Transcutaneous vagus nerve stimulation improves Long COVID symptoms in a female cohort: a pilot study.

Background: Long COVID, also known as Post-COVID-19 syndrome, is characterized by multisystemic symptoms that persists for weeks to years beyond acute infection. It disproportionately affects women and those with pre-existing anxiety/depression, conditions more prevalent in females. The vagus nerve, with its extensive innervation and regulation of critical bodily functions, has become a focal point for therapeutic interventions. Transcutaneous vagus nerve stimulation (t-VNS) has emerged as a promising non-invasive treatment for COVID-19 conditions. Methods: This pilot study assessed the efficacy of t-VNS in 24 female Long COVID patients (45.8 ± 11.7 years old; 20.2 ± 7.1 months since infection), who underwent a 10-day t-VNS intervention at home (30 min/session, twice a day). Cognition was considered the primary outcome, with anxiety, depression, sleep, fatigue, and smell as secondary outcomes. Outcomes were measured at baseline, post-intervention, and 1-month follow-up. Results: Significant improvements were observed in various cognitive functions, anxiety, depression, and sleep at post-intervention, with benefits remaining or progressing at 1-month follow-up. Improvements in fatigue were delayed, reaching statistical significance at 1-month follow-up compared to baseline. No significant changes were noted in olfactory performance. Conclusion: This pilot study provides preliminary evidence supporting the potential of t-VNS as a therapeutic intervention for female Long COVID patients. The encouraging results justify further rigorous investigation through larger, randomized controlled trials to confirm the efficacy of t-VNS, assess its generalizability to male cohorts, and explore biological markers to inform personalized treatment approaches. Our findings support the allocation of resources to conduct such trials and advance the understanding of t-VNS as a potential treatment for Long COVID.

Current therapy in amyotrophic lateral sclerosis (ALS): A review on past and future therapeutic strategies.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the first and second motoneurons (MNs), associated with muscle weakness, paralysis and finally death. The exact etiology of the disease still remains unclear. Currently, efforts to develop novel ALS treatments which target specific pathomechanisms are being studied. The mechanisms of ALS pathogenesis involve multiple factors, such as protein aggregation, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, apoptosis, inflammation etc. Unfortunately, to date, there are only two FDA-approved drugs for ALS, riluzole and edavarone, without curative treatment for ALS. Herein, we give an overview of the many pathways and review the recent discovery and preclinical characterization of neuroprotective compounds. Meanwhile, drug combination and other therapeutic approaches are also reviewed. In the last part, we analyze the reasons of clinical failure and propose perspective on the treatment of ALS in the future.

A simplified digital workflow for the rapid design and fabrication of interim fixed prostheses using an open-access software program.

A digital workflow for the rapid design and fabrication of interim fixed prostheses using an open-access software program and 3-dimensional printing technology is described. After obtaining intraoral scanning data, the prostheses are designed by offset, margin sculpting, and a Boolean operation. Then, the prostheses are finalized and manufactured additively. The use of the open-access software program and simplified design steps enhances the manufacturing efficiency and accessibility of computer-aided design and computer-aided manufacturing of interim restorations.

A Pilot, Predictive Surveillance Model in Pharmacovigilance Using Machine Learning Approaches.

INTRODUCTION: The identification of a new adverse event (AE) caused by a drug product is one of the key activities in the pharmaceutical industry to ensure the safety profile of a drug product. Machine learning (ML) has the potential to assist with signal detection and supplement traditional pharmacovigilance (PV) surveillance methods. This pilot ML modeling study was designed to detect potential safety signals for two AbbVie products and test the model's capability of detecting safety signals earlier than humans. METHODS: Drug X, a mature product with post-marketing data, and Drug Y, a recently approved drug in another therapeutic area, were selected. Gradient boosting-based ML approaches (e.g., XGBoost) were applied as the main modeling strategy. RESULTS: For Drug X, eight true signals were present in the test set. Among 12 potential new signals generated, four were true signals with a 50.0% sensitivity rate and a 33.3% positive predictive value (PPV) rate. Among the remaining eight potential new signals, one was confirmed as a signal and detected six months earlier than humans. For Drug Y, nine true signals were present in the test set. Among 13 potential new signals generated, five were true signals with a 55.6% sensitivity rate and a 38.5% PPV rate. Among the remaining eight potential new signals, none were confirmed as true signals upon human review. CONCLUSION: This model demonstrated acceptable accuracy for safety signal detection and potential for earlier detection when compared to humans. Expert judgment, flexibility, and critical thinking are essential human skills required for the final, accurate assessment of adverse event cases.

Modeling blood-brain barrier formation and cerebral cavernous malformations in human PSC-derived organoids.

The human blood-brain barrier (hBBB) is a highly specialized structure that regulates passage across blood and central nervous system (CNS) compartments. Despite its critical physiological role, there are no reliable in vitro models that can mimic hBBB development and function. Here, we constructed hBBB assembloids from brain and blood vessel organoids derived from human pluripotent stem cells. We validated the acquisition of blood-brain barrier (BBB)-specific molecular, cellular, transcriptomic, and functional characteristics and uncovered an extensive neuro-vascular crosstalk with a spatial pattern within hBBB assembloids. When we used patient-derived hBBB assembloids to model cerebral cavernous malformations (CCMs), we found that these assembloids recapitulated the cavernoma anatomy and BBB breakdown observed in patients. Upon comparison of phenotypes and transcriptome between patient-derived hBBB assembloids and primary human cavernoma tissues, we uncovered CCM-related molecular and cellular alterations. Taken together, we report hBBB assembloids that mimic the core properties of the hBBB and identify a potentially underlying cause of CCMs.

Loss-of-function mutation in DDX53 associated with hereditary spastic paraplegia-like disorder.

DEAD-box helicase 53 (DDX53) is a member of the DEAD-box protein family of RNA helicases. Unlike other family members that are responsible for RNA metabolism, the biological function of DDX53 and its impact on the human condition are unclear. Herein, we found a full-length DDX53 deletion mutation in a hereditary spastic paraplegia-like (HSP-like) patient with lower extremity spasticity, walking disorder, visual impairment, and lateral ventricular white matter lesions. Bioinformatic analysis revealed that DDX53 was mainly expressed in the cerebellar cortex and may function as a tissue-specific RNA helicase. Transcriptome analysis showed that the expression of multiple brain-associated genes involved in synapse organization, neuron function, and neuromuscular junctions was affected by DDX53 depletion. Moreover, RNA immunoprecipitation sequencing (RIP-seq) analysis showed that DDX53 interacted with 176 genes, and 96 of these genes were associated with the execution of neurofunction, particularly in the regulation of cell projection organization and nervous system development. Collectively, although a more specified cell or animal model is required to fully understand the functional role of DDX53 in the human brain, we report for the first time that the patient with DDX53 defects exhibits HSP-like symptoms and that DDX53 is essential for maintaining neuronal function, with loss-of-function mutation in DDX53 potentially leading to HSP due to impaired RNA metabolism in the nervous system. KEY MESSAGES: DDX53 deficiency was first reported to be associated with HSP disorder. DDX53 exhibited minimal impact on mitochondrial function. DDX53 impaired RNA metabolism in the nervous system.

Hidden diversity and potential ecological function of phosphorus acquisition genes in widespread terrestrial bacteriophages.

Phosphorus (P) limitation of ecosystem processes is widespread in terrestrial habitats. While a few auxiliary metabolic genes (AMGs) in bacteriophages from aquatic habitats are reported to have the potential to enhance P-acquisition ability of their hosts, little is known about the diversity and potential ecological function of P-acquisition genes encoded by terrestrial bacteriophages. Here, we analyze 333 soil metagenomes from five terrestrial habitat types across China and identify 75 viral operational taxonomic units (vOTUs) that encode 105 P-acquisition AMGs. These AMGs span 17 distinct functional genes involved in four primary processes of microbial P-acquisition. Among them, over 60% (11/17) have not been reported previously. We experimentally verify in-vitro enzymatic activities of two pyrophosphatases and one alkaline phosphatase encoded by P-acquisition vOTUs. Thirty-six percent of the 75 P-acquisition vOTUs are detectable in a published global topsoil metagenome dataset. Further analyses reveal that, under certain circumstances, the identified P-acquisition AMGs have a greater influence on soil P availability and are more dominant in soil metatranscriptomes than their corresponding bacterial genes. Overall, our results reinforce the necessity of incorporating viral contributions into biogeochemical P cycling.

A digital workflow for designing and manufacturing metal frameworks and removable partial dentures: A novel dental technique.

The purpose of this technical report is to demonstrate a fully digital workflow for designing and fabricating metal frameworks and removable partial dentures. After obtaining a digital cast of the dental arch with bilateral distal extension defect, computer-aided design software and 3D printing technology are used for the design and fabrication of the removable partial denture frameworks, denture teeth, and denture bases, instead of the traditional workflow. The assembly of the three components is facilitated through a meticulously structured framework. The technology, which prints metal frameworks, denture bases, and denture teeth through different processes with different materials, achieves full 3D printing technology for making removable partial dentures.

Formoterol Acting via ß2-Adrenoreceptor Restores Mitochondrial Dysfunction Caused by Parkinson's Disease-Related UQCRC1 Mutation and Improves Mitochondrial Homeostasis Including Dynamic and Transport.

Formoterol, a ß2-adrenergic receptor (ß2AR) agonist, shows promise in various diseases, but its effectiveness in Parkinson's disease (PD) is debated, with unclear regulation of mitochondrial homeostasis. This study employed a cell model featuring mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) variants associated with familial parkinsonism, demonstrating mitochondrial dysfunction and dynamic imbalance, exploring the therapeutic effects and underlying mechanisms of formoterol. Results revealed that 24-h formoterol treatment enhanced cell proliferation, viability, and neuroprotection against oxidative stress. Mitochondrial function, encompassing DNA copy number, repatriation, and complex III-linked respiration, was comprehensively restored, along with the dynamic rebalance of fusion/fission events. Formoterol reduced extensive hypertubulation, in contrast to mitophagy, by significantly upregulating protein Drp-1, in contrast to fusion protein Mfn2, mitophagy-related protein Parkin. The upstream mechanism involved the restoration of ERK signaling and the inhibition of Akt overactivity, contingent on the activation of ß2-adrenergic receptors. Formoterol additionally aided in segregating healthy mitochondria for distribution and transport, therefore normalizing mitochondrial arrangement in mutant cells. This study provides preliminary evidence that formoterol offers neuroprotection, acting as a mitochondrial dynamic balance regulator, making it a promising therapeutic candidate for PD.

Establishment of Human Pituitary Neuroendocrine Tumor Derived Organoid and Its Pilot Application for Drug Screening.

CONTEXT: Precision medicine for pituitary neuroendocrine tumors (PitNETs) is limited by the lack of reliable research models. OBJECTIVE: To generate patient-derived organoids (PDOs), which could serve as a platform for personalized drug screening for PitNET patients. DESIGN: From July 2019 to May 2022, a total of 32 human PitNET specimens were collected for the establishment of organoids with an optimized culture protocol. SETTING: This study was conducted at Sun Yat-Sen University Cancer Center. PATIENTS: PitNET patients who were pathologically confirmed were enrolled in this study. INTERVENTIONS: Histological staining and whole-exome sequencing were utilized to confirm the pathologic and genomic features of PDOs. A drug response assay on PDOs was also performed. MAIN OUTCOME MEASURES: PDOs retained key genetic and morphological features of their parental tumors. RESULTS: PDOs were successfully established from various types of PitNET samples with an overall success rate of 87.5%. Clinical nonfunctioning PitNETs-derived organoids (22/23, 95.7%) showed a higher likelihood of successful generation compared to those from functioning PitNETs (6/9, 66.7%). Preservation of cellular structure, subtype-specific neuroendocrine profiles, mutational features, and tumor microenvironment heterogeneity from parental tumors was observed. A distinctive response profile in drug tests was observed among the organoids from patients with different subtypes of PitNETs. With the validation of key characteristics from parental tumors in histological, genomic, and microenvironment heterogeneity consistency assays, we demonstrated the predictive value of the PDOs in testing individual drugs. CONCLUSION: The established PDOs, retaining typical features of parental tumors, indicate a translational significance in innovating personalized treatment for refractory PitNETs.

Deep Learning-Based Psoriasis Assessment: Harnessing Clinical Trial Imaging for Accurate Psoriasis Area Severity Index Prediction.

Introduction: Image-based machine learning holds great promise for facilitating clinical care; however, the datasets often used for model training differ from the interventional clinical trial-based findings frequently used to inform treatment guidelines. Here, we draw on longitudinal imaging of psoriasis patients undergoing treatment in the Ultima 2 clinical trial (NCT02684357), including 2,700 body images with psoriasis area severity index (PASI) annotations by uniformly trained dermatologists. Methods: An image-processing workflow integrating clinical photos of multiple body regions into one model pipeline was developed, which we refer to as the "One-Step PASI" framework due to its simultaneous body detection, lesion detection, and lesion severity classification. Group-stratified cross-validation was performed with 145 deep convolutional neural network models combined in an ensemble learning architecture. Results: The highest-performing model demonstrated a mean absolute error of 3.3, Lin's concordance correlation coefficient of 0.86, and Pearson correlation coefficient of 0.90 across a wide range of PASI scores comprising disease classifications of clear skin, mild, and moderate-to-severe disease. Within-person, time-series analysis of model performance demonstrated that PASI predictions closely tracked the trajectory of physician scores from severe to clear skin without systematically over- or underestimating PASI scores or percent changes from baseline. Conclusion: This study demonstrates the potential of image processing and deep learning to translate otherwise inaccessible clinical trial data into accurate, extensible machine learning models to assess therapeutic efficacy.

Single-cell multiplex chromatin and RNA interactions in ageing human brain.

Dynamically organized chromatin complexes often involve multiplex chromatin interactions and sometimes chromatin-associated RNA1-3. Chromatin complex compositions change during cellular differentiation and ageing, and are expected to be highly heterogeneous among terminally differentiated single cells4-7. Here we introduce the multinucleic acid interaction mapping in single cells (MUSIC) technique for concurrent profiling of multiplex chromatin interactions, gene expression and RNA-chromatin associations within individual nuclei. When applied to 14 human frontal cortex samples from older donors, MUSIC delineated diverse cortical cell types and states. We observed that nuclei exhibiting fewer short-range chromatin interactions were correlated with both an 'older' transcriptomic signature and Alzheimer's disease pathology. Furthermore, the cell type exhibiting chromatin contacts between cis expression quantitative trait loci and a promoter tends to be that in which these cis expression quantitative trait loci specifically affect the expression of their target gene. In addition, female cortical cells exhibit highly heterogeneous interactions between XIST non-coding RNA and chromosome X, along with diverse spatial organizations of the X chromosomes. MUSIC presents a potent tool for exploration of chromatin architecture and transcription at cellular resolution in complex tissues.

AgAu-modified quasi-MIL-53 hybrid nanozymes with triple enzyme-like activities for boosting biocatalytic disinfection.

Metal-organic frameworks (MOFs) have great potential for combating pathogenic bacterial infections and are expected to become an alternative to antibiotics. However, organic linkers obstruct and saturate the inorganic nodes of MOF structures, making it challenging to utilize the applied potential of metal centers. Here, we combined controlled ligand decarboxylation with noble metal nanoparticles to rationally remodel MIL-53, resulting in a hybrid nanozyme (AgAu@QMIL-53, AAQM) with excellent multiple enzyme-like activities that both eradicate bacteria and promote diabetic wound healing. Specifically, benefitting from oxidase (OXD)-like and peroxidase (POD)-like activities, AAQM converts oxygen (O2) and hydrogen peroxide (H2O2) into superoxide anion radicals (O2-) and hydroxyl radicals (OH) to eradicate bacteria. In in vitro antibacterial experiments, AAQM exhibited favorable killing efficacy against Pseudomonas aeruginosa (P. aeruginosa) and methicillin-resistant Staphylococcus aureus (MRSA) (>99 %). Notably, due to its superoxide (SOD)-like activity and outstanding reactive nitrogen species (RNS) elimination capacity, AAQM can produce adequate O2 and alleviate oxidative stress in diabetic wounds. Benefiting from the rational modification of MIL-53, the synthesized hybrid nanozyme can effectively kill bacteria while alleviating oxidative stress and ultimately promote infected diabetic wound healing. Overall, this biomimetic enzyme-catalyzed strategy will bring enlightenment to the design of self-antibacterial agents for efficient disinfection and wound healing simultaneously.

Prussian Blue Analogue-Derived Co3O4 as Catalysts for Enhanced Selective Oxidation of Cyclohexane Using Molecular Oxygen.

Selective conversion of inert C-H bonds in alkanes into high-value-added functional groups (alcohols, ketones, carboxylic acids, etc.) plays a vital role in establishing a green and sustainable chemical industry. Catalytic selective oxidation of cyclohexane to KA oil (cyclohexanol and cyclohexanone) is a typical representative of alkane functionalization. In this work, hollow cage-like Co3O4 (Co3O4-C) and particle Co3O4 (Co3O4-P) were synthesized by calcining two types of Prussian blue analogues (PBAs), which were used to catalyze the selective oxidation of cyclohexane. The Co3O4-C predominantly exposed (311) crystal plane is easier to adsorb cyclohexane than Co3O4-P, which is beneficial to shorten the induction period, accelerate the reaction rate, and improve the conversion. Consequently, Co3O4-C displayed a 10% conversion of cyclohexane within 1 h, and the KA oil selectivity reached 90%. The Co3O4-P exposed (220) crystal plane has a higher molar percentage of oxygen vacancies and more active oxygen species, as well as a strong cyclohexanone adsorption capacity, which is conducive to the deep oxidation of cyclohexanone to adipic acid and other diacid products. The mechanism analysis of cyclohexane oxidation catalyzed by PBA-based Co3O4 shows that it exemplifies the feasibility to tailor the surface of catalysts by modulating the PBAs, which ultimately influences their reaction performance for accelerating the reaction and maintaining high cyclohexane conversion and KA oil selectivity.

Advances focusing on the application of decellularization methods in tendon-bone healing.

BACKGROUND: The tendon or ligament is attached to the bone by a triphasic but continuous area of heterogeneous tissue called the tendon-bone interface (TBI). The rapid and functional regeneration of TBI is challenging owing to its complex composition and difficulty in self-healing. The development of new technologies, such as decellularization, has shown promise in the regeneration of TBI. Several ex vivo and in vivo studies have shown that decellularized grafts and decellularized biomaterial scaffolds achieved better efficacy in enhancing TBI healing. However further information on the type of review that is available is needed. AIM OF THE REVIEW: In this review, we discuss the current application of decellularization biomaterials in promoting TBI healing and the possible mechanisms involved. With this work, we would like to reveal how tissues or biomaterials that have been decellularized can improve tendon-bone healing and to provide a theoretical basis for future related studies. KEY SCIENTIFIC CONCEPTS OF THE REVIEW: Decellularization is an emerging technology that utilizes various chemical, enzymatic and/or physical strategies to remove cellular components from tissues while retaining the structure and composition of the extracellular matrix (ECM). After decellularization, the cellular components of the tissue that cause an immune response are removed, while various biologically active biofactors are retained. This review further explores how tissues or biomaterials that have been decellularized improve TBI healing.

Microplastics as emerging contaminants in textile dyeing sludge: Their impacts on co-combustion/pyrolysis products, residual metals, and temperature dependency of emissions.

As emerging contaminants in textile dyeing sludge (TDS), the presence and types of microplastics (MPs) inevitably influence the combustion and pyrolysis of TDS. Their effects on the co-combustion/pyrolysis emissions and residual metals of TDS remain poorly understood. This study aimed to quantify the impacts of polyethylene (PE) and polypropylene (PP) on the transports and transformations of gaseous emissions and residual metals generated during the TDS combustion and pyrolysis in the air, oxy-fuel, and nitrogen atmospheres. Thermal degradation of the MPs in TDS occurred between 242-600 °C. MPs decomposed and interacted with the organic components of TDS to the extent that they increased the release of VOCs, dominated by oxygenated VOCs and hydrocarbons under the incineration and pyrolysis conditions, respectively. The presence of PE exerted a limited impact on the concentration and chemical form of metals, while PP reduced the residual amount of most metals due to the decomposition of mineral additives. Also, PP (with CaCO3 filler) reduced the acid-extractable content of cadmium, copper, and manganese in the bottom slag or coke but increased that of chromium. This study provides actionable insights into optimizing gas emissions, energy recovery, and ash reuse, thus reinforcing the pollution control strategies for both the MPs and TDS.

Association between psychiatric disorders and glioma risk: evidence from Mendelian randomization analysis.

BACKGROUND: Observational studies have explored the association of psychiatric disorders and the risk of brain cancers. However, the causal effect of specific mental illness on glioma remains elusive due to the lack of solid evidence. METHODS: We performed a two-sample bidirectional Mendelian randomization (MR) analysis to explore the causal relationships between 5 common psychiatric disorders (schizophrenia, major depressive disorder, bipolar disorder, autism spectrum disorder, and panic disorder) and glioma. Summary statistics for psychiatric disorders and glioma were extracted from Psychiatric Genomics Consortium (PGC) and 8 genome-wide association study (GWAS) datasets respectively. We calculated the MR estimates for odds ratio of glioma associated with each psychiatric disorder by using inverse-variance weighting (IVW) method. Sensitivity analyses such as weighted median estimator, MR-Egger and MR-PRESSO were leveraged to assess the strength of causal inference. RESULTS: A total of 30,657 participants of European ancestry were included in this study. After correction for multiple testing, we found that genetically predicted schizophrenia was associated with a statistically significant increase in odds of non-glioblastoma multiforme (non-GBM) (OR = 1.13, 95% CI: 1.03-1.23, P = 0.0096). There is little evidence for the causal relationships between the other 4 psychiatric disorders with the risk of glioma. CONCLUSIONS: In this MR analysis, we revealed an increased risk of non-GBM glioma in individuals with schizophrenia, which gives an insight into the etiology of glioma.