Semen Strychni Pulveratum and vomicine alleviate neuroinflammation in amyotrophic lateral sclerosis through cGAS-STING-TBK1 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a fetal neuromuscular disorder characterized by the gradual deterioration of motor neurons. Semen Strychni pulveratum (SSP), a processed version of Semen Strychni (SS) powder, is widely used to treat ALS in China. Vomicine is one of the most primary components of SS. However, their pharmacological effects and mechanisms for ALS remain elusive. AIM OF THE STUDY: This study aimed to evaluate the neuroprotective and anti-neuroinflammatory effects of SSP and vomicine, as well as to explore their protective roles in ALS and the underlying mechanisms. MATERIALS AND METHODS: In vivo, 8-week-old hSOD1-WT mice and hSOD1-G93A mice were orally administered different concentrations of SSP (SSP-L = 5.46 mg/ml, SSP-M = 10.92 mg/ml or SSP-H = 16.38 mg/ml) once every other day for 8 weeks. A series of experiments, including body weight measurement, footprint tests, Hematoxylin & Eosin staining, and Nissl staining, were performed to evaluate the preventive effect of SSP. Immunofluorescence staining, western blotting, and RT-qPCR were subsequently performed to evaluate activation of the cGAS-STING-TBK1 pathway in the spinal cord. In vitro, hSOD1G93A NSC-34 cells were treated with vomicine to further explore the pharmacological mechanism of vomicine in the treatment of ALS via the cGAS-STING-TBK1 pathway. RESULTS: SSP improved motor function, body weight loss, gastrocnemius muscle atrophy, and motor neuron loss in the spine and cortex of hSOD1-G93A mice. Furthermore, the cGAS-STING-TBK1 pathway was activated in the spinal cord of hSOD1-G93A mice, with activation predominantly observed in neurons and microglia. However, the levels of cGAS, STING, and pTBK1 proteins and cGAS, IRF3, IL-6, and IL-1ß mRNA were reversed following intervention with SSP. Vomicine not only downregulated the levels of cGAS, TBK1, IL-6 and IFN-ß mRNA, but also the levels of cGAS and STING protein in hSOD1G93A NSC-34 cells. CONCLUSION: This study demonstrated that SSP and vomicine exert neuroprotective and anti-neuroinflammatory effects in the treatment of ALS. SSP and vomicine may reduce neuroinflammation by regulating the cGAS-STING-TBK1 pathway, and could thereby play a role in ALS treatment.

Rapid visual detection of Helicobacter pylori and vacA subtypes by Dual-Target RAA-LFD assay.

BACKGROUND: Helicobacter pylori (H. pylori) infects over 50% of the global population and is a significant risk factor for gastric cancer. The pathogenicity of H. pylori is primarily attributed to virulence factors such as vacA. Timely and accurate identification, along with genotyping of H. pylori virulence genes, are essential for effective clinical management and controlling its prevalence. METHODS: In this study, we developed a dual-target RAA-LFD assay for the rapid, visual detection of H. pylori genes (16s rRNA, ureA, vacA m1/m2), using recombinase aided amplification (RAA) combined with lateral flow dipstick (LFD) methods. Both 16s rRNA and ureA were selected as identification genes to ensure reliable detection accuracy. RESULTS: A RAA-LFD assay was developed to achieve dual-target amplification at a stable 37 °C within 20 min, followed by visualization using the lateral flow dipstick (LFD). The whole process, from amplification to results, took less than 30 min. The 95 % limit of detection (LOD) for 16 s rRNA and ureA, vacA m1, vacA m2 were determined as 3.8 × 10-2 ng/µL, 5.8 × 10-2 ng/µL and 1.4 × 10-2 ng/µL, respectively. No cross-reaction was observed in the detection of common pathogens including Escherichia coli, Klebsiella pneumoniae, Enterococcus faecalis, Staphylococcus aureus, Pseudomonas aeruginosa, and Bacillus subtilis, showing the assay's high specificity. In the evaluation of the clinical performance of the RAA-LFD assay. A total of 44 gastric juice samples were analyzed, immunofluorescence staining (IFS) and quantitative polymerase chain reaction (qPCR) were used as reference methods. The RAA-LFD results for the 16s rRNA and ureA genes showed complete agreement with qPCR findings, accurately identifying H. pylori infection as confirmed by IFS in 10 out of the 44 patients. Furthermore, the assay successfully genotyped vacA m1/m2 among the positive samples, showing complete agreement with qPCR results and achieving a kappa (κ) value of 1.00. CONCLUSION: The dual-target RAA-LFD assay developed in this study provides a rapid and reliable method for detecting and genotyping H. pylori within 30 min, minimizing dependency on sophisticated laboratory equipment and specialized personnel. Clinical validation confirms its efficacy as a promising tool for effectively control of its prevalence and aiding in the precise treatment of H. pylori-associated diseases.

Modulation of mechanosensation by endogenous dopaminergic signaling in the lateral parabrachial nucleus in mice.

Introduction: The lateral parabrachial nucleus (LPBN), a crucial hub for integrating and modulating diverse sensory information, is known to express both D1 and D2 dopamine receptors and receive dopaminergic inputs. However, the role of the LPBN's dopaminergic system in somatosensory processing remains largely unexplored. In this study, we investigated whether mechanical sensory stimulation triggers dopamine release in the LPBN and how D1- and D2-like receptor signaling in the LPBN influences mechanosensitivity in mice. Methods: We used a G-protein-coupled receptor-based dopamine sensor to monitor dopamine release in the LPBN and a von Frey filament assay to measure the mechanical threshold for nocifensive withdrawal in mouse hind paws after unilateral microinjection of D1- or D2-like receptor antagonist into the LPBN. Results: Noxious mechanical stimulation increased the dopamine sensor signal in the LPBN. Thresholds of nocifensive withdrawal from mechanical stimulation were decreased by the D1-like receptor antagonist SCH-23390 (0.1 µg) but increased by the D2-like receptor antagonist eticlopride (1 µg). In the intraplantar capsaicin injection model that develops mechanical hypersensitivity in the injected paw, the dopamine sensor signal in the LPBN was increased, and eticlopride (1 µg) in the LPBN significantly inhibited the capsaicin-induced mechanical hypersensitivity. Conclusions: These results suggest that endogenous dopaminergic signaling occurs in the LPBN upon noxious mechanical stimulation, inhibiting mechanosensitivity through D1-like receptors while enhancing it through D2-like receptors. D2-like receptor signaling in the LPBN may contribute to an injury-induced increase in mechanical nociception, indicating that inhibiting the receptor within the LPBN could offer potential as a novel analgesic strategy.

Why do acute healthcare staff behave unprofessionally towards each other and how can these behaviours be reduced? A realist review.

Background: Unprofessional behaviour in healthcare systems can negatively impact staff well-being, patient safety and organisational costs. Unprofessional behaviour encompasses a range of behaviours, including incivility, microaggressions, harassment and bullying. Despite efforts to combat unprofessional behaviour in healthcare settings, it remains prevalent. Interventions to reduce unprofessional behaviour in health care have been conducted - but how and why they may work is unclear. Given the complexity of the issue, a realist review methodology is an ideal approach to examining unprofessional behaviour in healthcare systems. Aim: To improve context-specific understanding of how, why and in what circumstances unprofessional behaviours between staff in acute healthcare settings occur and evidence of strategies implemented to mitigate, manage and prevent them. Methods: Realist synthesis methodology consistent with realist and meta-narrative evidence syntheses: evolving standards reporting guidelines. Data sources: Literature sources for building initial theories were identified from the original proposal and from informal searches of various websites. For theory refinement, we conducted systematic and purposive searches for peer-reviewed literature on databases such as EMBASE, Cumulative Index to Nursing and Allied Health Literature and MEDLINE databases as well as for grey literature. Searches were conducted iteratively from November 2021 to December 2022. Results: Initial theory-building drew on 38 sources. Searches resulted in 2878 titles and abstracts. In total, 148 sources were included in the review. Terminology and definitions used for unprofessional behaviours were inconsistent. This may present issues for policy and practice when trying to identify and address unprofessional behaviour. Contributors of unprofessional behaviour can be categorised into four areas: (1) workplace disempowerment, (2) organisational uncertainty, confusion and stress, (3) (lack of) social cohesion and (4) enablement of harmful cultures that tolerate unprofessional behaviours. Those at most risk of experiencing unprofessional behaviour are staff from a minoritised background. We identified 42 interventions in the literature to address unprofessional behaviour. These spanned five types: (1) single session (i.e. one-off), (2) multiple sessions, (3) single or multiple sessions combined with other actions (e.g. training session plus a code of conduct), (4) professional accountability and reporting interventions and (5) structured culture-change interventions. We identified 42 reports of interventions, with none conducted in the United Kingdom. Of these, 29 interventions were evaluated, with the majority (n = 23) reporting some measure of effectiveness. Interventions drew on 13 types of behaviour-change strategy designed to, for example: change social norms, improve awareness of unprofessional behaviour, or redesign the workplace. Interventions were impacted by 12 key dynamics, including focusing on individuals, lack of trust in management and non-existent logic models. Conclusions: Workplace disempowerment and organisational barriers are primary contributors to unprofessional behaviour. However, interventions predominantly focus on individual education or training without addressing systemic, organisational issues. Effectiveness of interventions to improve staff well-being or patient safety is uncertain. We provide 12 key dynamics and 15 implementation principles to guide organisations. Future work: Interventions need to: (1) be tested in a United Kingdom context, (2) draw on behavioural science principles and (3) target systemic, organisational issues. Limitations: This review focuses on interpersonal staff-to-staff unprofessional behaviour, in acute healthcare settings only and does not include non-intervention literature outside the United Kingdom or outside of health care. Study registration: This study was prospectively registered on PROSPERO CRD42021255490. The record is available from: www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021255490. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: NIHR131606) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 25. See the NIHR Funding and Awards website for further award information.

For this study, we asked: how, why and in what situations can unprofessional behaviour between healthcare staff working in acute care (usually hospitals) be reduced, managed and prevented? We wanted to research how people understand unprofessional behaviour, explore the circumstances leading to unprofessional behaviour and understand how existing approaches to addressing unprofessional behaviour worked (or did not work) across staff groups and acute healthcare organisations. We used a literature review method called a 'realist review', which differs from other review methods. A realist review focuses on understanding not only if interventions work but how and why they work, and for whom. This allowed us to analyse a wider range of relevant international literature ­ not only academic papers. We found 148 sources, which were relevant either because they described unprofessional behaviour or because they provided information on how to address unprofessional behaviour. Definitions of unprofessional behaviour varied, making it difficult to settle on one description. For example, unprofessional behaviour may involve incivility, bullying, harassment and/or microaggressions. We examined what might contribute to unprofessional behaviour and identified factors including uncertainty in the working environment. We found no United Kingdom-based interventions and only one from the United States of America that sought to reduce unprofessional behaviour towards minority groups. Strategies often tried to encourage staff to speak up, provide ways to report unprofessional behaviour or set social standards of behaviour. We also identified factors that may make it challenging for organisations to successfully select, implement and evaluate an intervention to address unprofessional behaviour. We recommend a system-wide approach to addressing unprofessional behaviour, including assessing the context and then implementing multiple approaches over a long time (rather than just once), because they are likely to have greater impact on changing culture. We are producing an implementation guide to support this process. Interventions need to enhance staff ability to feel safe at work, work effectively and support those more likely to experience unprofessional behaviour.

Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as TARDBP (TDP-43) and FUS. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (TBPH or caz) in Drosophila muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by foxo inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.

Resistance exercise in early-stage ALS patients, ALSFRS-R, Sickness Impact Profile ALS-19, and muscle transcriptome: a pilot study.

Amyotrophic lateral sclerosis (ALS) patients lack effective treatments to maintain motor and neuromuscular function. This study aimed to evaluate the effect of a home-based exercise program on muscle strength, ALS scores, and transcriptome in ALS patients, Clinical Trials.gov #NCT03201991 (28/06/2017). An open-label, non-randomized pilot clinical trial was conducted in seven individuals with early-stage ALS. Participants were given 3 months of home-based resistance exercise focusing on the quadriceps muscles. The strength of exercised muscle was evaluated using bilateral quadriceps strength with manual muscle testing, handheld dynamometers, five times sit-to-stand, and Timed-Up-and-Go before and after the exercise program. In addition, changes in the Sickness Impact Profile ALS-19 (SIP/ALS-19) as the functional outcome measure and the transcriptome of exercised muscles were compared before and after the exercise. The primary outcome of muscle strength did not change significantly by the exercise program. The exercise program maintained the SIP/ALS-19 and the ALS Functional Rating Scale-Revised (ALSFRS-R). Transcriptome analysis revealed that exercise reverted the expression level of genes decreased in ALS, including parvalbumin. Three months of moderately intense strength and conditioning exercise maintained muscle strength of the exercised muscle and ALSFRS-R scores and had a positive effect on patients' muscle transcriptome.

Prion protein pathology in Ubiquilin 2 models of ALS.

Mutations in UBQLN2 cause ALS and frontotemporal dementia (FTD). The pathological signature in UBQLN2 cases is deposition of highly unusual types of inclusions in the brain and spinal cord that stain positive for UBQLN2. However, what role these inclusions play in pathogenesis remains unclear. Here we show cellular prion protein (PrPC) is found in UBQLN2 inclusions in both mouse and human neuronal induced pluripotent (IPSC) models of UBQLN2 mutations, evidenced by the presence of aggregated forms of PrPC with UBQLN2 inclusions. Turnover studies indicated that the P497H UBQLN2 mutation slows PrPC protein degradation and leads to mislocalization of PrPC in the cytoplasm. Immunoprecipitation studies indicated UBQLN2 and PrPC bind together in a complex. The abnormalities in PrPC caused by UBQLN2 mutations may be relevant in disease pathogenesis.

The relationship between lung CT features and serum cryptococcal antigen titers in localized pulmonary cryptococcosis patients.

BACKGROUND: To explore the associations of computed tomography (CT) image features with the serum cryptococcal antigen (CrAg) titers measured by the lateral flow assay (LFA) in localized pulmonary cryptococcosis patients. METHODS: A retrospective analysis of patients with pathologically confirmed pulmonary cryptococcosis admitted to the First Affiliated Hospital of Xiamen University from January 2016 to December 2022 was performed. Clinical data, CT results, serum CrAg-LFA test results, and follow-up data were collected and analyzed. RESULTS: A total of 107 patients with localized pulmonary cryptococcosis were included, of which 31 had a single lesion in chest CT and the other 76 had multiple lesions. The positivity rate was (94.74% vs 64.52%) and titers of serum CrAg-LFA (1.77 ± 0.87 vs 0.91 ± 0.98) in the multiple lesion group were higher than those in the single lesion group, respectively. Multivariate linear regression analysis showed that the serum CrAg titers were positively associated with the number of lesions (ß, 0.08; 95% CI, 0.05 to 0.12) and the lesion size (ß, 0.40; 95% CI, 0.31 to 0.50) after adjusting other covariates. The serum CrAg-LFA titers of 60 pulmonary cryptococcosis patients showed a decreasing trend with the reduction in pulmonary lesion size after effective therapy. CONCLUSION: In pulmonary cryptococcosis patients, the number and size of lung lesions are positively correlated with the titers of the serum CrAg-LFA test. The CrAg-LFA test could be a useful tool for the diagnosis, severity assessment, and therapeutic monitoring of localized pulmonary cryptococcosis patients.

Pathology reduction and motor behavior improvement associated with ultrasound-mediated delivery of arctiin to the motor cortex in a mutant SOD1 mouse model of amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is marked by the deterioration of both cortical and spinal cord motor neurons. Despite the underlying causes of the disease remain elusive, there has been a growing attention on the well-being of cortical motor neurons in recent times. Focused ultrasound combined with microbubbles (FUS/MB) for opening the blood-brain barrier (BBB) provides a means for drug delivery to specific brain regions, holding significant promise for the treatment of neurological disorders. OBJECTIVES: We aim to explore the outcomes of FUS/MB-mediated delivery of arctiin (Arc), a natural compound with anti-inflammatory activities, to the cerebral motor cortex area by using a transgenic ALS mouse model. METHODS: The ALS mouse model with the SOD1G93A mutation was used and subjected to daily Arc administration with FUS/MB treatment twice a week. After six-week treatments, the motor performance was assessed by grip strength, wire hanging, and climbing-pole tests. Mouse brains, spinal cords and gastrocnemius muscle were harvested for histological staining. RESULTS: Compared with the mice given Arc administration only, the combined treatments of FUS/MB with Arc induced further mitigation of the motor function decline, accompanied by improved health of the gastrocnemius muscle. Furthermore, notable neuroprotective effect was evidenced by the amelioration of motor neuron failure in the cortex and lumbar spinal cord. CONCLUSION: These preliminary results indicated that the combined treatment of FUS/MB and arctiin exerted a potentially beneficial effect on neuromuscular function in the ALS disease.

The significance of low titer serum cryptococcal antigen testing from 2017 to 2023 performed in a tertiary care center.

Several false positive low serum cryptococcal antigen (SCrAg) reports by lateral flow assay (LFA) were identified in late 2016 at our tertiary care hospital. After the recall and correction of the problem in the reagent, we studied the significance of SCrAg LFA ≤ 1:10 from January 2017 to October 2023. Of 20 patients with 31 samples of SCrAg LFA ≤ 1:10, 14 patients (70%) were classified as true positives, four (20%) were indeterminate, and only two (10%) patients were false positives. If a new SCrAg LFA ≤ 1:10 is detected, it should be repeated, and additional workup should be pursued.

We studied the significance of low serum cryptococcal antigen (SCrAg) titer lateral flow assay (LFA) ≤ 1:10 from January 2017 to October 2023. Of 20 patients with SCrAg LFA ≤ 1:10, only two patients (10%) were false positives. If a new SCrAg ≤ 1:10 is detected, it should be repeated, and additional workup should be done.

Cervical spondylotic myelopathy in a 68-year-old man diagnosed with amyotrophic lateral sclerosis.

Owing to similar clinical presentations, cervical spondylotic myelopathy can mimic other neurological disorders. In this imaging case review (ICR), we describe a case of cervical spondylotic myelopathy in a patient diagnosed with amyotrophic lateral sclerosis. The key clinical features, imaging findings and differential diagnoses of cervical spondylotic myelopathy compared with amyotrophic lateral sclerosis are also presented.

Examen du cas par imagerieUne myélopathie spondylotique cervicale chez un patient de 68 ans atteint de sclérose latérale amyotrophiqueEn raison de présentations cliniques similaires, la myélopathie spondylotique cervicale peut simuler d'autres troubles neurologiques. Une myélopathie spondylotique cervicale (MSC) chez un patient de 68 ans atteint de sclérose latérale amyotrophique. Les principales caractéristiques cliniques, les résultats d'imagerie et les diagnostics différentiels de myélopathie spondylotique cervicale par rapport à la sclérose latérale amyotrophique sont également présentés.

Single-center external validation and reconstruction of multiple predictive models for skip lateral lymph node metastasis in papillary thyroid carcinoma.

Objective: The unique metastatic pattern of skip lateral lymph node metastasis (SLLNM) in PTC patients may lead to missed diagnosis of lateral cervical metastatic lymph nodes. Therefore, many different SLLNM prediction models were constructed. In this study, partially eligible models (Hu 2020, Wang 2020, and Zhao 2023 nomograms) were selected for external validation, and then new variables were incorporated for model reconstruction to extend clinical applicability. Methods: 576 PTC patients from our center were selected to evaluate the performance of the three nomograms using the receiver operating characteristic curve (ROC), calibration curves, and decision curve analyses (DCA). Three new variables were added to calibrate the model, including assessment of LN status on ultrasound (US-SLLNM), the distance from the tumor to the capsule (Capsular distance), and the number of central lymph node dissections (CLND number). Univariate and multivariate logistic regression analyses were used to screen independent predictors to reconstruct the model, and 1000 Bootstrap internal validations were performed. Results: SLLNM were present in 69/576 patients (12.0%). In external validation, the area under the ROC curves (AUCs) for Hu 2020, Wang 2020, and Zhao 2023 nomograms were 0.695 (95% CI:0.633-0.766), 0.792 (95% CI=0.73-0.845), and 0.769 (95% CI:0.713-0.824), respectively. The calibration curves for the three models were overall poorly fitted; DCA showed some net clinical benefit. Model differentiation and net clinical benefit improved by adding three new variables. Based on multivariate analysis, female, age, and maximum tumor diameter ≤ 10 mm, located at the upper pole, Capsular distance < 0mm, US-SLLNM, CLND number ≤ 5 were identified as independent predictors of SLLNM and were used to construct the new model. After 1000 Bootstrap internal validations, the mean AUC of the model was 0.870 (95% CI:0.839-0.901), the calibration curve was close to the ideal curve, and the net clinical benefit was significant. Conclusion: Overall, these nomograms were well differentiated and provided some net clinical benefit, but with varying degrees of underestimation or overestimation of the actual risk and high false-negative rates. New dynamic nomogram was constructed based on the addition of new variables and larger samples, showing better performance.

Rapid and equipment-free identification of papaya mealybug Paracoccus marginatus based on RPA-CRISPR/Cas12a.

BACKGROUND: Paracoccus marginatus has invaded many countries, spreading rapidly and causing significant economic losses to crops. Accurate detection during the monitoring process is critical to prevent its expansion into new areas, therefore it is necessary to develop efficient and reliable detection methods. Traditional detection methods are time-consuming and instrument-dependent owing to the morphological similarities and small sizes of P. marginatus and other mealybugs, therefore establishing an efficient, rapid, and sensitive method for field detection in resource-limited settings is critical. RESULTS: A sensitive and rapid detection system was developed to detect P. marginatus using recombinase polymerase amplification (RPA) combined with clustered regularly interspaced short palindromic repeats (CRISPR)/Cas12a. The RPA-CRISPR/Cas12a assay distinguished P. marginatus from 10 other mealybugs. The entire process can be completed in approximately an hour, and the identification results can be determined by the naked eye using lateral flow strips or a portable mini-UV torch. A method was developed to extract DNA from P. marginatus within 5 min. This method was combined with the RPA-CRISPR/Cas12a assay to achieve rapid and simple detection. In addition, two portable thermos cups with temperature displays were used to maintain the reagents and assay reactions in the field. CONCLUSION: This assay represents the first application of portable and easily available items (mini-UV torch and thermos cup) based on the combination of RPA and CRISPR/Cas12a for rapid pest detection. This method is rapid, highly specific, and instrument-flexible, allowing for the early monitoring of P. marginatus in the field. This study provides guidance for the development of suitable management strategies. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Performance of Organic Electrochemical Transistors with Ionic Liquid Crystal Elastomers as Solid Electrolytes.

Organic electrochemical transistors (OECTs) have emerged as attractive devices for bioelectronics, wearable electronics, soft robotics, and energy storage devices. The electrolyte, being a fundamental component of OECTs, plays a crucial role in their performance. Recently, it has been demonstrated that ionic liquid crystal elastomers (iLCEs) can be used as a solid electrolyte for OECTs. Their capabilities, however, have only been shown for relatively large size substrate-free OECTs. Here, we study the influence of the different alignments of iLCEs on steady state and transient behavior of OECTs using a lateral geometry with source, drain, and gate in the same plane. We achieve excellent electrical response with an ON/OFF switching ratio of >105 and minimal leakage current. The normalized maximum transconductance gm/w of the most sensitive iLCE was found to be 33 S m-1, which is one of the highest among all solid-state-based OECTs reported so far. Additionally, iLCEs show high stability and can be removed and reattached multiple times to the same OECT device without decreasing performance.

Environmental and molecular control of tissue-specific ionocyte differentiation in zebrafish.

Organisms cope with environmental fluctuations and maintain fitness in part via reversible phenotypic changes (acclimation). Aquatic animals are subject to dramatic seasonal fluctuations in water salinity, which affect osmolarity of their cells and consequently cellular function. Mechanosensory lateral line hair cells detect water motion for swimming behavior and are especially susceptible to salinity changes due to their direct contact with the environment. To maintain hair cell function when salinity decreases, neuromast (Nm)-associated ionocytes differentiate and invade lateral line neuromasts. The signals that trigger the adaptive differentiation of Nm ionocytes are unknown. We demonstrate that new Nm ionocytes are rapidly specified and selectively triggered to proliferate by low Ca2+ and Na+/Cl- levels. We further show that Nm ionocyte recruitment and induction is affected by hair cell activity. Once specified, Nm ionocyte differentiation and survival are associated with sequential activation of different Notch pathway components, a process different from other tissue-specific ionocytes. In summary, we show how environmental changes activate a signaling cascade that leads to physiological adaptation. This may prove essential for survival not only in seasonal changing environments but also changing climates.

Lateral meniscus posterior root repairs show superior healing, reduced meniscal extrusion and improved clinical outcomes compared to medial meniscus posterior root repairs: A systematic review.

PURPOSE: To systematically review and summarize the available literature on (1) postoperative healing rates, meniscal extrusion (ME) and clinical outcomes following lateral (LMPRR) versus medial (MMPRR) root repair and (2) potential correlations between residual ME and healing outcomes. METHODS: A comprehensive literature search was conducted using the Scopus, PubMed and Embase databases. Clinical studies evaluating healing status on second-look arthroscopy and magnetic resonance imaging (MRI) after LMPRR and MMPRR were included. Study quality was assessed using the Methodological Index for Non-Randomized Studies criteria and the modified Coleman Methodology Score. RESULTS: Twenty-three studies comprising 871 patients with LMPRR (n = 406) and MMPRR (n = 465) were included. Overall, 223 (54.9% of total) and 149 (32.04% of total) patients underwent second-look arthroscopy in the LMPRR and MMPRR groups, respectively. Complete root healing was observed in 190 (85.2%) patients in the LMPRR group versus 78 (52.3%) in the MMPRR group (p < 0.001). There were six (2.7%) failed repairs in the LMPRR group compared to 21 (14.09%) in the MMPRR group (p < 0.001). On postoperative MRI, 109 (75.7%) root repairs were healed in the LMPRR group compared to 192 (53.3%) in the MMPRR group (p < 0.001). Failure rates were lower after all-inside and transtibial pullout repairs in the LMPRR group but higher in the MMPRR group, with no significant mean difference between preoperative and postoperative ME in the MMPRR group (p = 0.95). Significantly better clinical outcomes were observed in the LMPRR group compared to the MMPRR group. A greater degree of postoperative ME was associated with lower healing rates (R = -0.78, p < 0.0005). Postoperative ME did not influence clinical outcomes (R = 0.28, p = 0.29). CONCLUSIONS: Lateral meniscus posterior root repairs showed higher healing rates compared to MMPRR on both second-look arthroscopy and postoperative MRI. Meniscal extrusion decreased after LMPRR but not after MMPRR. Greater residual ME correlated inversely with healing rates, as more extrusion was associated with lower healing. Postoperative clinical improvement did not affect ME or healing status. STUDY DESIGN: Systematic review of level III and IV studies. LEVEL OF EVIDENCE: Level IV.

Elevated serum circulating cell-free mitochondrial DNA in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: The substantial role of inflammation in amyotrophic lateral sclerosis (ALS) is gaining support from recent research. Studies indicate that circulating cell-free mitochondrial DNA (ccf-mtDNA) can activate the immune system and is associated with neurodegenerative diseases. This research was designed to quantify ccf-mtDNA levels in the serum of ALS patients. METHODS: The medical records of ALS patients were reviewed. Serum ccf-mtDNA levels of patients with ALS (n = 62) and age-matched healthy controls (n = 46) were measured and compared. Additionally, serum interleukin-6 (IL-6) levels were measured using an enzyme-linked immunosorbent assay in 26 ALS patients. Correlations between variables were analyzed. RESULTS: Serum ccf-mtDNA was notably higher in the patients with ALS. When stratified by genotype, the superoxide dismutase 1 (SOD1) mutation group showed the greatest increase in ccf-mtDNA levels relative to other ALS patients. Among all 108 individuals, a cut-off set at 1.1 × 105 mtDNA copies on a receiver-operating characteristic curve identified patients with ALS with 80.7% sensitivity and 50.0% specificity; the area under the curve was 0.69 (p < 0.001). Furthermore, serum ccf-mtDNA levels correlated negatively with the progression rate of ALS (ΔFS; rs = -0.26, p = 0.044), but not the ALSFRS-R score (rs = 0.06, p = 0.625). Importantly, the correlation between ccf-mtDNA and ΔFS was more pronounced in the SOD1 mutation group (rs = -0.62, p = 0.018). Lastly, a significant positive association was observed between serum ccf-mtDNA levels and IL-6 levels in ALS (r s= 0.41, p = 0.038). CONCLUSION: Our study found increased serum ccf-mtDNA in ALS patients, suggesting a link to inflammatory processes and disease mechanism. Moreover, ccf-mtDNA could be an indicator for ALS progression, especially in those with the SOD1 mutation.

Current and emerging technologies to develop Point-of-Care Diagnostics in medical mycology.

INTRODUCTION: Advances in diagnostic technologies, particularly Point-of-Care Diagnostics (POCDs), have revolutionized clinical practice by providing rapid, user-friendly, and affordable testing at or near the patient's location. POCDs have been increasingly introduced in medical mycology and hold promise to improve patient outcomes in a variety of important human fungal diseases. AREAS COVERED: This review focuses on validated POCDs, particularly lateral flow assays (LFAs), for various fungal diseases. Additionally, we discuss emerging innovative techniques such as body fluid analysis, imaging methods, loop-mediated isothermal amplification (LAMP), microfluidic systems, clustered regularly interspaced short palindromic repeats (CRISPR)-based diagnostics, and the emerging role of artificial intelligence. EXPERT OPINION: Compact and user-friendly POCDs have been increasingly introduced in medical mycology, and some of these tests (e.g. Cryptococcus and Histoplasma antigen LFAs) have become mainstream diagnostics, while others, such as LFA in invasive aspergillosis show promise to become part of our routine diagnostic armamentarium. POCDs offer immense benefits such as timely and accurate diagnostic results, reduced patient discomfort, and lower healthcare costs and might contribute to antifungal stewardship. Integrated fluidics combined with microtechnology having multiplex capabilities will be pivotal in medical mycology.

An amygdalar oscillator coordinates cellular and behavioral rhythms.

Circadian rhythms are generated by the master pacemaker suprachiasmatic nucleus (SCN) in concert with local clocks throughout the body. Although many brain regions exhibit cycling clock gene expression, the identity of a discrete extra-SCN brain oscillator that produces rhythmic behavior has remained elusive. Here, we show that an extra-SCN oscillator in the lateral amygdala (LA) is defined by expression of the clock-output molecule mWAKE/ANKFN1. mWAKE is enriched in the anterior/dorsal LA (adLA), and, strikingly, selective disruption of clock function or excitatory signaling in adLAmWAKE neurons abolishes Period2 (PER2) rhythms throughout the LA. mWAKE levels rise at night and promote rhythmic excitability of adLAmWAKE neurons by upregulating Ca2+-activated K+ channel activity specifically at night. adLAmWAKE neurons coordinate rhythmic sensory perception and anxiety in a clock-dependent and WAKE-dependent manner. Together, these data reveal the cellular identity of an extra-SCN brain oscillator and suggest a multi-level hierarchical system organizing molecular and behavioral rhythms.

The causal association between epilepsy and amyotrophic lateral sclerosis: A two-sample Mendelian randomization study.

OBJECTIVES: Epilepsy and amyotrophic lateral sclerosis (ALS) are common neurological disorders. The association between the two disorders has been raised in observational studies. However, it is uncertain to what extent they have mutual causal effects. In this study, we aimed to investigate their causal association using a two-sample Mendelian randomization (MR) method. METHODS: We performed a two-sample bidirectional MR analysis to evaluate the causal association of epilepsy with the risk of ALS. Publicly published genome-wide association study statistics for epilepsy and ALS were used in the study. The primary analysis included genetic variants with a p value of less than 1 × 10-5 as instrumental variables. We applied several alternative methods, including inverse variance weighting, weighted median, simple mode, weighted mode, MR-Egger regression and MR pleiotropy residual sum and outlier, and statistical graphs to assess the associations of epilepsy and its subtype with the risk of ALS. Reverse MR analyses were also performed to examine the association of ALS with the risk of epilepsy. RESULTS: The primary MR analysis found no causal effect of epilepsy on risk of ALS (odds ration [OR]: 1.133, 95% confidence interval [CI]: 0.964-1.332, p = .130). Among subtypes of epilepsy, it also failed to observe any causal association between general epilepsy and ALS (OR: 1.036, 95% CI: 0.969-1.108, P = .300). However, focal epilepsy contributed to an increase in the risk of ALS (OR: 1.177, 95% CI: 1.027-1.348, p = .019). Moreover, the investigation of reverse causalities did not reveal significant results. CONCLUSIONS: The current study supports a causal influence of focal epilepsy on ALS risk. Future studies are needed to explore its potential role in ALS.