bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improved NAAT assay for the diagnosis of onchocerciasis and its use for detection of circulating cell free DNA
Authors: Bennuru Sasisekhar , Kodua Frimpong , Dahlstrom Eric , Nutman Thomas B 
Published: September 2023

AbstractMass drug administration (MDA) programs aimed at control and elimination of onchocerciasis relies on annual or semi-annual distribution of Ivermectin (IVM) that target the microfialarial (mf) stage of the parasiteOnchocerca volvulus. The co-endemicity of onchocerciasis with other filarial species often leads to interruptions in the control programs. A much-needed tool for the elimination efforts are sensitive diagnostic assays that can help differentiate from other co-endemic filarial infections or xenomonitoring approaches. qPCR assays targeting highly repeated elements in the genomes have allowed for increased sensitivity of detection that are pathogen-specific. Utilizing NGS data, qPCR assays were designed to target 15 highly repeated targets fromO. volvulusand 11 fromO. ochengi. The two most sensitive and specific repeats Ov15R and Ov16R fromO. volvulusand OoR1 and OoR5 fromO. ochengi, were selected for further testing.The analytical sensitivity of both Ov15R and Ov16R were similar with limits of detection (LOD) at 1 fg ofO. volvulusgenomic DNA (gDNA), and 100% specificity and ∼32-fold sensitive than O-150 qPCR. Similarly, OoR1 and OoR5 had LOD of 100 fg ofO. ochengigDNA. Using DNA obtained previously from skin snips, Ov16R identified 17 additional samples as positive for infections when compared to O-150.Further, to eliminate the need for time-dependent sample acquisition, we evaluated the efficiency of plasma-derived circulating cell-free DNA (ccfDNA) to detectO. volvulusinfections and as a potential modality for testing cure of infection. Plasma-derived ccfDNA failed to amplify Ov16R. In contrast using a small set of urine-derived ccfDNA samples from Ov-infected individuals had varying levels of detectability as early as 12-24 hours post-treatment. To enable processing of larger volumes of urine for better sensitivity, a modified chitosan-based filter technique was developed as proof-of-concept that efficiently captured gDNA from 1-15ml of urine.Interestingly, Ov15R, Ov16R and O-150 map to the same contigs ofO. volvulusgenome. This prompted the redesign of O-150 qPCR that resulted in O-150-New qPCR assay that performs on par with Ov15R/Ov16R, thus offering more sensitive and specific diagnosis ofO. volvulusthat can easily be configured to field-friendly formats such as LAMP or RPA.
Excellence is a habit: Enhancing predictions of language impairment by identifying stable features in clinical perfusion scans
Authors: Teghipco Alex , Kim Hana , Rorden Chris , Newman-Norlund Roger , Sharif Massoud , Sikorski Darek , Hillis Argye E. 
Published: September 2023

AbstractPerfusion images guide acute stroke management, yet few studies have been able to systematically investigate CT perfusion collected during routine care because the measures are stored in proprietary formats incompatible with conventional research analysis pipelines. We illustrate the potential of harnessing granular data from these routine scans by using them to identify the association between specific areas of hypoperfusion and severity of object naming impairment in 43 acute stroke patients. Traditionally, similar analyses in such sample sizes face a dilemma—simple models risk being too constrained to make accurate predictions, while complex models risk overfitting and producing poor out-of-sample predictions. We demonstrate that evaluating the stability rather than out-of-sample predictive capacity of features in a nested cross-validation scheme can be an effective way of controlling model complexity and stabilizing model estimates across a variety of different regression techniques. Specifically, we show that introducing this step can determine model significance, even when the regression model already contains an embedded feature selection or dimensionality reduction step, or if a subset of features is manually selected prior to training based on expert knowledge. After improving model performance using more complex regression techniques, we discover that object naming performance relies on an extended language network encompassing regions thought to play a larger role in different naming tasks, right hemisphere regions distal to the site of injury, and regions and tracts that are less typically associated with language function. Our findings especially emphasize the role of the left superior temporal gyrus, uncinate fasciculus, and posterior insula in successful prediction of object naming impairment. Collectively, these results highlight the untapped potential of clinical CT perfusion images and demonstrate a flexible framework for enabling prediction in the limited sample sizes that currently dominate clinical neuroimaging.
Gaps in the phenotype descriptions of ultra-rare genetic conditions: review and multicenter consensus reporting guidelines
Authors: AlMail Ali , Jamjoom Ahmed , Pan Amy , Feng Min Yi , Chau Vann , D’Gama Alissa , Howell Katherine , Liang Nicole S.Y. , McTague Amy , Poduri Annapurna , Wiltrout Kimberly ,   IPCHiP Executive Committee, Bassett Anne S. , Christodoulou John , Dupuis Lucie , Gill Peter , Levy Tess , Siper Paige , Stark Zornitza , Vorstman Jacob A.S. , Diskin Catherine , Jewitt Natalie , Baribeau Danielle , Costain Gregory 
Published: September 2023

ABSTRACTBackgroundGenome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-first ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear.MethodsWe identified reports published from 2017-2021 in ten genetics journals of novel Mendelian disorders ascertained genotype-first. We adjudicated the quality and detail of the phenotype data via 46 questions pertaining to six priority domains: (I) Development, cognition, and mental health; (II) Feeding and growth; (III) Medication use and treatment history; (IV) Pain, sleep, and quality of life; (V) Adulthood; and (VI) Epilepsy. For a subset of articles, all subsequent published follow-up case descriptions were identified and assessed in a similar manner. A modified Delphi approach was used to develop consensus reporting guidelines, with input from content experts across four countries.ResultsIn total, 200 of 3243 screened publications met inclusion criteria. Relevant phenotypic details across each of the six domains were rated superficial or deficient in >87% of papers. For example, less than 10% of publications provided details regarding neuropsychiatric diagnoses and “behavioural issues”, or about the type/nature of feeding problems. Follow-up reports (n=95) rarely addressed the limitations of the original reports. Reporting guidelines were developed for each domain.ConclusionPhenotype information relevant to clinical management, genetic counseling, and the stated priorities of patients and families is lacking for many newly described genetic diseases. Use of the proposed guidelines could improve phenotype reporting in the genomic era.
Millimeter-sized battery-free epidural cortical stimulators
Authors: Woods Joshua E. , Singer Amanda L. , Alrashdan Fatima , Tan Wendy , Tan Chunfeng , Sheth Sunil A. , Sheth Sameer A. , Robinson Jacob T. 
Published: September 2023

AbstractRefractory neurological and psychiatric disorders are increasingly treated with brain stimulation therapies using implanted neuromodulation devices. Current commercially available stimulation systems, however, are limited by the need for implantable pulse generators and wired power; the complexity of this architecture creates multiple failure points including lead fractures, migration, and infection. Enabling less invasive approaches could increase access to these therapies. Here we demonstrate the first millimeter-sized leadless brain stimulator in large animal and human subjects. This Digitally programmable Over-brain Therapeutic (or DOT) is approximately 1 cm in width yet can produce sufficient energy to stimulate cortical activity on-demand through the dura. This extreme miniaturization is possible using recently developed magnetoelectric wireless power transfer that allows us to reach power levels required to stimulate the surface of the brain without direct contact to the cortical surface. This externally powered cortical stimulation (XCS) opens the possibility of simple minimally invasive surgical procedures to enable precise, long-lasting, and at-home neuromodulation with tiny implants that never contact the surface of the brain.
Immunohistochemical Study of Histone Protein 3 Modification in Pediatric Osteosarcoma Identifies Reduced H3K27me3 as a Marker of Poor Treatment Response
Authors: Kondratowski Sebastian , Cohen Danielle , Deyell Rebecca J. , Sandhu Ash , Bush Jonathan W 
Published: September 2023

Summary/AbstractThe most common pediatric primary malignant bone tumor, osteosarcoma, is often described as genetically non-recurrent and heterogeneous. Neoadjuvant chemotherapy is typically followed by resection and assessment of treatment response, which helps inform prognosis. Identifying biomarkers that may impact chemotherapy response and survival could aid in upfront risk stratification and identify patients in highest need of innovative therapies for future clinical trials. Relative to conventional genetics, little is known about osteosarcoma epigenetics. We aimed to characterize the methylation and phosphorylation status in osteosarcoma using histone markers found in primary diagnostic biopsies and their paired metastases. We constructed two tissue microarray sets from 58 primary diagnostic samples and 54 temporally-separated but related metastatic or recurrent samples, with tissue blocks available from 2002-2022. Clinical charts were reviewed for post-therapy necrosis response, presence of metastatic disease or recurrence, and overall survival. We evaluated 6 histone H3 residues using immunohistochemistry, including H3K4me3, H3K9me3, H3K27me2, H3K27me3, H3S10T11phos, and H3S28phos. Tumors were scored with low (<25%) or high (≥25%) nuclear staining of tumor cells. Diagnostic biopsies with low H3K27me3 nuclear staining were associated with poor treatment response (≤90% necrosis) at the time of definitive excision (P<0.05). We observed loss of H3S10T11phos expression in metastatic and recurrent resections specimens compared to the primary tumor (P<0.05). Expression patterns for the remaining histone markers did not show significant associations with disease parameters or survival. Although larger cohort studies are needed, these results support the expanded evaluation of histone markers, particularly H3K27me3 and H3S10T11phos, in osteosarcoma biology and risk stratification.
Dynamics of motor direction representation in the primate premotor and primary motor cortices during sensorimotor learning
Authors: Ebina Teppei , Sasagawa Akitaka , Hong Dokyeong , Setsuie Rieko , Obara Keitaro , Masamizu Yoshito , Kondo Masashi , Terada Shin-Ichiro , Ozawa Katsuya , Uemura Masato , Takaji Masafumi , Watakabe Akiya , Kobayashi Kenta , Ohki Kenichi , Yamamori Tetsuo , Murayama Masanori , Matsuzaki Masanori 
Published: September 2023

SummarySensorimotor learning requires reorganization of neuronal activity in the premotor cortex (PM) and primary motor cortex (M1). However, how PM- and M1-specific reorganization occurs in primates remains unclear. We conducted calcium imaging of these areas in common marmosets while they learned a two-target reaching (pull/push) task. Throughout learning, the dorsorostral PM (PMdr) showed peak activity earlier than the dorsocaudal PM (PMdc) and M1. PMdr showed decreased representation of newly introduced (push) movement, whereas PMdc and M1 maintained high representation. Many task-related neurons in PMdc and M1 exhibited a strong preference to either movement direction. PMdc neurons dynamically switched their preferred direction, whereas M1 neurons stably retained their preferred direction. Differences in preferred direction between adjacent neurons in PMdc increased during learning. These results suggest that in primate sensorimotor learning, dynamic motor representation in PMdc converts the cognitive sensorimotor signals of PMdr to stable and specific motor representation of M1.
Representation of Protein Dynamics Disentangled by Time-structure-based Prior
Authors: Ishizone Tsuyoshi , Matsunaga Yasuhiro , Fuchigami Sotaro , Nakamura Kazuyuki 
Published: September 2023

AbstractRepresentation learning (RL) is a universal technique for deriving low-dimensional disentangled representations from high-dimensional observations, aiding a multitude of downstream tasks. RL has been extensively applied to various data types, including images and natural language. Here, we analyze molecular dynamics (MD) simulation data of biomolecules in terms of RL to obtain disentangled representations related to their conformational transitions. Currently, state-of-the-art RL techniques, which are mainly motivated by the variational principle, try to capture slow motions in the representation (latent) space. Here, we propose two methods based on alternative perspective on thedisentanglementin the representation space. The methods introduce a simple prior that imposes temporal constraints in the representation space, serving as a regularization term to facilitate capturing disentangled representations of dynamics. The introduction of this simple prior aids in characterizing the conformational transitions of proteins. Indeed, comparison with other methods via the analysis of MD simulation trajectories for alanine dipeptide and chignolin validates that the proposed methods construct Markov state models (MSMs) whose implied time scales are comparable to state-of-the-art methods. By coarse-graining MSMs, we further show the methods aid to detect physically important interactions for conformational transitions. Overall, our methods provide good representations of complex biomolecular dynamics for downstream tasks, allowing for better interpretations of conformational transitions.
Whole blood mitochondrial copy number in clinical populations with mood disorders: a meta-analysis
Authors: Calarco Cali A. , Keppetipola Swarnapali M. , Kumar Gautam , Shipper Andrea G. , Lobo Mary Kay 
Published: September 2023

AbstractBackgroundMajor depressive disorder (MDD) and bipolar disorder (BD), are globally prevalent, contributing to significant disease burden and adverse health outcomes. These mood disorders are associated with changes in many aspects of brain reward pathways, yet cellular and molecular changes in the brain are not readily available in clinical populations. Therefore, the use of biomarkers as proxies for changes in the brain are necessary. The proliferation of mitochondria in blood has emerged as a potentially useful biomarker, yet a clear consensus on how these mood disorders impact mitochondrial DNA copy number (mtDNAcn) has not been reached.MethodsFollowing PRISMA guidelines for a systematic search, 22 papers met inclusion criteria for meta-analysis (10 MDD, 10 BD, 2 both MDD and BD). We extracted demographic, disorder, and methodological information with mtDNAcn. Using the metafor package for R, calculated effect sizes were used in random effects or meta regression models for MDD and BD.ResultsOur results show a trending increase in mtDNAcn in patients with MDD, which reaches significance when one study with outlying demographic characteristics is excluded. Overall, there was no effect of BD on mtDNAcn, however, further subgroup and meta-regression analysis indicated the effects on mtDNAcn are dependent on BD type.ConclusionsTogether our data suggest whole blood/leukocyte mtDNAcn may be a useful biomarker for mood disorders, with MDD and BD Type II associated with higher mtDNAcn, and BD Type I associated with lower mtDNAcn. Further study of blood mtDNAcn could predict downstream health outcomes or treatment responsivity in individuals with mood disorders.
Sensation and expectation are embedded in mouse motor cortical activity
Authors: Holey Brooke E. , Schneider David M. 
Published: September 2023

AbstractDuring behavior, the motor cortex sends copies of motor-related signals to sensory cortices. It remains unclear whether these corollary discharge signals strictly encode movement or whether they also encode sensory experience and expectation. Here, we combine closed-loop behavior with large-scale physiology, projection-pattern specific recordings, and circuit perturbations to show that neurons in mouse secondary motor cortex (M2) encode sensation and are influenced by expectation. When a movement unexpectedly produces a sound, M2 becomes dominated by sound-evoked activity. Sound responses in M2 are inherited partially from the auditory cortex and are routed back to the auditory cortex, providing a path for the dynamic exchange of sensory-motor information during behavior. When the acoustic consequences of a movement become predictable, M2 responses to self-generated sounds are selectively gated off. These changes in single-cell responses are reflected in population dynamics, which are influenced by both sensation and expectation. Together, these findings reveal the rich embedding of sensory and expectation signals in motor cortical activity.
Single-cell optogenetics reveals attenuation-by-suppression in visual cortical neurons
Authors: LaFosse Paul K. , Zhou Zhishang , O’Rawe Jonathan F. , Friedman Nina G. , Scott Victoria M. , Deng Yanting , Histed Mark H. 
Published: September 2023

AbstractThe relationship between neurons’ input and spiking output is central to brain computation. Studiesin vitroand in anesthetized animals suggest nonlinearities emerge in cells’ input-output (activation) functions as network activity increases, yet how neurons transform inputsin vivohas been unclear. Here, we characterize cortical principal neurons’ activation functions in awake mice using two-photon optogenetics. We deliver fixed inputs at the soma while neurons’ activity varies with sensory stimuli. We find responses to fixed optogenetic input are nearly unchanged as neurons are excited, reflecting a linear response regime above neurons’ resting point. In contrast, responses are dramatically attenuated by suppression. This attenuation is a powerful means to filter inputs arriving to suppressed cells, privileging other inputs arriving to excited neurons. These results have two major implications. First, somatic neural activation functionsin vivoaccord with the activation functions used in recent machine learning systems. Second, neurons’ IO functions can filter sensory inputs — not only do sensory stimuli change neurons’ spiking outputs, but these changes also affect responses to input, attenuating responses to some inputs while leaving others unchanged.Significance statementHow neurons transform their inputs into outputs is a fundamental building block of brain computation. Past studies have measured neurons’ input-output (IO) functionsin vitroor in anesthetized states. Here, we measure neurons’ IO functions in the awake and intact brain, where ongoing network activity can influence neurons’ responses to input. Using state-of-the-art optogenetic methods to deliver precise inputs to neurons near the cell body, or soma, we discover neurons have a supralinear-to-linear IO function, contrary to previous findings of threshold-linear, strongly saturating, or power law IO functions. This supralinear-to-linear somatic IO function shape allows neurons to decrease their responses to, or filter, inputs while they are suppressed below their resting firing rates, a computation we term attenuation-by-suppression.
Bacterial composition changes in canine plaque over periodontal disease severity and daily care practices
Authors: Watanabe Ayano , Okada Junichi , Niwa Ryo , Inui Yukiko , Ito Kohei , Shimokawa Yutaka , Kihira Miho 
Published: September 2023

AbstractBackgroundPeriodontal disease (PD) is a common oral disease in dogs and humans. Dogs have distinctly different oral environments from humans. Although common bacteria are observed in both species, profiling of the causative bacteria for the progression of PD in dogs is limited compared to humans.ResultsOur study examined the shifts in the bacterial community within canine plaque as PD intensifies, analyzing plaque samples from 48 dogs at various PD stages. Additionally, we examined the impact of a tooth-brushing regimen using a dental gel on twelve dogs. We revealed a correlation between the age of the dogs and the severity of PD. As PD advanced, we noted a marked increase inPorphyromonasabundance, a key pathogenic genus. Conversely,Conchiformibiusprevalence diminished in higher PD levels. Furthermore, a regimen of two week brushing with a dental gel resulted in a notable decrease inPorphyromonaslevels and five of the twelve dogs improve severity.ConclusionsOur findings suggest the potential efficacy of daily brushing with dental gels, incorporating compounds proven effective in humans, for managing PD in dogs. This study demonstrates a distinct disease progression in dogs compared to humans, underscoring the need for continued research and innovation in veterinary oral healthcare.
A novel, scenario-based approach to comparing non-pharmaceutical intervention strategies across nations
Authors: Calabrese Justin M. , Schüler Lennart , Fu Xiaoming , Gawel Erik , Zozmann Heinrich , Bumberger Jan , Quaas Martin , Wolf Gerome , Attinger Sabine 
Published: September 2023

AbstractComparing COVID-19 non-pharmaceutical intervention (NPI) strategies across nations is a key step in preparing for future pandemics. Conventional comparisons, which rank individual NPI effects, are limited by: 1) vastly different political, economic, and social conditions among nations, 2) NPIs typically being applied as packages of interventions, and 3) an exclusive focus on epidemiological outcomes of interventions. Here, we develop a coupled epidemiological-behavioural-macroeconomic model that allows us to transfer NPI strategies from a reference nation to a focal nation while preserving the packaged nature of NPIs, controlling for differences among nations, and quantifying epidemiological, behavioural and economic outcomes. As a demonstration, we take Germany as our focal nation during Spring 2020, and New Zealand and Switzerland as reference nations with contrasting NPI strategies. We show that, while New Zealand’s more aggressive strategy would have yielded modest epidemiological gains in Germany, it would have resulted in substantially higher economic costs while dramatically reducing social contacts. In contrast, Switzerland’s more lenient NPI strategy would have prolonged the first wave in Germany, but would have also have increased relative costs. Our results demonstrate that Germany’s intermediate strategy was effective in quelling the first wave while mitigating both economic and social costs.