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Concussions present with a myriad of symptomatic and cognitive concerns; however, the relationship between these functional disruptions and the underlying changes in the brain are not yet well understood. Hubs, or brain regions that are connected to many different functional networks, may be specifically disrupted after concussion. Given the implications in concussion research, we quantified hub disruption within the default mode network (DMN) and between the DMN and other brain networks. We collected resting-state functional magnetic resonance imaging data from collegiate student-athletes (n = 44) at three time points: baseline (before beginning their athletic season), acute post-injury (approximately 48h after a diagnosed concussion), and recovery (after starting return-to-play progression, but before returning to contact). We used self-reported symptoms and computerized cognitive assessments collected across similar time points to link these functional connectivity changes to clinical outcomes. Concussion resulted in increased connectivity between regions within the DMN compared with baseline and recovery, and this post-injury connectivity was more positively related to symptoms and more negatively related to visual memory performance compared with baseline and recovery. Further, concussion led to decreased connectivity between DMN hubs and visual network non-hubs relative to baseline and recovery, and this post-injury connectivity was more negatively related to somatic symptoms and more positively related to visual memory performance compared with baseline and recovery. Relationships between functional connectivity, symptoms, and cognition were not significantly different at baseline versus recovery. These results highlight a unique relationship between self-reported symptoms, visual memory performance, and acute functional connectivity changes involving DMN hubs after concussion in athletes. This may provide evidence for a disrupted balance of within- and between-network communication highlighting possible network inefficiencies after concussion. These results aid in our understanding of the pathophysiological disruptions after concussion and inform our understanding of the associations between disruptions in brain connectivity and specific clinical presentations acutely post-injury.

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Recent years have seen a surge in the use of diffusion MRI to map connectomes in humans, paralleled by a similar increase in processing and analysis choices. Yet these different steps and their effects are rarely compared systematically. Here, in a healthy young adult population (n = 294), we characterized the impact of a range of analysis pipelines on one widely studied property of the human connectome: its degree distribution. We evaluated the effects of 40 pipelines (comparing common choices of parcellation, streamline seeding, tractography algorithm, and streamline propagation constraint) and 44 group-representative connectome reconstruction schemes on highly connected hub regions. We found that hub location is highly variable between pipelines. The choice of parcellation has a major influence on hub architecture, and hub connectivity is highly correlated with regional surface area in most of the assessed pipelines (ρ > 0.70 in 69% of the pipelines), particularly when using weighted networks. Overall, our results demonstrate the need for prudent decision-making when processing diffusion MRI data, and for carefully considering how different processing choices can influence connectome organization.

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Oral Squamous Cell Carcinoma (OSCC) accounts for more than 90% of all kinds of oral neoplasms that develop in the oral cavity. It is a type of malignancy that shows high morbidity and recurrence rate, but data on the disease's target genes and biomarkers is still insufficient. In this study, in silico studies have been performed to find out the novel target genes and their potential therapeutic inhibitors for the effective and efficient treatment of OSCC. The DESeq2 package of RStudio was used in the current investigation to screen and identify differentially expressed genes for OSCC. As a result of gene expression analysis, the top 10 novel genes were identified using the Cytohubba plugin of Cytoscape, and among them, the ubiquitin-conjugating enzyme (UBE2D1) was found to be upregulated and playing a significant role in the progression of human oral cancers. Following this, naturally occurring compounds were virtually evaluated and simulated against the discovered novel target as prospective drugs utilizing the Maestro, Schrodinger, and Gromacs software. In a simulated screening of naturally occurring potential inhibitors against the novel target UBE2D1, Epigallocatechin 3-gallate, Quercetin, Luteoline, Curcumin, and Baicalein were identified as potent inhibitors. Novel identified gene UBE2D1 has a significant role in the proliferation of human cancers through suppression of 'guardian of genome' p53 via ubiquitination dependent pathway. Therefore, the treatment of OSCC may benefit significantly from targeting this gene and its discovered naturally occurring inhibitors.Communicated by Ramaswamy H. Sarma.

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PUF RNA-binding proteins are conserved stem cell regulators. Four PUF proteins govern self-renewal of Caenorhabditis elegans germline stem cells together with two intrinsically disordered proteins, LST-1 and SYGL-1. Based on yeast two-hybrid results, we previously proposed a composite self-renewal hub in the stem cell regulatory network, with eight PUF partnerships and extensive redundancy. Here, we investigate LST-1-PUF and SYGL-1-PUF partnerships and their molecular activities in their natural context - nematode stem cells. We confirm LST-1-PUF partnerships and their specificity to self-renewal PUFs by co-immunoprecipitation and show that an LST-1(AmBm) mutant defective for PUF-interacting motifs does not complex with PUFs in nematodes. LST-1(AmBm) is used to explore the in vivo functional significance of the LST-1-PUF partnership. Tethered LST-1 requires this partnership to repress expression of a reporter RNA, and LST-1 requires the partnership to co-immunoprecipitate with NTL-1/Not1 of the CCR4-NOT complex. We suggest that the partnership provides multiple molecular interactions that work together to form an effector complex on PUF target RNAs in vivo. Comparison of LST-1-PUF and Nanos-Pumilio reveals fundamental molecular differences, making LST-1-PUF a distinct paradigm for PUF partnerships.

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To understand the mechanisms underlying preserved and impaired cognitive function in healthy aging and dementia, respectively, the spatial relationships of brain networks and mechanisms of their resilience should be understood. The hub regions of the brain, such as the multisensory integration and default mode networks, are critical for within- and between-network communication, remain well-preserved during aging, and play an essential role in compensatory processes. On the other hand, these brain hubs are the preferred sites for lesions in neurodegenerative dementias, such as Alzheimer's disease. Disrupted primary information processing networks, such as the auditory, visual, and sensorimotor networks, may lead to overactivity of the multisensory integration networks and accumulation of pathological proteins that cause dementia. At the cellular level, the brain hub regions contain many synapses and require a large amount of energy. These regions are rich in ATP-related gene expression and had high glucose metabolism as demonstrated on positron emission tomography (PET). Importantly, the number and function of mitochondria, which are the center of ATP production, decline by about 8% every 10 years. Dementia patients often have dysfunction of the ubiquitin-proteasome and autophagy-lysosome systems, which require large amounts of ATP. If there is low energy supply but the demand is high, the risk of disease can be high. Imbalance between energy supply and demand may cause accumulation of pathological proteins and play an important role in the development of dementia. This energy imbalance may explain why brain hub regions are vulnerable to damage in different dementias. Here, we review (1) the characteristics of gray matter network, white matter network, and resting state functional network changes related to resilience in healthy aging, (2) the mode of resting state functional network disruption in neurodegenerative dementia, and (3) the cellular mechanisms associated with the disruption.

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The complexity of the widespread language network makes it challenging for accurate localization and lateralization. Using large-scale connectivity and graph-theoretical analyses of task-based magnetoencephalography (MEG), we aimed to provide robust representations of receptive and expressive language processes, comparable with spatial profiles of corresponding functional magnetic resonance imaging (fMRI). We examined MEG and fMRI data from 12 healthy young adults (age 20-37 years) completing covert auditory word-recognition task (WRT) and covert auditory verb-generation task (VGT). For MEG language mapping, broadband (3-30 Hz) beamformer sources were estimated, voxel-level connectivity was quantified using phase locking value, and highly connected hubs were characterized using eigenvector centrality graph measure. fMRI data were analyzed using a classic general linear model approach. A laterality index (LI) was computed for 20 language-specific frontotemporal regions for both MEG and fMRI. MEG network analysis showed bilateral and symmetrically distributed hubs within the left and right superior temporal gyrus (STG) during WRT and predominant hubs in left inferior prefrontal gyrus (IFG) during VGT. MEG and fMRI localization maps showed high correlation values within frontotemporal regions during WRT and VGT (r = 0.63, 0.74, q < 0.05, respectively). Despite good concordance in localization, notable discordances were observed in lateralization between MEG and fMRI. During WRT, MEG favored a left-hemispheric dominance of left STG (LI = 0.25 ±â€¯0.22) whereas fMRI supported a bilateral representation of STG (LI = 0.08 ±â€¯0.2). Laterality of MEG and fMRI during VGT consistently showed a strong asymmetry in left IFG regions (MEG-LI = 0.45 ±â€¯0.35 and fMRI-LI = 0.46 ±â€¯0.13). Our results demonstrate the utility of a large-scale connectivity and graph theoretical analyses for robust identification of language-specific regions. MEG hubs are in great agreement with the literature in revealing with canonical and extra-canonical language sites, thus providing additional support for the underlying topological organization of receptive and expressive language cortices. Discordances in lateralization may emphasize the need for multimodal integration of MEG and fMRI to obtain an excellent predictive value in a heterogeneous healthy population and patients with neurosurgical conditions.

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Inherited and somatic rare diseases result from >200,000 genetic variants leading to loss- or gain-of-toxic function, often caused by protein misfolding. Many of these misfolded variants fail to properly interact with other proteins. Understanding the link between factors mediating the transcription, translation, and protein folding of these disease-associated variants remains a major challenge in cell biology. Herein, we utilized the cystic fibrosis transmembrane conductance regulator (CFTR) protein as a model and performed a proteomics-based high-throughput screen (HTS) to identify pathways and components affecting the folding and function of the most common cystic fibrosis-associated mutation, the F508del variant of CFTR. Using a shortest-path algorithm we developed, we mapped HTS hits to the CFTR interactome to provide functional context to the targets and identified the eukaryotic translation initiation factor 3a (eIF3a) as a central hub for the biogenesis of CFTR. Of note, siRNA-mediated silencing of eIF3a reduced the polysome-to-monosome ratio in F508del-expressing cells, which, in turn, decreased the translation of CFTR variants, leading to increased CFTR stability, trafficking, and function at the cell surface. This finding suggested that eIF3a is involved in mediating the impact of genetic variations in CFTR on the folding of this protein. We posit that the number of ribosomes on a CFTR mRNA transcript is inversely correlated with the stability of the translated polypeptide. Polysome-based translation challenges the capacity of the proteostasis environment to balance message fidelity with protein folding, leading to disease. We suggest that this deficit can be corrected through control of translation initiation.

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OBJECTIVE: Previous studies have associated network hubs and epileptiform activity, such as spikes and high frequency oscillations (HFOs), with the epileptogenic zone. The epileptogenic zone is approximated by the area that generates interictal epileptiform activity: the irritative zone. Our aim was to determine the relation between network hubs and the irritative zone. METHODS: Interictal resting-state MEG recordings of 12 patients with refractory epilepsy were analysed. Beamformer-based virtual electrodes were calculated at 70 locations around the epileptic spikes (irritative zone) and in the contralateral hemisphere. Spikes and HFOs were marked in all virtual electrodes. A minimum spanning tree network was generated based on functional connectivity (phase lag index; PLI) between all virtual electrodes to calculate the betweenness centrality, an indicator of hub status of network nodes. RESULTS: Betweenness centrality was low, and PLI was high, in virtual electrodes close to the centre of the irritative zone, and in virtual electrodes with many spikes and HFOs. CONCLUSION: Node centrality increases with distance from brain areas with spikes and HFOs, consistent with the idea that the irritative zone is a functionally isolated part of the epileptic network during the interictal state. SIGNIFICANCE: A new hypothesis about a pathological hub located remotely from the irritative zone and seizure onset zone opens new ways for surgery when epileptogenic areas and eloquent cortex coincide.

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INTRODUCTION: The burden of poisoning exposures in Africa is a significant public health concern, yet only ten African countries have poisons information centres. The establishment of poisons centres was subsequently identified as a priority. This article focuses on workshop discussions with international multi-sector stakeholders in Eastern Africa regarding the possibility of a sub-regional poisons centre serving multiple countries. METHODS: The project was led by an independent consultant under the guidance of an international steering group. Steering group members provided input at international multi-stakeholder meetings and during monthly teleconferences. RESULTS: Participants of the stakeholder meetings agreed that the establishment of a sub-regional poisons centre in Eastern Africa was necessary and feasible. Virtual collaboration is possible due to recent technological developments, and the overall suggestion was for countries to establish their own poisons centres and to network and coordinate these centres through a network hub. CONCLUSION: A number of benefits might result from such a poisons centre network hub, including: (1) Improved cooperation between countries on poisoning problems; (2) Harmonisation and strengthening of research and surveillance; (3) Common standards and best practices e.g. regulating chemicals, data management, and staff training; and (4) Greater bargaining power to secure resources. Further investigation is needed to identify the most suitable location for the network hub, the activities it should fulfil, and the availability of specialists in poisons information who could become members of the hub.

INTRODUCTION: La charge que représentent les expositions à l'empoisonnement en Afrique est une préoccupation de santé publique importante, et pourtant, seuls une dizaine de pays africains sont dotés de centres d'information antipoison. La création de centres antipoison a donc été identifiée comme une priorité. Cet article se concentre sur les discussions de l'atelier organisé avec les parties prenantes multisectorielles internationales en Afrique de l'Est concernant la possibilité de la création d'un centre antipoison sous-régional desservant plusieurs pays. MÉTHODES: Le projet a été mené par un consultant indépendant, sous la direction d'un groupe de pilotage international. Les membres du groupe de pilotage ont apporté leur contribution lors de réunions internationales multipartites et de téléconférences mensuelles. RÉSULTATS: Les participants des réunions des parties prenantes ont convenu que la mise en place d'un centre antipoison sous-régional en Afrique de l'Est était nécessaire et faisable. La collaboration virtuelle est possible grâce aux récents développements technologiques, et la suggestion générale était que les pays établissent leurs propres centres antipoison et mettent en réseau et coordonnent ces centres par le biais d'une tête de réseau. CONCLUSION: Une telle tête de réseau de centres antipoison pourrait présenter un certain nombre d'avantages, notamment: (1) Une amélioration de la coopération entre les pays sur les problèmes d'empoisonnement; (2) Une harmonisation et un renforcement de la recherche et de la surveillance; (3) Des normes communes et des meilleures pratiques, par exemple la réglementation des produits chimiques, la gestion des données et la formation du personnel; (4) Une meilleure position de négociation pour obtenir des ressources. Une enquête plus approfondie est nécessaire pour identifier l'emplacement le plus approprié pour la tête de réseau, les activités qu'elle devra remplir et la disponibilité de spécialistes en information antipoison qui pourraient participer à cette tête de réseau.

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Long non-coding RNAs (lncRNAs) play key roles in diverse biological processes. Moreover, the development and progression of cancer often involves the combined actions of several lncRNAs. Here we propose a multi-step method for constructing lncRNA-lncRNA functional synergistic networks (LFSNs) through co-regulation of functional modules having three features: common coexpressed genes of lncRNA pairs, enrichment in the same functional category and close proximity within protein interaction networks. Applied to three cancers, we constructed cancer-specific LFSNs and found that they exhibit a scale free and modular architecture. In addition, cancer-associated lncRNAs tend to be hubs and are enriched within modules. Although there is little synergistic pairing of lncRNAs across cancers, lncRNA pairs involved in the same cancer hallmarks by regulating same or different biological processes. Finally, we identify prognostic biomarkers within cancer lncRNA expression datasets using modules derived from LFSNs. In summary, this proof-of-principle study indicates synergistic lncRNA pairs can be identified through integrative analysis of genome-wide expression data sets and functional information.

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