Theory and evidence-base for a digital platform for the delivery of language tests during awake craniotomy and collaborative brain mapping.

Objectives: Build the theoretical and evidence-base for a digital platform (map-OR) which delivers intraoperative language tests during awake craniotomy and facilitates collaborative sharing of brain mapping data. Design: Mixed methodology study including two scoping reviews, international survey, synthesis of development guiding principles and a risk assessment using failure modes and effects analysis. Setting: The two scoping reviews examined the literature published in the English language. International survey was completed by members of awake craniotomy teams from 14 countries. Main outcome measures: Scoping review 1: number of technologies described for language mapping during awake craniotomy. Scoping review 2: barriers and facilitators to adopting novel technology in surgery. International survey: degree of language mapping technology penetration into clinical practice. Results: A total of 12 research articles describing 6 technologies were included. The technologies required a range of hardware components including portable devices, virtual reality headsets and large integrated multiscreen stacks. The facilitators and barriers of technology adoption in surgery were extracted from 11 studies and mapped onto the 4 Unified Theory of Acceptance and Use of Technology constructs. A total of 37 awake craniotomy teams from 14 countries completed the survey. Of the responses, 20 (54.1%) delivered their language tests digitally, 10 (27.0%) delivered tests using cards and 7 (18.9%) used a combination of both. The most commonly used devices were tablet computers (67.7%; n=21) and the most common software used was Microsoft PowerPoint (60.6%; n=20). Four key risks for the proposed digital platform were identified, the highest risk being a software and internet connectivity failure during surgery. Conclusions: This work represents a rigorous and structured approach to the development of a digital platform for standardized intraoperative language testing during awake craniotomy and for collaborative sharing of brain mapping data. Trial registration number: Scoping review protocol registrations in OSF registries (scoping review 1: osf.io/su9xm; scoping review 2: osf.io/x4wsc).

Dysfunction of synaptic endocytic trafficking in Parkinson's disease.

Parkinson's disease is characterized by the selective degeneration of dopamine neurons in the nigrostriatal pathway and dopamine deficiency in the striatum. The precise reasons behind the specific degeneration of these dopamine neurons remain largely elusive. Genetic investigations have identified over 20 causative PARK genes and 90 genomic risk loci associated with both familial and sporadic Parkinson's disease. Notably, several of these genes are linked to the synaptic vesicle recycling process, particularly the clathrin-mediated endocytosis pathway. This suggests that impaired synaptic vesicle recycling might represent an early feature of Parkinson's disease, followed by axonal degeneration and the eventual loss of dopamine cell bodies in the midbrain via a "dying back" mechanism. Recently, several new animal and cellular models with Parkinson's disease-linked mutations affecting the endocytic pathway have been created and extensively characterized. These models faithfully recapitulate certain Parkinson's disease-like features at the animal, circuit, and cellular levels, and exhibit defects in synaptic membrane trafficking, further supporting the findings from human genetics and clinical studies. In this review, we will first summarize the cellular and molecular findings from the models of two Parkinson's disease-linked clathrin uncoating proteins: auxilin (DNAJC6/PARK19) and synaptojanin 1 (SYNJ1/PARK20). The mouse models carrying these two PARK gene mutations phenocopy each other with specific dopamine terminal pathology and display a potent synergistic effect. Subsequently, we will delve into the involvement of several clathrin-mediated endocytosis-related proteins (GAK, endophilin A1, SAC2/INPP5F, synaptotagmin-11), identified as Parkinson's disease risk factors through genome-wide association studies, in Parkinson's disease pathogenesis. We will also explore the direct or indirect roles of some common Parkinson's disease-linked proteins (alpha-synuclein (PARK1/4), Parkin (PARK2), and LRRK2 (PARK8)) in synaptic endocytic trafficking. Additionally, we will discuss the emerging novel functions of these endocytic proteins in downstream membrane traffic pathways, particularly autophagy. Given that synaptic dysfunction is considered as an early event in Parkinson's disease, a deeper understanding of the cellular mechanisms underlying synaptic vesicle endocytic trafficking may unveil novel targets for early diagnosis and the development of interventional therapies for Parkinson's disease. Future research should aim to elucidate why generalized synaptic endocytic dysfunction leads to the selective degeneration of nigrostriatal dopamine neurons in Parkinson's disease.

Mutations in Parkinsonism-linked endocytic proteins synaptojanin1 and auxilin have synergistic effects on dopaminergic axonal pathology.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by defective dopaminergic (DAergic) input to the striatum. Mutations in two genes encoding synaptically enriched clathrin-uncoating factors, synaptojanin 1 (SJ1) and auxilin, have been implicated in atypical Parkinsonism. SJ1 knock-in (SJ1-KIRQ) mice carrying a disease-linked mutation display neurological manifestations reminiscent of Parkinsonism. Here we report that auxilin knockout (Aux-KO) mice display dystrophic changes of a subset of nigrostriatal DAergic terminals similar to those of SJ1-KIRQ mice. Furthermore, Aux-KO/SJ1-KIRQ double mutant mice have shorter lifespan and more severe synaptic defects than single mutant mice. These include increase in dystrophic striatal nerve terminals positive for DAergic markers and for the PD risk protein SV2C, as well as adaptive changes in striatal interneurons. The synergistic effect of the two mutations demonstrates a special lability of DAergic neurons to defects in clathrin uncoating, with implications for PD pathogenesis in at least some forms of this condition.

A Digital Health Intervention for Concussion: Development and Clinical Feasibility Study.

BACKGROUND: Concussion is a common condition that can lead to a constellation of symptoms that affect quality of life, social integration, and return to work. There are several evidence-based behavioral and psychological interventions that have been found to improve postconcussion symptom burden. However, these are not routinely delivered, and individuals receive limited support during their concussion recovery. OBJECTIVE: This study aimed to develop and test the feasibility of a digital health intervention using a systematic evidence-, theory-, and person-based approach. METHODS: This was a mixed methodology study involving a scoping review (n=21), behavioral analysis, and logic model to inform the intervention design and content. During development, the intervention was optimized with feedback from individuals who had experienced concussions (n=12) and health care professionals (n=11). The intervention was then offered to patients presenting to the emergency department with a concussion (n=50). Participants used the intervention freely and input symptom data as part of the program. A number of outcome measures were obtained, including participant engagement with the intervention, postconcussion symptom burden, and attitudes toward the intervention. A selection of participants (n=15) took part in in-depth qualitative interviews to understand their attitudes toward the intervention and how to improve it. RESULTS: Engagement with the intervention functionality was 90% (45/50) for the symptom diary, 62% (31/50) for sleep time setting, 56% (28/50) for the alcohol tracker, 48% (24/50) for exercise day setting, 34% (17/50) for the thought diary, and 32% (16/50) for the goal setter. Metrics indicated high levels of early engagement that trailed off throughout the course of the intervention, with an average daily completion rate of the symptom diary of 28.23% (494/1750). A quarter of the study participants (13/50, 26%) were classified as high engagers who interacted with all the functionalities within the intervention. Quantitative and qualitative feedback indicated a high level of usability and positive perception of the intervention. Daily symptom diaries (n=494) demonstrated a wide variation in individual participant symptom burden but a decline in average burden over time. For participants with Rivermead scores on completion of HeadOn, there was a strong positive correlation (r=0.86; P<.001) between their average daily HeadOn symptom diary score and their end-of-program Rivermead score. Insights from the interviews were then fed back into development to optimize the intervention and facilitate engagement. CONCLUSIONS: Using this systematic approach, we developed a digital health intervention for individuals who have experienced a concussion that is designed to facilitate positive behavior change. Symptom data input as part of the intervention provided insights into postconcussion symptom burden and recovery trajectories. TRIAL REGISTRATION: ClinicalTrials.gov NCT05069948; https://clinicaltrials.gov/ct2/show/NCT05069948.

Profiling of 3D Genome Organization in Nasopharyngeal Cancer Needle Biopsy Patient Samples by a Modified Hi-C Approach.

Nasopharyngeal cancer (NPC), a cancer derived from epithelial cells in the nasopharynx, is a cancer common in China, Southeast Asia, and Africa. The three-dimensional (3D) genome organization of nasopharyngeal cancer is poorly understood. A major challenge in understanding the 3D genome organization of cancer samples is the lack of a method for the characterization of chromatin interactions in solid cancer needle biopsy samples. Here, we developed Biop-C, a modified in situ Hi-C method using solid cancer needle biopsy samples. We applied Biop-C to characterize three nasopharyngeal cancer solid cancer needle biopsy patient samples. We identified topologically associated domains (TADs), chromatin interaction loops, and frequently interacting regions (FIREs) at key oncogenes in nasopharyngeal cancer from the Biop-C heatmaps. We observed that the genomic features are shared at some important oncogenes, but the patients also display extensive heterogeneity at certain genomic loci. On analyzing the super enhancer landscape in nasopharyngeal cancer cell lines, we found that the super enhancers are associated with FIREs and can be linked to distal genes via chromatin loops in NPC. Taken together, our results demonstrate the utility of our Biop-C method in investigating 3D genome organization in solid cancers.

Prediction of antimicrobial peptides based on sequence alignment and support vector machine-pairwise algorithm utilizing LZ-complexity.

This study concerns an attempt to establish a new method for predicting antimicrobial peptides (AMPs) which are important to the immune system. Recently, researchers are interested in designing alternative drugs based on AMPs because they have found that a large number of bacterial strains have become resistant to available antibiotics. However, researchers have encountered obstacles in the AMPs designing process as experiments to extract AMPs from protein sequences are costly and require a long set-up time. Therefore, a computational tool for AMPs prediction is needed to resolve this problem. In this study, an integrated algorithm is newly introduced to predict AMPs by integrating sequence alignment and support vector machine- (SVM-) LZ complexity pairwise algorithm. It was observed that, when all sequences in the training set are used, the sensitivity of the proposed algorithm is 95.28% in jackknife test and 87.59% in independent test, while the sensitivity obtained for jackknife test and independent test is 88.74% and 78.70%, respectively, when only the sequences that has less than 70% similarity are used. Applying the proposed algorithm may allow researchers to effectively predict AMPs from unknown protein peptide sequences with higher sensitivity.