bluuebunny/crossref_metadata_2025_split huggingface dataset:
Short-Duration, Pulsatile, Electrical Stimulation Therapy Accelerates Axon Regeneration and Recovery following Tibial Nerve Injury and Repair in Rats
Authors: Roh Joseph , Schellhardt Lauren , Keane Grace C. , Hunter Daniel A. , Moore Amy M. , Snyder-Warwick Alison K. , Mackinnon Susan E. , Wood Matthew D. 
Published: February 2022

Background:
Repair of nerve injuries can fail to achieve adequate functional recovery. Electrical stimulation applied at the time of nerve repair can accelerate axon regeneration, which may improve the likelihood of recovery. However, widespread use of electrical stimulation may be limited by treatment protocols that increase operative time and complexity. This study evaluated whether a short-duration electrical stimulation protocol (10 minutes) was efficacious to enhance regeneration following nerve repair using rat models.

Methods:
Lewis and Thy1–green fluorescent protein rats were randomized to three groups: 0 minutes of electrical stimulation (no electrical stimulation; control), 10 minutes of electrical stimulation, and 60 minutes of electrical stimulation. All groups underwent tibial nerve transection and repair. In the intervention groups, electrical stimulation was delivered after nerve repair. Outcomes were assessed using immunohistochemistry, histology, and serial walking track analysis.

Results:
Two weeks after nerve repair, Thy1–green fluorescent protein rats demonstrated increased green fluorescent protein–positive axon outgrowth from the repair site with electrical stimulation compared to no electrical stimulation. Serial measurement of walking tracks after nerve repair revealed recovery was achieved more rapidly in both electrical stimulation groups as compared to no electrical stimulation. Histologic analysis of nerve distal to the repair at 8 weeks revealed robust axon regeneration in all groups.

Conclusions:
As little as 10 minutes of intraoperative electrical stimulation therapy increased early axon regeneration and facilitated functional recovery following nerve transection with repair. Also, as early axon outgrowth increased following electrical stimulation with nerve repair, these findings suggest electrical stimulation facilitated recovery because of earlier axon growth across the suture-repaired site into the distal nerve to reach end-organ targets.

Clinical Relevance Statement:
Brief (10-minute) electrical stimulation therapy can provide similar benefits to the 60-minute protocol in an acute sciatic nerve transection/repair rat model and merit further studies, as they represent a translational advantage.
The Anatomy behind Eyebrow Positioning: A Clinical Guide Based on Current Anatomic Concepts
Authors: Cotofana Sebastian , Solish Nowell , Gallagher Conor , Beleznay Katie , Hernandez Claudia A. , Bertucci Vince 
Published: February 2022

Background:
The position of the eyebrow is known to reflect emotional status and to provide a plethora of nonverbal information. Although the eyebrow has no direct attachment to underlying bone, it is subject to the interplay between the various periorbital muscles, which when acting together, permit important nonverbal cues to be conveyed. Understanding the balance and interplay between these muscles is of crucial importance when targeting the periorbital area with neuromodulators. The authors’ aims were to summarize current anatomic and clinical knowledge so as to provide a foundation that physicians can rely on to improve and increase the predictability of patient outcomes when treating the periorbital region with neuromodulators for aesthetic purposes.

Methods:
This narrative review is based on the anatomic and clinical experience of the authors dissecting and treating the periorbital region with specific focus on the glabella and the forehead.

Results:
This narrative review covers (1) a brief description of the relevant periorbital muscle anatomy, (2) an analysis of each muscle’s contribution to various facial expressions, and (3) an anatomic and physiologic simulation of the muscular effects of specific neuromodulator injection sites.

Conclusion:
By understanding functional anatomy of the periorbital muscles and combining this knowledge with individualized assessment and treatment planning, it is possible to achieve aesthetically pleasing, predictable, and reproducible treatment outcomes that positively impact perception of nonverbal cues when administering neuromodulators.
Differences in time-critical interventions and radiological examinations between adult and older trauma patients: A national register-based study
Authors: Cuevas-Østrem Mathias , Wisborg Torben , Røise Olav , Jeppesen Elisabeth 
Published: February 2022

BACKGROUND
Older trauma patients are reported to receive lower levels of care than younger adults. Differences in clinical management between adult and older trauma patients hold important information about potential trauma system improvement targets. The aim of this study was to compare prehospital and early in-hospital management of adult and older trauma patients, focusing on time-critical interventions and radiological examinations.

METHODS
Retrospective analysis of the Norwegian Trauma Registry for 2015 through 2018. Trauma patients 16 years or older met by a trauma team and with New Injury Severity Score of 9 or greater were included, dichotomized into age groups 16 years to 64 years and 65 years or older. Prehospital and emergency department clinical management, advanced airway management, chest decompression, and admission radiological examinations was compared between groups applying descriptive statistics and appropriate statistical tests.

RESULTS
There were 9543 patients included, of which 28% (n = 2711) were 65 years or older. Older patients, irrespective of injury severity, were less likely attended by a prehospital doctor/paramedic team (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.57–0.71), conveyed by air ambulance (OR, 0.65; 95% CI, 0.58–0.73), and transported directly to a trauma center (OR, 0.86; 95% CI, 0.79–0.94). Time-critical intervention and primary survey radiological examination rates only differed between age groups among patients with New Injury Severity Score of 25 or greater, showing lower rates for older adults (advanced airway management: OR, 0.60; 95% CI, 0.47–0.76; chest decompression: OR, 0.46; 95% CI, 0.25–0.85; x-ray chest: OR, 0.54; 95% CI, 0.39–0.75; x-ray pelvis: OR, 0.69; 95% CI, 0.57–0.84). However, for the patients attended by a doctor/paramedic team, there were no management differences between age groups.

CONCLUSION
Older trauma patients were less likely to receive advanced prehospital care compared with younger adults. Older patients with very severe injuries received fewer time-critical interventions and radiological examinations. Improved dispatch of doctor/paramedic teams to older adults and assessment of the impact the observed differences have on outcome are future research priorities.

LEVEL OF EVIDENCE
Therapeutic/Care Management; Level III.
Demography and linked selection interact to shape the genomic landscape of codistributed woodpeckers during the Ice Age
Authors: Moreira Lucas R. , Klicka John , Smith Brian Tilston 
Published: February 2022

AbstractThe glacial cycles of the Pleistocene had a global impact on the evolution of species. Although the influence of genetic drift on population genetic dynamics is well understood, the role of selection in shaping patterns of genomic variation during these dramatic climatic changes is less clear. We used whole genome resequencing data to investigate the interplay between demography and natural selection and their influence on the genomic landscape of Downy and Hairy Woodpecker, species co-distributed in previously glaciated North America. Our results revealed a dynamic population history with repeated cycles of bottleneck and expansion, and genetic structure associated with glacial refugia. Levels of nucleotide diversity varied substantially along the genomes of Downy and Hairy Woodpecker, but this variation was highly correlated between the two species, suggesting the presence of conserved genomic features. Nucleotide diversity in both species was positively correlated with recombination rate and negatively correlated with gene density, suggesting that linked selection played a role in reducing diversity in regions of low recombination and high density of targets of selection. Despite strong temporal fluctuations in Ne, our demographic analyses indicate that Downy and Hairy Woodpecker were able to maintain relatively large effective population sizes during glaciations, which might have favored natural selection. The magnitude of the effect of linked selection seems to have been modulated by the individual demographic trajectory of populations and species, such that purifying selection has been more efficient in removing deleterious alleles in Hairy Woodpecker owing to its larger long-term Ne. These results highlight that while drift captures the expected signature of contracting and expanding populations during climatic perturbations, the interaction of multiple processes produces a predictable and highly heterogeneous genomic landscape.
Nonlinearities and Timescales in Temporal Interference Stimulation
Authors: Plovie Tom , Schoeters Ruben , Tarnaud Thomas , Martens Luc , Joseph Wout , Tanghe Emmeric 
Published: February 2022

ABSTRACTIn temporal interference (TI) stimulation, neuronal cells react to two interfering sinusoidal electric fields with a slightly different frequency. It was previously seen that for the same input intensity, the neurons do not react to a purely sinusoidal signal. This study aims to get a better understanding of the mechanism underlying TI neuromodulation, which is largely unknown. To this end, single-compartment models are used to simulate computationally the response of neurons to the sinusoidal and TI waveform. This study compares different neuron models to get insight into which models are able to reproduce the experimental observations. It was found that integrate- and-fire models do not entirely reflect the experimental behavior while the Hodgkin-Huxley and Frankenhaeuser-Huxley model do reflect this behavior. Changing the characteristics of the ion gates in the Frankenhaeuser-Huxley model alters the response to both the sinusoidal and TI signal, possibly reducing the firing threshold of the sinusoidal input below that of the TI input. The model results show that TI stimulation is not qualitatively impacted by nonlinearities in the current-voltage relation. In contrast, ion channels have a significant impact on the neuronal response. This paper makes advances both in terms of biophysical insight into the neuron as well as the insight in computational modelling of TI stimulation.
Expression analysis of Huntington disease mouse models reveals robust striatum disease signatures
Authors: Obenauer John C. , Chen Jian , Andreeva Viktoria , Aaronson Jeffrey S. , Lee Ramee , Caricasole Andrea , Rosinski Jim 
Published: February 2022

AbstractHuntington’s disease is caused by expanded trinucleotide repeats in the huntingtin gene (HTT), and a higher number of repeats is associated with an earlier age of disease onset. Although the causative gene has been identified, its connections to the observed disease phenotypes is still unclear. Mouse models engineered to contain increasing numbers of trinucleotide repeats were sacrificed at different ages to detect RNA-level and protein-level changes specific to each repeat length and age in order to examine the transcriptional and translational characteristics of the disease. RNA-seq and quantitative proteomics data were collected on 14 types of tissues at up to 8 repeat lengths and in up to 3 different ages, and differential gene and protein expression were examined. A modified method of imputing missing proteomics data was employed and is described here. The most dysregulated tissue at both the RNA and protein levels was the striatum, and a strong gender effect was observed in all of the liver experiments. The full differential expression results are available to the research community on theHDinHD.orgwebsite. The results of multiple expression tests in the striatum were combined to generate an RNA disease signature and a protein disease signature, and the signatures were validated in external data sets. These signatures represent molecular readouts of disease progression in HD mice, which further characterizes their HD-related phenotype and can be useful in the preclinical evaluation of candidate therapeutic interventions.Author SummaryMouse models of Huntington’s disease were engineered to allow a detailed examination of how the disease causes changes in gene activity in a variety of tissues. Among the 14 tissues studied, the one most affected by the disease in our experiments was the striatum, a brain region involved in voluntary movement. The liver results showed large differences in gene activity between the male and female mice. In our analysis, we propose a minor change in how proteomics data is typically analyzed in order to improve the ranking of significant results. Using the striatum data in this study and in others, we identified robust genetic signatures of disease at both the RNA and protein levels.
Evaluation of the α-synuclein PET radiotracer (d3)-[11C]MODAG-001 in pigs
Authors: Raval Nakul Ravi , Madsen Clara Aabye , Shalgunov Vladimir , Nasser Arafat , Battisti Umberto Maria , Beaman Emily Eufaula , Juhl Morten , Jørgensen Louise Møller , Herth Matthias Manfred , Hansen Hanne Demant , Plavén-Sigray Pontus , Knudsen Gitte Moos 
Published: February 2022

AbstractBackgroundA positron emission tomography (PET) radiotracer to neuroimage α-synuclein aggregates would be a crucial addition for early diagnosis and treatment development in disorders such as Parkinson’s disease, where elevated aggregate levels is a histopathological hallmark. The radiotracer (d3)-[11C]MODAG-001 has recently shown promise for visualization of α-synuclein pre-formed fibrils (α-PFF) in rodents. We here test the radiotracer in a pig model where proteins are intracerebrally injected immediately before scanning. Four pigs were injected in one hemisphere with 150 µg α-PFF, and in the other hemisphere, either 75 µg α-PFF or human brain homogenate from either dementia with Lewy bodies (DLB) or Alzheimer’s disease (AD) was injected. All pigs underwent one or two (d3)-[11C]MODAG-001 PET scans, quantified with the non-invasive Logan graphical analysis using the occipital cortex as a reference region.ResultsThe α-PFF and AD homogenate injected brain regions had high uptake of (d3)-[11C]MODAG-001 compared to the occipital cortex or cerebellum. BPND values in 150 µg α-PFF injected regions was 0.78, and in the AD homogenate injected regions was 0.73. By contrast, the DLB homogenate injected region did not differ in uptake and clearance compared to the reference regions. The time-activity curves and BPND values in the 150 µg and 75 µg injected region of α-PFFs show a dose-dependent effect, and the PET signal could be blocked by pretreatment with unlabeled MODAG-001.ConclusionWe find that both α-PFF and AD brain homogenates give rise to increased binding of (d3)-[11C]MODAG-001 when injected into the pig brain. Despite its limited specificity for cerebral α-synuclein pathology, (d3)-[11C]MODAG-001 shows promise as a lead tracer for future radiotracer development.
The usefulness of sparse k-means in metabolomics data: An example from breast cancer data
Authors: Goudo Misa , Sugimoto Masahiro , Hiwa Satoru , Hiroyasu Tomoyuki 
Published: February 2022

AbstractIn processing metabolomics data, multidimensional quantitative data from thousands of metabolites are often sparse, that is, only a small fraction of metabolites are relevant to the phenotype of interest. Clustering is therefore used to discover subtypes from omics data. Sparse processing, which selects important metabolites from the total omics data, is an effective clustering technique. This study investigated the effectiveness of sparse k-means for metabolomics data. Specifically, sparse k-means was used to cluster blood lipid metabolite data of breast cancer patients in two studies: (1) before and after menopause, and (2) pre- and postoperative chemotherapy. In both cases, sparse k-means showed comparable discrimination accuracy with fewer metabolites than k-means. Furthermore, when the L1 norm values were varied, no significant changes were observed. The mean silhouette coefficients of sparse k-means and k-means were (1) 0.38 ± 0.14 (S.D.) and 0.17 ± 0.01, (2) 0.38 ± 0.07 and 0.17 ± 0.01, indicating that feature selection using sparse k-means can improve clustering results. In addition, metabolite selection using sparse k-means was consistent regardless of the test data or the constrained value of the L1 norm, indicating robustness.
An orderly sequence of autonomic and neural events at transient arousal changes
Authors: Gu Yameng , Han Feng , Sainburg Lucas E. , Schade Margeaux M. , Buxton Orfeu M. , Duyn Jeff H. , Liu Xiao 
Published: February 2022

AbstractResting-state functional magnetic resonance imaging (rsfMRI) allows the study of functional brain connectivity based on spatially structured variations in neuronal activity. Proper evaluation of connectivity requires removal of non-neural contributions to the fMRI signal, in particular hemodynamic changes associated with autonomic variability. Regression analysis based on autonomic indicator signals has been used for this purpose, but may be inadequate if neuronal and autonomic activity covary. To investigate this potential co-variation, we performed rsfMRI experiments while concurrently acquiring electroencephalography and autonomic indicator signals, including heart rate, respiratory depth, and peripheral vascular tone. We identified a recurrent and systematic pattern of fMRI, EEG, and autonomic changes coincidental with intermittent arousal, suggesting arousal modulation. The temporal relationship between the various signals indicated combined neural and autonomic contribution to the fMRI signal, both of which involve widespread brain areas. The fMRI changes included brief signal reductions in salience and default-mode networks, and the thalamus, followed by a biphasic global change. These results suggest that proper measurement of functional connectivity with fMRI requires accounting for the full spectrum of autonomic and neural changes, as well as their co-variation during arousal state transitions.
Decoding molecular programs in melanoma brain metastases
Authors: Radke Josefine , Schumann Elisa , Onken Julia , Koll Randi , Acker Güliz , Bodnar Bohdan , Senger Carolin , Tierling Sascha , Möbs Markus , Vajkoczy Peter , Vidal Anna , Högler Sandra , Kodajova Petra , Westphal Dana , Meier Friedegund , Heppner Frank , Kreuzer-Redmer Susanne , Grebien Florian , Jürchott Karsten , Redmer Torben 
Published: February 2022

AbstractThe systemic dissemination of tumor cells and the spatiotemporal development of organ- metastases are associated with loss of therapeutic control and decreased overall survival (OS). The emergence of solitary or multiple brain metastases is frequently observed in melanoma patients and responsible for disease progression and dismal prognosis. Here, we used whole transcriptome and methylome profiling as well as targeted sequencing (TargetSeq) of intraoperative/snap frozen or archived melanoma brain metastases to unravel molecular subgroups and subclonal heterogeneity. We discovered that E-cadherin (Ecad)/BRAFV600E/K, CD271/NRASQ61L/R/K, and tumor infiltrated lymphocytes (TIL)-status molecularly subdivided tumors into proliferative/pigmented and invasive/stem-like irrespective of the intracranial location. Moreover, we identified 46 differentially methylated regions in promoters of 14 genes, subdividing MBM into BRAFmutand NRASmutsubgroups. We observed that therapy-resistant, migratory CD271+/Ecadnegsubclones derived from Ecad+tumors in an epithelial-mesenchymal transition (EMT)-like process and fostered intracranial progression. Hence, CD271highMBM present a therapy-resistant, progressive subset of tumors that are refractory to conventional therapeutic strategies. The knockdown of CD271 or SOX4 inin vitroestablished, MBM-derived cell lines decreased cell migration, proliferation, and number of suspension cells that were shed by cell lines of progressive tumors. In summary, we propose that an Ecad-to-CD271 switch of MBM is a rate-limiting process that potentially determines intracranial progression in melanoma patients. The therapeutic control of this process may prevent intracranial progression, increasing patient’s overall survival.
A Fast and Intuitive Method for Calculating Dynamic Network Reconfiguration and Node Flexibility
Authors: Chinichian Narges , Kruschwitz Johann D. , Reinhardt Pablo , Palm Maximilian , Wellan Sarah A. , Erk Susanne , Heinz Andreas , Walter Henrik , Veer Ilya M. 
Published: February 2022

AbstractDynamic interactions between brain regions, either during rest or performance of cognitive tasks, have been studied extensively using a wide variance of methods. Although some of these methods allow elegant mathematical interpretations of the data, they can easily become computationally expensive or difficult to interpret and compare between subjects or groups. Here, we propose an intuitive and computationally efficient method to measure dynamic reconfiguration of brain regions, also termed flexibility. Our flexibility measure is defined in relation to an a-priori set of biologically plausible brain modules (or networks) and does not rely on a stochastic data-driven module estimation, which, in turn, minimizes computational burden. The change of affiliation of brain regions over time with respect to these a-priori template modules is used as an indicator of brain network flexibility. We demonstrate that our proposed method yields highly similar patterns of whole-brain network reconfiguration (i.e., flexibility) during a working memory task as compared to a previous study that uses a data-driven, but computationally more expensive method. This result illustrates that the use of a fixed modular framework allows for valid, yet more efficient estimation of whole-brain flexibility, while the method additionally supports more fine-grained flexibility analyses restricted to biologically plausible brain networks.