bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variability and Impact of Musculoskeletal Modeling Parameters for the Human Elbow
Authors: Hardesty Russell , Jeong Byeongchan , Gemoets Darren E. 
Published: November 2022

ABSTRACTMusculoskeletal modeling has significant potential as a translational and clinical research tool for examining neuromuscular injuries and disorders. However its adoption has been limited due, in part, to the difficulty of measuring the subject-specific physiological measures that define model parameters. These measurements may require substantial time and expensive methods, such as MRI, to determine the parameters of a model and thus ensure its accuracy. We used a Monte Carlo simulation to examine the impact of parameter variability on the ill-defined, inverse approximation of muscle activity. We first amalgamated previously published measurements of the physiological characteristics of the upper/lower arm and the biceps/triceps muscles. We then used the observed distributions of these measurements to set physiologically plausible boundaries on uniform distributions and then generated perturbed parameter sets. We computed the root mean squared error (RMSE) between muscle activity patterns generated by the perturbed model parameters to those generated by the original parameters. Regression models were fit to the RMSE of the approximated muscle activity patterns to determine the sensitivity of the simulation results to variation in each parameter. We found that variation in parameters associated with muscle physiology had the most effect on RMSE, suggesting that these parameters may require subject-specific scaling, whereas parameters associated with skeletal bodies had less effect, and might be safely approximated by their population means.
An Artificial Intelligence Framework for Optimal Drug Design
Authors: Ramey Grace , Vargas Santiago , De Alwis Dinesh , Alexandrova Anastassia N. , Distefano Joe , Bloomingdale Peter 
Published: November 2022

AbstractWe introduce the concept of optimal drug design (ODD) as the use of an AI framework to optimize the exposure, safety, and efficacy of drugs. To exemplify the concept of ODD, we developed an artificial intelligence framework that integrates de novo molecular design, quantitative structure activity relationships, and pharmacokinetic-pharmacodynamic modeling. Specifically, our computational architecture has integrated a generative algorithm for small molecule design with a hybrid physiologically-based pharmacokinetic machine learning (PBPK-ML) model, which was applied to generate and optimize drug candidates for enhanced brain exposure. Publicly sourced data on the plasma and brain pharmacokinetics of 77 small molecule drugs in rats was used for model development. We have observed an approximate 30-fold and 120-fold increase on average in predicted brain exposure for AI generated molecules compared to known central nervous system drugs and randomly selected small organic molecules. We believe that with additional data and mechanistic modeling this in silico pipeline could facilitate the discovery of a new wave of optimally designed medicines for the treatment of CNS diseases.Graphical AbstractArtificial Intelligence Framework for the Optimization of Brain Pharmacokinetics.A genetic algorithm consisting of cross-breeding, mutating, scoring, and refining was used for de novo generation of a population of new molecular structures. SELFIE representations of molecules were used as input to a variational autoencoder for de novo generation/refinement of individual drug candidates. Molecular descriptors of individual drug candidates are generated and used as input into a trained neural network to generate drug-specific pharmacokinetic (PK) parameters. PK parameters are used as input into a physiologically-based pharmacokinetic (PBPK) model of the brain to predict brain PK of the drug candidate. Brain concentration-time profiles are integrated to obtain an area-under the curve (AUC), a metric of brain exposure, which is used to score and inform the design of new generations of molecules. Iterations of this framework generate novel drug candidates optimized for greater brain exposure. Created with BioRender.
Evolutionary Innovation by Polyploidy
Authors: Hatakeyama Tetsuhiro S. , Ohbayashi Ryudo 
Published: November 2022

AbstractThe preferred conditions for evolutionary innovation is a fundamental question, but little is known, in part because the question involves rare events. We focused on the potential role of polyploidy in the evolution of novel traits. There are two hypotheses regarding the effects of polyploidy on evolution: Polyploidy reduces the effect of a single mutation and slows evolution. In contrast, the gene redundancy introduced by polyploidy will promote neofunctionalization and accelerate evolution. Does polyploidy speed up or slow down evolution? In this study, we proposed a simple model of polyploid cells and showed that the evolutionary rate of polyploids is similar to or much slower than that of haploids under neutral selection or during gradual evolution. However, on a fitness landscape where cells should jump over a lethal valley to increase their fitness, the probability of evolution in polyploidy could be drastically increased, and the optimal number of chromosomes was identified. We theoretically discussed the existence of this optimal chromosome numbers from the large deviation theory. Furthermore, we proposed that the optimization for achieving evolutionary innovation could determine the range of chromosome number in polyploid bacteria.
The impact of the COVID-19 pandemic on the reporting of violence against children
Authors: dos Santos Souza Andrade Camila , Nascimento Costa Maria da Conceição , Alves Bonfim Trad Leny , Santos da Natividade Marcio , dos Santos de Jesus Eliene , Oliveira de Carvalho-Sauer Rita de Cássia 
Published: November 2022

ABSTRACTObjectiveTo verify the impact (effect) of the COVID-19 pandemic on the rates of reporting of interpersonal violence against children aged 0-11 years old in Salvador, Bahia, from 2020 to 2021.MethodsThe study used two epidemiological approaches: a) temporal aggregation and b) an individual cross section, based on cases of interpersonal violence against children reported in SINAN from 2009 to 2021. Annual rates of reporting of interpersonal violence against children (per 10,000) and percentages were calculated according to different strata of each variable of interest. The temporal trend was analyzed using the simple linear regression method (R2=0.6955) applied to the rates from 2014 to 2019, the period in which they showed the most consistency.ResultsThe rates of reporting of violence against children showed a large variation, with a mean of 4.7/10,000. In 2021, the rate was 7/10,000 (a 45.8% increase on the previous year). Regression analysis indicated a mean reduction of 0.337/10,000 a year, and expected rates of 4.62 and 4.28/10,000, respectively, for 2020 and 2021.ConclusionThe occurrence of COVID-19 and, particularly, the increase in the number of reported cases of interpersonal violence against children in the second year of the pandemic in Bahia suggest that these events may be directly or indirectly related. More robust studies are needed to confirm this relationship.
Communicating sickle cell trait results after newborn screening: Approaches and implications to families
Authors: Bukini Daima , Msirikale Irene , Marco Emanuela , Msangawale Michael , Chirande Lulu , Mbekenga Columba , Manji Karim , Makani Julie 
Published: November 2022

AbstractIntroductionTanzania is amongst the countries in Africa with one of the highest prevalence of individuals with Sickle Cell Trait (SCT). Identifying individuals with SCT is important as they may potentially have children with Sickle Cell Disease (SCD). Interventions such as Newborn Screening (NBS) for SCD can identify individuals carrying the gene very early on to explore strategies for primary prevention.AimThis study aims to document experiences and perspectives of families who have received SCT results for their children through the NBS Program. We were interested to learn their perspectives on the communication approaches used and implications of the results to families. Our overall goal is to evaluate what approaches works best to support comprehension, understanding of genetic testing, concepts of inheritability and general understanding of SCD. We further aim to explore key issues considered by families as most important to inform not only methods, but also most locally relevant content to guide genetic counselling sessions.MethodsIn total 29 families provided with SCT results participated in six (6) Focus Group Discussions. Families were recruited through NBS program implemented between June to September 2021. Analysis of the data was done through thematic content analysis.ResultsFindings were categorized into two main categories; (1) Key issues to consider when communicating sickle cell trait results to families. The following themes were identified under this category; (1a) Language used to explain the results (1b) Methods used to provide the results (1c) Who was provided with the results (1d) Families comprehension of the results and (1e) What influences families’ understanding of the results(2) What are the implications of the results to families. The following themes were identified under this category; (2a) How results influenced future reproductive choices (2b) How will the information be kept within families (2c) Age a child will start to be informed about the results (2d) How results influence gender blames within families.ConclusionUnderstanding how to ensure genetic results have been properly communicated is core in developing a genetic counselling program. In places where the programs are not well established, there is a need to explore contexts specific approaches to inform ethically relevant communication models that incorporated families and patient perspectives. This study un-packed the different aspects to consider when developing proper communication models and further highlighted issues to explore with families after receiving the results, with the hope that this information will help to inform genetic counselling sessions in places with high SCD burden.
3D Spheroid Primary Human Hepatocytes for Prediction of Cytochrome P450 and Drug Transporter Induction
Authors: Järvinen Erkka , Hammer Helen S. , Pötz Oliver , Ingelman-Sundberg Magnus , Stage Tore B. 
Published: November 2022

ABSTRACTPrimary human hepatocytes (PHHs) have been the gold standardin vitromodel for the human liver and are crucial to predict hepatic drug-drug interactions. The aim of this work was to assess the utility of 3D spheroid PHHs to study induction of important cytochrome P450 (CYP) enzymes and drug transporters. 3D spheroid PHHs from three different donors were treated for four days with rifampicin, dicloxacillin, flucloxacillin, phenobarbital, carbamazepine, efavirenz, omeprazole or β-naphthoflavone. Induction of CYPs 1A1, 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, P-gp/ABCB1, MRP2/ABCC2, ABCG2, OCT1/SLC22A1, SLC22A7, SLCO1B1andSLCO1B3were evaluated at mRNA and protein levels. Enzyme activity of CYP3A4, CYP2B6, CYP2C19 and CYP2D6 were also assessed. Induction of CYP3A4 protein and mRNA correlated well for all donors and compounds and had a maximal induction of 5-to 6-fold for rifampicin, which closely correlates to induction observed in clinical studies. Similar estimates were found for dicloxacillin and flucloxacillin, which also correlates to findings from clinical studies. Rifampicin induced the mRNA ofCYP2B6andCYP2C8by 9- and 12-fold, while the protein levels of these CYPs reached 2- and 3-fold induction, respectively. Rifampicin induced CYP2C9 protein by 1.4-fold, while the induction of CYP2C9 mRNA was over 2-fold in all donors. Rifampicin inducedABCB1,ABCC2andABCG2by 2-fold. In conclusion, 3D spheroid PHHs is a valid model to investigate mRNA and protein induction of hepatic drug metabolizing enzymes and transporters, and this model provides a solid basis to study induction of CYPs and transporters, which translates to clinical relevance.
Openness to experience is associated with neural and performance measures of memory in older adults
Authors: Stolz Christopher , Bulla Ariane , Soch Joram , Schott Björn H. , Richter Anni 
Published: November 2022

AbstractAge-related decline in episodic memory performance is a well-replicated finding across numerous studies. Recent studies focusing on aging and individual differences found that the Big Five personality trait Openness to Experience is associated with better episodic memory performance in older adults, but the associated neural mechanisms are largely unclear. Here we investigated the relationship between Openness and memory network function in a sample of 352 participants (143 older adults, 50-80 years; 209 young adults, 18-35 years). Participants underwent functional magnetic resonance imaging (fMRI) during a visual memory encoding task. Functional memory brain-network integrity was assessed using the SAME scores (similarity of activations during memory encoding), which reflect the similarity of a participant’s memory network activity compared to prototypical fMRI activity patterns of young adults. Openness was assessed using the NEO Five Factor Inventory (NEO-FFI). Older vs. young adults showed lower memory performance and higher deviation of fMRI activity patterns (i.e., lower SAME scores). Specifically in older adults, high Openness was associated with better memory performance, and mediation analysis showed that this relationship was partially mediated by higher SAME scores. Our results suggest that trait Openness may constitute a protective factor in cognitive aging by better preservation of the brain’s memory network.
Non-random mating between nesting sites of Hawaiian hawksbill turtles: demographic discontinuity within a small isolated population
Authors: Horne John B. , Frey Amy , Gaos Alexander R. , Martin Summer , Dutton Peter H. 
Published: November 2022

AbstractHawksbill sea turtles (Eretmochelys imbricata) from the Hawaiian archipelago form a small, genetically isolated, population consisting of only a few tens of individuals breeding annually. Most females nest on the island of Hawai’i, but little is known about the demographics of this rookery. This study used genetic relatedness, inferred from 135 microhaplotype markers, to determine breeding sex-ratios, estimate female nesting frequency, and assess relationships between individuals nesting on different beaches. Samples were collected during the 2017 nesting season and final data included 13 nesting females and 1,002 unhatched embryos, salvaged from 41 nests, 13 of which had no observed mother. Results show that most females used a single nesting beach laying 1-5 nests each. From female and offspring alleles the paternal genotypes of 12 breeding males were reconstructed and many showed high relatedness to their mates. Pairwise relatedness of offspring revealed one instance of polygyny but otherwise suggest a 1:1 breeding-sex ratio. Relatedness analysis and spatial-autocorrelation of genotypes indicate non-random mating among complexes of nesting beaches, for both sexes, suggesting strong natal philopatry. Nesting complexes also showed unique patterns of inbreeding and outbreeding across loci, further indicating that Hawaiian hawksbill turtles have demographically discontinuous nesting populations at a fine spatial scale.
Zic3 enables bimodal regulation of tyrosine hydroxylase expression in dopaminergic neurons of olfactory bulb and midbrain
Authors: Bhaskar Smitha , Gowda Jeevan , Hegde Akshay , Rao Thumu Surya Chandra , Ramanan Narendrakumar , Prasanna Jyothi , Kumar Anujith 
Published: November 2022

AbstractDopaminergic (DA) neurons in the Olfactory bulb (OB) are involved in odor detection and discrimination. Transcription factor (TF) regulatory network responsible for their fate specification remains poorly understood and the spatial regulation of DA neurons remains elusive. In this study, mice exposed to odor stimulant exhibited specific upregulation of Zinc finger transcription factor of Cerebellum (ZIC) 3 along with Tyrosine Hydroxylase (TH). Stringent co-expression analysis showed ZIC3 and TH dual positive neurons in OB. Genetic manipulation showed ZIC3 to be both essential and sufficient to drive TH expression and essential for odor perception. ZIC3 interacts with ER81 and binds to region encompassing ER81 binding site in DA neurons and is indispensable for TH expression. In midbrain (MB), in the absence of ER81, ZIC3 switches its molecular partner and binds toPitx3promoter-a DA fate determinant. Under ectopic expression of ER81 in MB DA neurons, propensity of ZIC3 binding toPitx3promoter is compromised and its occupancy onThpromoter encompassing ER81 binding site is established, finally culminating in desired TH expression. Together, these findings reveal a unique ZIC3 mediated bimodal regulation of TH in OB and MB to ultimately facilitate DAergic fate.
Preservation of Conditioned Behavior Based on UV Light Sensitivity in Dissected Tail Halves of Planarians- a Proof by DNN
Authors: Shimojo Kensuke , Shimojo Eiko , Katsuragi Reiya , Akashi Takuya , Shimojo Shinsuke 
Published: November 2022

AbstractPlanarians are aquatic worms with powerful regenerative and memory retention abilities. This paper examines whether a dissected tail half of a Planarian (Dugesia Dorotocephala) can retain and exhibit a previously-conditioned response, possibly before the regeneration of the head and the ganglia. We conditioned intact Planarians in a Pavlovian procedure with an electric shock (ES) as the unconditioned stimulus and weak ultraviolet (UV) light as the conditioned stimulus. Then, we dissected their bodies into halves, keeping the dissected tail halves. Starting from the 2nd day after dissection, we presented the same UV light 3 times daily while video-recording the responses. The recorded responses were then classified by a DNN: a VGG16 model was pre-trained by ImageNet for extracting features from images and additionally trained with 211 responses to ES and 118 to UV light before conditioning/dissection to categorize planarians’ reactions into “UV-induced” or “ES-induced” reactions. The cross-validated accuracy in categorization was 83.6%. We then let the DNN analyze 99 recorded responses to UV from 20 individual conditioned tail halves. 96.8 % of their reactions were classified as “ES-induced” (against 22.0% wrongly classified as “ES-induced” for unconditioned samples under UV), indicating they have shown the “Conditioned Response” (p<3.06E-30). This provides evidence that planarians can conserve and reveal a learned response even without the head/ganglia, as it takes approximately 7 days for the head/ganglia to regenerate versus the given 2-3 days. Although similar findings have been reported repeatedly in the literature, this is the first positive evidence with automated procedures and DNN classification. The result implies the presence of a decentralized nervous structure outside of its head/ganglia that allows a tail half to retain memory and execute motion accordingly, despite their cephalization.
Falign: An effective alignment tool for long noisy 3C data
Authors: Chen Ying , Lin Zhuo-Bin , Niu Long-Jian , Zhong Jia-Yong , Liu Yi-Zhi , Hou Chun-Hui , Luo Feng , Xiao Chuan-Le 
Published: November 2022

AbstractFragmented long noisy reads (FLNRs), such as Pore-C, contain multiple fragments of varied length separated by restriction enzyme sites. Existing alignment tools have a low mapping rate for short fragments and find incorrect fragment boundaries, which affects the utilization of FLNRs for downstream studies. Here, we develop Falign, a sequence alignment method that is adapted to the nature of FLNRs. Falign adopts a two-phase approach to efficiently align both long and short fragments. Falign uses the restriction enzyme sites on the reference genome as boundaries, which avoids the problem of destroyed fragment boundaries on FLNRs. Falign employs a multiple-stage searching mechanism to effectively recover the alignments of FLNRs with multiple fragments and interchromosomal fragments. Experiments on simulated and experimental fragmented long noisy 3C datasets show that Falign can effectively recover the constructs of reads and the sampled loci of the fragments. Falign allows significantly higher data utilization for FLNRs.
TRPA1 activation in non-sensory supporting cells contributes to regulation of cochlear sensitivity after acoustic trauma
Authors: Vélez-Ortega A. Catalina , Stepanyan Ruben , Edelmann Stephanie E. , Torres-Gallego Sara , Park Channy , Marinkova Desislava A. , Nowacki Joshua S. , Sinha Ghanshyam P. , Frolenkov Gregory I. 
Published: November 2022

ABSTRACTTRPA1 channels are expressed in nociceptive neurons, where they detect noxious stimuli, and in the mammalian cochlea, where their function is unknown. Here we show that TRPA1 activation in the supporting non-sensory Hensen’s cells causes prolonged Ca2+responses, which propagate across the organ of Corti and cause long-lasting contractions of pillar and Deiters’ cells. Caged Ca2+experiments demonstrated that, similar to Deiters’ cells, pillar cells also possess Ca2+-dependent contractile machinery. TRPA1 channels are activated by endogenous products of oxidative stress and by extracellular ATP. Since both these stimuli are presentin vivoafter acoustic trauma, TRPA1 activation after noise may affect cochlear sensitivity through supporting cell contractions. Consistently, TRPA1 deficiency results in larger but less prolonged noise-induced temporary shift of hearing thresholds, accompanied by permanent changes of latency and shape of the auditory brainstem responses. We conclude that TRPA1 contributes to the regulation of cochlear sensitivity after acoustic trauma.
Composition, structure and robustness of Lichen guilds
Authors: Duran-Nebreda Salva , Valverde Sergi 
Published: November 2022

ABSTRACTSymbiosis is a major engine of evolutionary innovation underlying the many extant complex organisms. Lichens are a paradigmatic example that offers a unique perspective on the role of symbiosis in ecological success and evolutionary diversification. Lichen studies have produced a wealth of information regarding the importance of symbiosis in many different species, but they frequently focus on a few species, limiting our understanding of large-scale phenomena such as guilds. Guilds are groupings of lichens that assist each other’s proliferation and are intimately linked by a shared set of photobionts, constituting an extensive network of relationships. To characterize the network of lichen symbionts, we used a large data set (n= 206 publications) of natural photobiont-mycobiont associations. The entire lichen network was found to be modular, but this organization does not replicate taxonomic information in the data set, prompting a reconsideration of lichen guild structure and composition. The characteristic scale of effective information reveals that the major lichen guilds are better represented as clusters with several substructures rather than as monolithic communities. Heterogeneous guild structure fosters robustness, with keystone species functioning as bridges between guilds and whose extinction would endanger global stability.
Robust expression of transgenes inDrosophila melanogaster
Authors: Lidsky Peter V. , Dmitriev Sergey E. , Andino Raul 
Published: November 2022

AbstractDrosophilais a classic experimental system used in fundamental and biopharmaceutical research. Manipulating gene expression in the larvae and adult flies can facilitate basic and translational studies. Here we report a method for robust transgene overexpression inDrosophila melanogaster.This approach is compatible with the UAS/Gal4 gene expression system. The improved expression involves a gene expression cassette that prevents transgenic mRNA transcript degradation by the nonsense-mediated RNA decay pathway. The protection is mediated by CrPV and DCV IRES sequences that apparently encode cryptic polyadenylation sites and NMD inhibitors. Stabilization of the transgene mRNA results in a >40-fold increase in its levels.