bluuebunny/crossref_metadata_2025 huggingface dataset:
Heterotopic Ossification Complicating Traumatic Ulnar Nerve Palsy in a Child
Authors: AlSahli Alaa Mohammed , AlHujayri Abdulaziz K. , AlShenaifi Abdulaziz , AlDekhayel Salah
Published: February 2022

Heterotopic ossification (HO) refers to the process of forming bony tissues in extra-skeletal sites such as muscles and soft tissues. This pathological process most commonly commences following trauma, surgery, and fractures. Rarely, HO can compress nearby neurovascular structures. To the best of our knowledge, however, no previous reports exist of HO serving as second-hit to partially injured ulnar nerve in the pediatric population. We present a case of a 6-year-old girl with complete high ulnar nerve palsy caused by medial epicondylar fracture followed by development of HO around the elbow. The patient was initially managed conservatively. Four months after the first visit, she presented with complete ulnar nerve palsy that was not evident on the initial presentation. Based on further investigations, she was taken to OR for release of the cubital tunnel and anterior transposition of ulnar nerve. On further follow-up, the patient regained sensory and motor functions of the ulnar nerve with minimum sequalae. Post-traumatic ulnar nerve injury is well described in the literature as resulting from initial trauma or as an iatrogenic injury following fracture reduction and fixation. HO in the pediatric age group is considerably rare, occurring after trauma and burn injuries. Surgical timing of HO release remains controversial. No previous reports of HO complicating traumatic ulnar nerve palsy in pediatric patients exist. In the current case report, partial ulnar nerve injury was initially due to medial epicondylar fracture, but it had progressed to full blown ulnar palsy secondary to superimposed HO. Early HO takedown combined with decompression of ulnar nerve are crucial to ensure complete nerve recovery.
Pseudoaneurysm of the Superficial Palmar Arch in a 6-month-old Child: A Case Report
Authors: Kwiecien Grzegorz J. , Garbuzov Anna , Boonipat Thanapoom , Houdek Matthew T. , Moran Steven L.
Published: February 2022

Hand aneurysms in infants are extremely rare and, unlike their adult counterparts, cannot be explained by repetitive trauma to the palm. When they occur, they are most often located in the ulnar artery. Usually there is no history of trauma, and an alternative diagnosis like malignancy must be excluded. Helpful physical findings to aid diagnosis include rapid appearance of a mass over the course of a few days, pulsatile nature, and location along the ulnar side of the hand. These cases can be challenging and excisional biopsy may be required if the lesion is thrombosed and does not have a characteristic appearance on imaging. Aneurysms located in the palmar arch or common digital arteries are usually treated with simple excision, while those located in the ulnar artery often require repair or reconstruction. Here we present a unique case of an infant with a pseudoaneurysm involving the superficial palmar arch on the radial side of the hand with a likely congenital etiology. Diagnostic challenges and treatment options are discussed.
Technique of Abdominal Wall Tissue Expansion for the Treatment of Massive Complicated Ventral Hernias
Authors: Celestin Arthur R. , Barron Sivana , Haddad Anthony , Jia Emmeline , Morgenstern Monica , Diamond Shawn , Plaster Blakely , Cauley Ryan P. , Morris Donald J.
Published: February 2022

Abdominal wall tissue expansion is a unique technique that seeks to augment and expand both the fascial and subcutaneous tissues/skin layers to achieve durable closure of otherwise challenging ventral hernias. In addition to allowing primary fascial closure in a majority of cases, this technique enables reduced tension on the closure, potentially decreasing the recurrence rate. This article describes the senior author’s surgical technique for abdominal wall tissue expansion in massive complicated ventral hernias. The plastic surgeon is at a unique advantage to assist with the repair of massive complicated ventral hernias given their comfort with complex tissue handling and expandable devices. This specialized technique thus provides an opportunity for plastic surgeons to serve as expert co-surgeons with general surgery colleagues to help achieve superior outcomes in patients with these challenging hernias.
Simultaneous Closure of the Cleft Alveolus and Hard Palate with Concomitant Bone Grafting
Authors: Kim Erinn N. , Moss Whitney D. , Kunkel Ryan P. , Yamashiro Duane K. , Gociman Barbu R.
Published: February 2022

Cleft repair has been in constant evolution since its inception. Conventional repair of the cleft hard palate involves closure of nasal and oral mucosa without bony reconstitution. In many instances, this approach is adequate, but, particularly in complete clefts, the lack of bony support can lead to collapse of the maxillary arch, dental crowding, and posterior cross-bite. To address these shortcomings, our institution performs a two-staged palatoplasty with concomitant bone grafting of the alveolus and hard palate in the second stage. A retrospective review of children who underwent a two-staged palatoplasty at our institution was performed. These patients’ records and images were reviewed for complications and changes in maxillary morphology. Fourteen patients with complete clefts had a two-staged palatoplasty with bone grafting in the second stage. The mean age at surgery was 37.5 months, and the mean follow-up was 16 months. One patient had resorption of the alveolar bone graft requiring additional bone grafting. The remaining patients were without complications and had good consolidation of the bone graft on follow-up imaging. Our early results support that there is a low complication rate (7% regrafting) in those patients who underwent bone grafting at the time of cleft palate repair with early evidence of bony consolidation on imaging and clinical examination. Wide exposure during the repair allows complete grafting of the maxillary bony deficit, which is not possible with traditional alveolar cleft repair and may alleviate the shortcoming of soft-tissue closure only. Future study is necessary to determine long-term outcomes.
Joint Associations of Obesity and Cardiorespiratory Fitness With Coronary Artery Calcium Composition
Authors: Jae Sae Young , Kim Hyun Jeong , Lee Kyung Hyun , Kunutsor Setor K. , Heffernan Kevin S. , Choi Yoon-Ho , Kang Mira
Published: February 2022

Introduction:

The purpose of this study was to examine the individual and joint associations of obesity and cardiorespiratory fitness (CRF) with indices of coronary artery calcification (CAC) in 2090 middle-aged men.

Methods:

Obesity was defined as a body mass index (BMI) ≥25 kg/m2 and a waist circumference (WC) ≥90 cm. Cardiorespiratory fitness was operationally defined as peak oxygen uptake (V˙o
2peak) directly measured using gas analysis. Participants were then divided into unfit and fit categories based on age-specific V˙o
2peak percentiles. Agatston scores >100 and volume and density scores >75th percentile were defined as indices of CAC, signifying advanced subclinical atherosclerosis.

Results:

Obese men had increased CAC Agatston, volume, and density scores, while higher CRF was associated with lower Agatston and volume scores after adjusting for potential confounders. In the joint analysis, unfit-obese men had higher CAC Agatston and CAC volume. The fit-obesity category was not associated with CAC Agatston (OR = 0.91: 95% CI, 0.66-1.25, for BMI and OR = 1.21: 95% CI, 0.86-1.70, for WC) and CAC volume (OR = 1.14: 95% CI, 0.85-1.53, for BMI and OR = 1.23: 95% CI, 0.90-1.69, for WC), which were similar to estimates for the fit-normal weight category.

Conclusions:

These findings demonstrate that while obesity is positively associated with the prevalence of moderate to severe CAC scores, CRF is inversely associated with the prevalence of moderate to severe CAC scores. Additionally, the combination of being fit and obese was not associated with CAC scores, which could potentially reinforce the fat-but-fit paradigm.
Risk Factors for Longer Pediatric Intensive Care Unit Length of Stay Among Children Who Required Escalation of Care Within 24 Hours of Admission
Authors: Kapileshwarkar Yamini , Floess Katherine E. , Astle Michele , Tripathi Sandeep
Published: February 2022

Objective

Children who require early escalation of care (EOC) to the pediatric intensive care unit (PICU) after floor admission have higher mortality and increased hospital length of stay (LOS) as compared with direct emergency department (ED) admissions. This study was designed to identify subgroups of patients within this cohort (EOC to PICU within 24 hours of hospital admission) who have worse outcomes (actual PICU LOS [aLOS] > predicted PICU LOS [pLOS]).

Methods

This was a retrospective single-center cohort study. Patients who required EOC to PICU from January 2015 to December 2019 within 24 hours of admission were included. Postoperative patients, missing cause of EOC, and mortality were excluded. Predicted LOS was calculated based on Pediatric Risk of Mortality scores. Patients with aLOS > pLOS (group A) were compared with patients with aLOS ≤ pLOS (group B). Multivariable logistic regression was performed to adjust for confounders.

Results

Of 587 patients transferred to PICU after hospital admission during the study period, 286 patients met the study criteria (group A, n = 69; group B, n = 217). The 2 groups were similar in age, race, the severity of illness, and ED vitals and therapies. A higher proportion of patients in group B had EOC ≤ 6 hours of admission (51.1% vs 36.2%, P = 0.03), and a higher proportion in group A required Mechanical ventilation (56% vs 34%, P = 0.01). On multivariable regression, patients who required EOC to PICU after 6 hours after admission (adjusted odds ratio, 2.27; 95% confidence interval [CI] 1.2, 4.0), p,<0.01) and patients admitted to the floor from referral hospitals (adjusted odds ratio, 1.8; 95% confidence interval, 1.0–3.2), P = 0.04) had higher risk of greater than PLOS.

Conclusions

Among patients who required EOC to PICU, risk factors associated with aLOS > pLOS were patients who required EOC to PICU longer than 6 hours after admission to the hospital and patients admitted to the floor as a transfer from referral hospitals.
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.
Impact of neurite alignment on organelle motion
Authors: Mytiliniou Maria , Wondergem Joeri A. J. , Schmidt Thomas , Heinrich Doris
Published: February 2022

Intracellular transport is pivotal for cell growth and survival. Malfunctions in this process have been associated with devastating neurodegenerative diseases, highlighting the need for a deeper understanding of the mechanisms involved. Here, we use an experimental methodology that leads neurites of differentiated PC12 cells into either one of two configurations: a one-dimensional configuration, where the neurites align along lines, or a two-dimensional configuration, where the neurites adopt a random orientation and shape on a flat substrate. We subsequently monitored the motion of functional organelles, the lysosomes, inside the neurites. Implementing a time-resolved analysis of the mean-squared displacement, we quantitatively characterized distinct motion modes of the lysosomes. Our results indicate that neurite alignment gives rise to faster diffusive and super-diffusive lysosomal motion than the situation in which the neurites are randomly oriented. After inducing lysosome swelling through an osmotic challenge by sucrose, we confirmed the predicted slowdown in diffusive mobility. Surprisingly, we found that the swelling-induced mobility change affected each of the (sub-/super-)diffusive motion modes differently and depended on the alignment configuration of the neurites. Our findings imply that intracellular transport is significantly and robustly dependent on cell morphology, which might in part be controlled by the extracellular matrix.
Virtual manipulation of tail postures of a gliding barn owl (
Tyto alba
) demonstrates drag minimization when gliding
Authors: Song Jialei , Cheney Jorn A. , Bomphrey Richard J. , Usherwood James R.
Published: February 2022

Aerodynamic functions of the avian tail have been studied previously using observations of bird flight, physical models in wind tunnels, theoretical modelling and flow visualization. However, none of these approaches has provided rigorous, quantitative evidence concerning tail functions because (i) appropriate manipulation and controls cannot be achieved using live animals and (ii) the aerodynamic interplay between the wings and body challenges reductive theoretical or physical modelling approaches. Here, we have developed a comprehensive analytical drag model, calibrated by high-fidelity computational fluid dynamics (CFD), and used it to investigate the aerodynamic action of the tail by virtually manipulating its posture. The bird geometry used for CFD was reconstructed previously using stereo-photogrammetry of a freely gliding barn owl (
Tyto alba
) and we validated the CFD simulations against wake measurements. Using this CFD-calibrated drag model, we predicted the drag production for 16 gliding flights with a range of tail postures. These observed postures are set in the context of a wider parameter sweep of theoretical postures, where the tail spread and elevation angles were manipulated independently. The observed postures of our gliding bird corresponded to near minimal total drag.
Salsipaludibacter albus gen. nov., sp. nov., a novel actinobacterial strain isolate from a Portuguese solar saltern and proposal of Salsipaludibacteraceae fam. nov. and Salsipaludibacterales ord. nov.
Authors: Almeida Eduarda , Henriques Valentina , Wiegand Sandra , Albuquerque Luciana , Schumann Peter , Kohn Timo , Jogler Christian , Simões da Costa Milton , Lobo-da-Cunha Alexandre , de Fátima Carvalho Maria , Lage Olga Maria
Published: February 2022

A novel micro-organism designated AS10Twas isolated from dry salt collected from Aveiro saltern in the north of Portugal. Cells were Gram-stain-positive, non-motile, non-endospore-forming, rod-shaped and aerobic. Strain AS10Twas characterized by long filaments of rod-shaped cells, presenting also coccoid cellular forms at the end of the filaments, unveiling some pleomorphism. Rod-shaped cells varied from 0.3 to 0.6 µm wide and from 0.6 to 2 µm long. Growth of AS10Toccurred at 15–40 °C (optimum, 20–30 °C), 0–10% (w/v) NaCl (optimum, 2%) and pH 4.5–11.0 (optimum, pH 8.0–11.0). The peptidoglycan type was A1ϒ-type with 3-hydroxy-diaminopimelic acid. The major fatty acids were C16:0, iso-C14:0, C17:0and C14:0. The major respiratory quinone was MK-9(H4). Phylogenetic analysis based on 16S rRNA gene sequences showed that strain AS10Twas similar to actinobacterial members of the classNitriliruptoria, withNitriliruptor alkaliphilusANL-iso2Tbeing the closest relative the species with a sequence pairwise similarity of 91.21%. Average nucleotide identity, average amino acid identity andin silicoDNA–DNA hybridization values between strain AS10TandN. alkaliphilusANL-iso2Twere 71.34, 53.57 and 18.90%, respectively. The genome DNA G+C content of AS10Twas 71.8 mol%. Based on genomic, phylogenetic, phenotypic and chemotaxonomic studies, we describe a new species of a novel genus represented by strain AS10T(=LMG 31937T=CECT 30148T) for which we propose the nameSalsipaludibacter albusgen. nov., sp. nov. We also propose that this organism represents a new family namedSalsipaludibacteraceaefam. nov. of a novel order namedSalsipaludibacteralesord. nov.
Noviherbaspirillum aridicola sp. nov., isolated from an arid soil in Pakistan
Authors: Khan Inam Ullah , Saqib Muhammad , Amin Arshia , Hussain Firasat , Li Li , Liu Yong-Hong , Fang Bao-Zhu , Ahmed Iftikhar , Li Wen-Jun
Published: February 2022

Strain NCCP-691T was isolated from a soil sample collected from an arid soil in Karak, Khyber Pakhtunkhwa, Pakistan. Phenotypically, the cells were Gram-stain-negative, aerobic and motile rods. The organism was able to grow between 20–40 °C (optimum at 30–37 °C), at pH 5.5–8.0 (optimum at pH 7.0–7.2) and tolerated 0–1.5% NaCl (w/v) (optimum at 0–0.5). Based on 16S rRNA gene sequences, strain NCCP-691T formed a distinct phylogenetic clade with

Noviherbaspirillum arenae

,

N

.

agri

, N. denitrificans and

N

.

autotrophicum

(having sequence similarities of 99.0; 98.1; 98.0 and 97.7% respectively). Phylogenetic analyses based on the whole genome sequences confirmed that strain NCCP-691T should be affiliated to the genus

Noviherbaspirillum

. The average nucleotide identity values compared to other species of

Noviherbaspirillum

were below 95–96 % and digital DNA–DNA hybridization values were less than 70 %. Chemotaxonomic analyses showed that the strain had ubiquinone-8, as the only respiratory quinine. The major cellular fatty acids were summed feature 3 (C16 : 1 ω 7 c/C16 : 1 ω 6 c, 35.9 %), summed feature 8 (C18 : 1 ω 7 c/C18 : 1 ω 6 c, 26.9 %) and C16 : 0 (22.9 %) and the polar lipid profile was composed of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and phosphatidylcholine. The genomic DNA G+C content was 65.5 mol% (from draft genome). Genome analyses showed that strain NCCP-691T had terpene and arylpolyene biosynthetic genes clusters and genes related to resistance against heavy metals. Based on phylogenetic analyses, phenotypic features and genomic comparison, it is proposed that strain NCCP-691T is a novel species of the genus

Noviherbaspirillum

and the name Noviherbaspirillum aridicola sp. nov. is proposed. Type strain is NCCP-691T (=KCTC 52721T=CGMCC 1.13600T).
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

The 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

In 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

Huntington’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 Summary

Mouse 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

Background

A 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.

Results

The 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.

Conclusion

We 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

In 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

Resting-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

The 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

Abstract

Dynamic 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.
Functional geometry of auditory cortical resting state networks derived from intracranial electrophysiology
Authors: Banks Matthew I. , Krause Bryan M. , Berger D. Graham , Campbell Declan I. , Boes Aaron D. , Bruss Joel E. , Kovach Christopher K. , Kawasaki Hiroto , Steinschneider Mitchell , Nourski Kirill V.
Published: February 2022

Understanding central auditory processing critically depends on defining underlying auditory cortical networks and their relationship to the rest of the brain. We addressed these questions using resting state functional connectivity derived from human intracranial electroencephalography. Mapping recording sites into a low-dimensional space where proximity represents functional similarity revealed a hierarchical organization. At fine scale, a group of auditory cortical regions excluded several higher order auditory areas and segregated maximally from prefrontal cortex. On mesoscale, the proximity of limbic structures to auditory cortex suggested a limbic stream that parallels the classically described ventral and dorsal auditory processing streams. Identities of global hubs in anterior temporal and cingulate cortex depended on frequency band, consistent with diverse roles in semantic and cognitive processing. On a macro scale, observed hemispheric asymmetries were not specific for speech and language networks. This approach can be applied to multivariate brain data with respect to development, behavior, and disorders.

Blurb

We describe the organization of human neocortex on multiple spatial scalesbased on resting state intracranial electrophysiology. We focus on cortical regions involved in auditory processing and examine inter-regional hierarchical relationships, network topology, and hemispheric lateralization. This work introduces a powerful analytical tool to examine mechanisms of altered arousal states, brain development, and neuropsychiatric disorders.
Coupling comprehensive pesticide-wide association study to iPSC dopaminergic screening identifies and classifies Parkinson-relevant pesticides
Authors: Paul Kimberly C , Krolewski Richard C , Moreno Edinson Lucumi , Blank Jack , Holton Kris , Ahfeldt Tim , Furlong Melissa , Yu Yu , Cockburn Myles , Thompson Laura K , Bronstein Jeff , Rubin Lee L. , Khurana Vikram , Ritz Beate
Published: February 2022

Parkinson’s disease (PD) is a complex, multi-factorial neurodegenerative disease, known to involve genetic, aging-related components, but also to be highly sensitive to environmental factors. In particular, ample evidence links pesticides to PD etiology. Here, establishing a field-to-bench paradigm, we have combined record-based exposure assessment in a population-based epidemiologic study of PD with testing in dopaminergic neurons produced from iPSCs to further identify and classify PD-relevant pesticides. First, agricultural pesticide-application records in California enabled us to investigate exposure to nearly 300 specific pesticides and PD risk in a comprehensive, pesticide-wide association study (PWAS). We implicated long-term exposure to 53 pesticide active ingredients in PD risk and identified their relevant co-exposure profiles. Second, to identify which of these pesticides might contribute to PD through direct effects on dopaminergic neurons, we employed a live-cell imaging screening paradigm in which neurons, definitively identified with a tyrosine hydroxylase reporter, were exposed to 43 of the high-risk pesticides. Using detailed morphometric measures, we found 10 pesticides were directly toxic to these neurons. Further, we analyzed pesticides typically used in combinations in cotton farming. Among these “cotton cluster” pesticides, co-exposures resulted in markedly greater toxicity than any single pesticide. Trifluralin was a pivotal driver of toxicity to dopaminergic neurons and led to marked mitochondrial dysfunction. Our field-to-bench paradigm may prove useful to mechanistically dissect pesticide exposure implicated in PD risk, and guide agricultural policy in the future.
A potent SARS-CoV-2 neutralizing antibody recognizing a conserved epitope with broad mutant variant and SARS-CoV activity
Authors: Pelzek Adam J. , Ebtehaj Sanam , Lulo James , Zhang Lucy , Balduf Olivia , Dolan Lindsay , Zhang Chaohua , Wan Shengqin , An Gang , Kankam Awo , Chan Eugene , Murphy Shaun P.
Published: February 2022

COVID-19 is the deadliest respiratory virus pandemic since 1918 and the latest of several coronavirus epidemics and pandemics in recent years. Despite the unprecedented response by both the government and private sectors to develop vaccines and therapies, the evolution of SARS-CoV-2 variants resistant to these interventions reveals a crucial need for therapeutics that maintain their efficacy against current and future mutant variants. Here we describe a SARS-CoV-2 neutralizing antibody, ABP-310, with potent activity against all variants tested including the Omicron variant. ABP-310 also displays potent neutralizing activity against SARS-CoV, highlighting the conserved nature of the ABP-310 epitope. By targeting a conserved epitope, we believe that ABP-310 has therapeutic promise not only against the current SARS-CoV-2 variants but would be expected to maintain efficacy against future variants and possibly even novel coronaviruses.
Rapid, High-Throughput, Cost Effective Whole Genome Sequencing of SARS-CoV-2 Using a Condensed One Hour Library Preparation of the Illumina DNA Prep Kit
Authors: Hickman Rebecca , Nguyen Jason , Lee Tracy D. , Tyson John R. , Azana Robert , Tsang Frankie , Hoang Linda , Prystajecky Natalie
Published: February 2022

The ongoing COVID-19 pandemic necessitates cost-effective, high-throughput, and timely genomic sequencing of SARS-CoV-2 viruses for outbreak investigations, identifying variants of concern (VoC), characterizing vaccine breakthrough infections, and public health surveillance. Additionally, the enormous demand of genomic sequencing on supply chains and the resulting shortages of laboratory supplies necessitate the use of low-reagent and low-consumable methods. Here, we report an optimized library preparation method where the same protocol can be used in a STAT scenario, from sample to sequencer in as little as eight hours, and a high-throughput scenario, where one technologist can perform 576 library preparations over the course of one 8-hour shift. This new method uses Freed et al.’s 1200 bp primer sets (Biol Methods Protoc 5:bpaa014, 2020, https://doi.org/10.1093/biomethods/bpaa014) and a modified and truncated Illumina DNA Prep workflow (Illumina, CA, USA). Compared to the original, application of this new method in hundreds of clinical specimens demonstrated equivalent results to the full-length DNA Prep workflow at 45% the cost, 15% of consumables required (such as pipet tips), 25% of manual hands-on time, and 15% of on-instrument time if performing on a liquid handler, with no compromise in sequence quality. Results suggest that this new method is a rapid, simple, cost-effective, and high-quality SARS-CoV-2 whole genome sequencing protocol.