanied by a blunted lusitropic effect, suggesting that the increased ß2-AR control is an intrinsic compensatory mechanism to maintain PLN/SERCA2a-mediated calcium dynamics and cardiac relaxation. Mechanistically, this was due to a local loss of cAMP-degrading phosphodiesterase 4 associated specifically with the PLN/SERCA2a complex. CONCLUSION: These newly identified alterations of cAMP dynamics at the subcellular level in HFpEF should provide mechanistic understanding of microdomain remodelling and pave the way towards new therapies.

Shrimp SIRT4 promotes white spot syndrome virus replication.

In WSSV pathogenesis, the molecular mechanisms and the key host factors that regulate the viral replication and morphogenesis remain unclear. However, like most viruses, WSSV is known to induce metabolic reprogramming in several metabolic pathways including the host glutamine metabolism, and several recent reports have suggested that the sirtuins SIRT3, SIRT4, and SIRT5, which belong to a family of NAD+-dependent deacetylases, play an important role in this regulation. Here we focus on characterizing LvSIRT4 from Litopenaeus vannamei and investigate its role in regulating glutamine dehydrogenase (GDH), an important enzyme that promotes glutaminolysis and viral replication. We found that LvSIRT4 silencing led to significant decreases in both WSSV gene expression and the number of viral genome copies. Conversely, overexpression of LvSIRT4 led to significant increases in the expression of WSSV genes and the WSSV genome copy number. Immunostaining in Sf9 insect cells confirmed the presence of LvSIRT4 in the mitochondria and the co-localization of LvSIRT4 and LvGDH in the same cellular locations. In vivo gene silencing of LvSIRT4 significantly reduced the gene expression of LvGDH whereas LvSIRT4 overexpression had no effect. However, neither silencing nor overexpression had any effect on the protein expression levels of LvGDH. Lastly, although GDH activity in uninfected shrimp was unchanged, the GDH enzyme activity in WSSV-infected shrimp was significantly increased after both LvSIRT4 silencing and overexpression. This suggests that although there may be no direct regulation, LvSIRT4 might still be able to indirectly regulate LvGDH via the mediation of one or more WSSV proteins that have yet to be identified.

NET formation is a default epigenetic program controlled by PAD4 in apoptotic neutrophils.

Neutrophil extracellular traps (NETs) not only counteract bacterial and fungal pathogens but can also promote thrombosis, autoimmunity, and sterile inflammation. The presence of citrullinated histones, generated by the peptidylarginine deiminase 4 (PAD4), is synonymous with NETosis and is considered independent of apoptosis. Mitochondrial- and death receptor-mediated apoptosis promote gasdermin E (GSDME)-dependent calcium mobilization and membrane permeabilization leading to histone H3 citrullination (H3Cit), nuclear DNA extrusion, and cytoplast formation. H3Cit is concentrated at the promoter in bone marrow neutrophils and redistributes in a coordinated process from promoter to intergenic and intronic regions during apoptosis. Loss of GSDME prevents nuclear and plasma membrane disruption of apoptotic neutrophils but prolongs early apoptosis-induced cellular changes to the chromatin and cytoplasmic granules. Apoptotic signaling engages PAD4 in neutrophils, establishing a cellular state that is primed for NETosis, but that occurs only upon membrane disruption by GSDME, thereby redefining the end of life for neutrophils.

Randomized Trial on the Effect of an Oral Spleen Tyrosine Kinase Inhibitor in the Treatment of IgA Nephropathy.

Introduction: We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells. Methods: This study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors. The primary end point was reduction of proteinuria. Secondary end points included change from baseline in estimated glomerular filtration rate (eGFR) and kidney histology. Results: Although we could not detect significant reduction in proteinuria with fostamatinib overall, in a predetermined subgroup analysis, there was a trend for dose-dependent reduction in median proteinuria (from baseline to 24 weeks by 14%, 27%, and 36% in the placebo, fostamatinib 100 mg, and 150 mg groups, respectively) in patients with baseline urinary protein-to-creatinine ratios (UPCR) more than 1000 mg/g. Kidney function (eGFR) remained stable in all groups. Fostamatinib was well-tolerated. Side effects included diarrhea, hypertension, and increased liver enzymes. Thirty-nine patients underwent repeat biopsy showing reductions in SYK staining associated with therapy at low dose (-1.5 vs. 1.7 SYK+ cells/glomerulus in the placebo group, P < 0.05). Conclusions: There was a trend toward reduction in proteinuria with fostamatinib in a predefined analysis of high risk patients with IgAN despite maximal care, as defined by baseline UPCR greater than 1000 mg/g. Further study may be warranted.

Comparison of the 12-month impact of COVID-19 and SARS on physiological capacity and health-related quality of life.

BACKGROUND: Little is known about the differences in medium to long-term recovery on spirometry, 6-minute walking distance (6MWD) and health-related quality of life (HRQoL) between COVID-19 and SARS. METHODS: We performed a 12-month prospective study on COVID-19 survivors. The changes in dynamic lung volumes at spirometry (%predicted FEV1, %predicted FVC), 6MWD and HRQoL at 1-3, 6 to 12 months were compared against a historical cohort of SARS survivors using the same study protocol. The residual radiological changes in HRCT in COVID-19 survivors were correlated with their functional capacity. RESULTS: 108 COVID-19 survivors of various disease severity (asymptomatic 2.9%, mild 33.3%, moderate 47.2%, severe 8.3%, critical 8.3%) were recruited. When compared with 97 SARS survivors, 108 COVID-19 survivors were older (48.1 ± 16.4 vs. 36.1 ± 9.5 years, p < 0.001) and required less additional support during hospitalization; with lower dynamic lung volumes, shorter 6MWD and better physical component score. Both groups of survivors had comparable changes in these parameters at subsequent follow-ups. Both COVID-19 and SARS survivors had similar mental component score (MCS) at 6 and 12 months. COVID-19 survivors initially experienced less (between-group difference, -3.1, 95% confidence interval [CI] -5.5 to -0.7, p = 0.012) and then more improvement (between-group difference 2.9, 95%, CI 0.8 to 5.1, p = 0.007) than SARS survivors in the MCS at 1-3 to 6 months and 6 to 12 months respectively. Forty (44.0%) out of 91 COVID-19 survivors had residual abnormalities on HRCT at 12 months, with a negative correlation between the severity scores of parenchymal changes and 6MWD (r=-0.239, p < 0.05). CONCLUSIONS: COVID-19 survivors demonstrated a similar recovery speed in dynamic lung volumes and exercise capacity, but different paces of psychological recovery as SARS survivors in the convalescent phase. The severity of parenchymal changes in HRCT is negatively correlated with the 6MWD of COVID-19 survivors. TRIAL REGISTRATION: This prospective study was registered at ClinicalTrials.gov on 2 November 2020 (Identifier: NCT04611243).

Machine Learning Integrated Workflow for Predicting Schwann Cell Viability on Conductive MXene Biointerfaces.

Severe injuries to the peripheral nervous system (PNS) require Schwann cells to aid in neuronal regeneration. Low-frequency electrical stimulation is known to induce the cogrowth of neurons and Schwann cells in an injured PNS. However, the correlations between electrical stimulation and Schwann cell viability are complex and not well understood. In this work, we develop a machine learning (ML)-integrated workflow that uses conductive hydrogel biointerfaces to evaluate the impacts of fabrication parameters and electrical stimulation on the Schwann cell viability. First, a hydrogel array with varying MXene and peptide loadings is fabricated, which serves as conductive biointerfaces to incubate Schwann cells and introduce various electrical stimulation (at different voltages and frequencies). Upon specific fabrication parameters and stimulation, the cell viability is evaluated and input into an artificial neural network model to train the model. Additionally, a data augmentation method is applied to synthesize 1000-fold virtual data points, enabling the construction of a high-accuracy prediction model (with a testing mean absolute error ≤11%). By harnessing the model's predictive power, we can accurately predict Schwann cell viability based on a given set of fabrication/stimulation parameters. Finally, the SHapley Additive exPlanations model interpretation provides several data-scientific insights that are validated by microscopic cellular observations. Our hybrid approach, involving conductive biointerface fabrication, ML algorithms, and data analysis, offers an unconventional platform to construct a preclinical prediction model at the cellular level.

Immune responses and safety of COVID-19 vaccination in atypical hemolytic uremic syndrome patients in Taiwan.

Atypical hemolytic uremic syndrome is a rare, life-threatening disorder which can be triggered by COVID 19 infection and COVID 19 vaccination then induce multiple organ failure. Our study is the first to evaluate immune responses to COVID-19 vaccination and safety in a cohort of patients in a local single-center study in Taiwan.. Results indicate that vaccines effectively shield aHUS patients from severe COVID-19 complications without significant safety concerns. A double booster dose for the third vaccine is essential for optimal efficacy. Anti-complement therapy did not influence vaccination effectiveness. Transplant aHUS patients had the lowest immune response titers, indicating a need for additional vaccine doses. Compared to healthcare workers, aHUS patients had poor T-cell responses. We noted a superior trend with mixed-type COVID-19 vaccinations in aHUS patients, while fixed-type mRNA demonstrated better results in healthcare workers. Our findings endorse COVID-19 vaccination as a potent strategy to safeguard aHUS patients from severe complications, emphasizing the importance of vigilant monitoring pre- and post-vaccination.