bluuebunny/crossref_metadata_2025 huggingface dataset:
Variability and Impact of Musculoskeletal Modeling Parameters for the Human Elbow
Authors: Hardesty Russell , Jeong Byeongchan , Gemoets Darren E.
Published: November 2022

Musculoskeletal 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

We 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 Abstract

Artificial 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

The 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

Objective

To 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.

Methods

The 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.

Results

The 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.

Conclusion

The 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

Introduction

Tanzania 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.

Aim

This 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.

Methods

In 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.

Results

Findings 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.

Conclusion

Understanding 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

Primary 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

Age-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

Hawksbill 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

Dopaminergic (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

Planarians 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

Fragmented 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

TRPA1 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

Symbiosis 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

Drosophilais 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.
Influence of Diphenyl Diselenide on Thiol Redox Homeostasis and Electrogenic Membrane Transport in Rotenone-Induced Parkinson’s Disease
Authors: Ologunagba Titilayo Ibironke , Olorundare Bunmi Olaoluwa , Iyanda Titilope , Adewole Adenike , Kade Ige Joseph
Published: November 2022

The central role of oxidative stress in the etiology of Parkinsons disease defines a key therapeutic role for antioxidant compounds in the management of the disease. Redox-sensitive proteins such as the Na+/K+-ATPase have also been implicated as one of the targets of oxidative stress. The present study sought to investigate the role of diphenyl diselenide (DPDSe) in amelioration of disturbed redox homeostasis and modulation of enzyme activity caused by rotenone administration to Wistar albino rats. In determining the best route of rotenone administration, animals were grouped into four namely: control, oral, intraperitoneal (IP) and subcutanoeus (SC) and administered rotenone (3mg/kg) via oral, intraperitoneal (IP) and subcutaneous routes, with controls receiving the vehicle (2% DMSO + 98% normal saline (0.85%)). Having observed a more deleterious impact in the with he IP route, this mode of rotenone administration was selected along with oral administration of DPDSe (10mg/kg). this was done with four groups of animals namely: control, DPDSe, rotenone and DPDSe+rotenone. The effect of treatment was evaluated after seven days for total and non-protein thiol levels, lipid peroxidation and Na+/K+-ATPase activity. The result demonstrated the antioxidant potential of DPDSe in attenuating depletion of thiols, and lipid peroxidation caused by rotenone. It is apparent that DPDSe is a promising therapeutic agent in the management of PD, hence further investigations into its impact on different pathways is expedient in the search for an effective treatment for PD.

Highlights

Intraperitoneal administration of rotenone gives a comparatively faster development of Parkinson’s disease features in rodents

Rotenone mediates depletion of total and non-protein thiol levels in the pathogenesis of Parkinson’s disease

Diphenyl diselenide significantly attenuates thiol depletion and lipid peroxidation mediated by rotenone

Rotenone-mediated inactivation of Na+/K+-ATPase in Parkinson’s disease etiology may involve ATP depletion
System-wide mapping of neuropeptide-GPCR interactions inC. elegans
Authors: Beets Isabel , Zels Sven , Vandewyer Elke , Demeulemeester Jonas , Caers Jelle , Baytemur Esra , Schafer William R. , Vértes Petra E. , Mirabeau Olivier , Schoofs Liliane
Published: November 2022

Neuropeptides are ancient, widespread signaling molecules that underpin almost all brain functions. They constitute a broad ligand-receptor network, mainly by binding to G protein-coupled receptors (GPCRs). However, the organization of the peptidergic network and roles of many neuropeptides remain elusive, as our insight into neuropeptide-receptor interactions is limited and many peptide GPCRs in animal models and humans are still orphan receptors. Here we report a genome-wide neuropeptide-GPCR interaction map inC. elegans. By reverse pharmacology screening of over 55,384 possible interactions, we identify 461 cognate peptide-GPCR couples that uncover a broad signaling network with specific and complex combinatorial interactions encoded across and within single peptidergic genes. These interactions provide insights into neuropeptide functions and evolution. Combining our dataset with phylogenetic analysis supports peptide-receptor co-evolution and conservation of at least 14 bilaterian peptidergic systems inC. elegans. This resource lays a foundation for system-wide analysis of the peptidergic network.

Highlights

System-wide reverse pharmacology deorphanizes 68C. eleganspeptide GPCRs

Discovery of 461 peptide-GPCR pairs and additional ligands for characterized GPCRs

Neuropeptides show specific and complex combinatorial receptor interactions

Peptide-GPCR pairs support long-range conservation and expansion of peptide systems
Chromosome fissions and fusions act as barriers to gene flow betweenBrenthisfritillary butterflies
Authors: Mackintosh Alexander , Vila Roger , Laetsch Dominik R. , Hayward Alex , Martin Simon H. , Lohse Konrad
Published: November 2022

Chromosome rearrangements are thought to promote reproductive isolation between incipient species. However, it is unclear how often, and under what conditions, fission and fusion rearrangements act as barriers to gene flow. Here we investigate speciation between two largely sympatric fritillary butterflies,Brenthis daphneand B. ino. We use a composite likelihood approach to infer the demographic history of these species from whole genome sequence data. We then compare chromosome-level genome assemblies of individuals from each species and identify a total of nine chromosome fissions and fusions. Finally, we fit a demographic model where effective population sizes and effective migration rate vary across the genome, allowing us to quantify the effects of chromosome rearrangements on reproductive isolation. We show that chromosomes involved in rearrangements experienced less effective migration since the onset of species divergence and that genomic regions near rearrangement points have a further reduction in effective migration rate. Our results suggest that the evolution of multiple rearrangements in theB. daphneandB. inopopulations, including alternative fusions of the same chromosomes, have resulted in a reduction in gene flow. While fission and fusion of chromosomes are unlikely to be the only processes that have led to speciation between these butterflies, this study shows that these rearrangements can directly promote reproductive isolation and may be involved in speciation when karyotypes evolve quickly.
Nucleocytoplasmic transport of active HER2 causes fractional escape from the DCIS-like state
Authors: Wang Lixin , Paudel B. Bishal , McKnight R. Anthony , Janes Kevin A.
Published: November 2022

Activation of HER2/ErbB2 coincides with escape from ductal carcinoma in situ (DCIS) premalignancy and disrupts 3D organization of cultured breast-epithelial spheroids. The 3D phenotype is infrequent, however, and mechanisms for its incomplete penetrance have been elusive. Using inducible HER2/ErbB2–EGFR/ErbB1 heterodimers, we matched phenotype penetrance to the frequency of co-occurring transcriptomic changes and uncovered a reconfiguration in the karyopherin network regulating ErbB nucleocytoplasmic transport. Induction of the exportin CSE1L inhibits nuclear accumulation of ErbBs, whereas nuclear ErbBs silence the importin KPNA1 by inducing miR-205. When these negative feedbacks are incorporated into a validated systems model of nucleocytoplasmic transport, steady-state localization of ErbB cargo becomes ultrasensitive to initial CSE1L abundance. Erbb2-driven carcinomas with Cse1l deficiency outgrow less irregularly from mammary ducts, and NLS-attenuating mutants or variants of HER2 favor escape in 3D culture. We conclude here that adaptive nucleocytoplasmic relocalization of HER2 creates a systems-level molecular switch at the premalignant-to-malignant transition.
Breast cancer progression and metastasis to lymph nodes reveals cancer cell plasticity and MHC class II-mediated immune regulation
Authors: Lei Pin-Ji , Pereira Ethel R. , Andersson Patrik , Amoozgar Zohreh , Van Wijnbergen Jan Willem , O’Melia Meghan , Zhou Hengbo , Chatterjee Sampurna , Ho William W. , Posada Jessica M. , Kumar Ashwin Srinivasan , Morita Satoru , Chung Charlie , Ergin Ilgin , Jones Dennis , Huang Peigen , Beyaz Semir , Padera Timothy P.
Published: November 2022

Tumor-draining lymph nodes are critical sites for generating tumor antigen-specific T cells and are associated with durable immune responses. However, lymph nodes are often the first site of metastasis and lymph node metastases portend worse outcomes. Through cross-species single cell gene expression analysis of breast cancer progression and metastasis to lymph nodes, we uncovered features that define the heterogeneity, plasticity, and immune evasion of cancer cells. Notably, a subpopulation of metastatic cancer cells in the lymph node were marked by high levels of MHC class II (MHC-II) gene expression both in mice and humans. Mechanistically, the IFN-γ and JAK/STAT signaling pathways mediate MHC-II expression in cancer cells. Ablation of IFNGR1/2 or CIITA, the transactivator of MHC-II, in cancer cells prevented tumor progression. Interestingly, MHC-II+ cancer cells lacked co-stimulatory molecule expression, engendered the expansion of regulatory T cells and blunted CD4+ effector T cells in the tumor-draining lymph nodes and favor tumor progression. Overall, our data suggests that cancer cell plasticity during breast cancer progression and metastasis to lymph nodes endows metastatic cells with the ability to avoid immune surveillance. These data provide the basis for new opportunities to therapeutically stimulate anti-cancer immune responses against local and systemic metastases.
Mouse behaviour on the trial-unique non-matching-to-location (TUNL) touchscreen task reflects a mixture of distinct working memory codes and response biases
Authors: Bennett Daniel , Nakamura Jay , Vinnakota Chitra , Sokolenko Elysia , Nithianantharajah Jess , van den Buuse Maarten , Jones Nigel C. , Sundram Suresh , Hill Rachel
Published: November 2022

The trial-unique non-matching to location (TUNL) touchscreen task shows promise as a translational assay of working memory deficits in disorders including autism, ADHD, and schizophrenia. Although it is commonly assumed that the TUNL task predominantly measures spatial working memory in rodents, this proposition has not previously been tested. In this project, we used computational modelling of behaviour from mice performing the TUNL task (totalN= 163 mice across three datasets; 158,843 total trials). Contrary to common assumptions, behaviour on the TUNL task did not exclusively reflect spatial working memory. Instead, choice behaviour was explained as a mixture of both retrospective (spatial) working memory and prospective working memory for an intended behavioural response, as well as animal-specific response biases. We suggest that these findings can be understood within a resource-rational cognitive framework, and propose several task-design principles that we predict will maximise spatial working memory and minimise alternative behavioural strategies.
Punishment Risk Task: Monitoring anxiogenic states during goal directed actions in mice
Authors: Parker Kyle E. , Arackal Joel S. , Hunter Sarah C. , Hammarsten Carl , McCall Jordan G.
Published: November 2022

Summary/Abstract

Canonical preclinical studies of anxiety-related behavioral states use exploration of novel spaces to test approach-avoidance conflicts such as the open field test, elevated plus maze, and light-dark box. However, these assays cannot evaluate complicated behaviors in which competing states of motivation result in anxiogenic behaviors. Furthermore, these assays can only test the approach-avoidance conflict once due to a reliance on spatial novelty. Here we demonstrate the punishment risk task (PRT) in male and female, group- and singly-housed mice, a model initially described in singly-housed male rats by Park and Moghaddam (2017). The task tests how probabilistic punishment affects reward-seeking behavior. In particular, it measures the delay to pursue a reward (sweetened food pellet) while the likelihood of punishment (foot shock) actively impinges reward-associated actions. Here, we found that mice show increased latency to respond to food reward cues in trials in which the probability of punishment is highest. Further, anxiolytic treatment with diazepam or propranolol block any increase in response latency, indicating the model’s potential to for study of anxiogenesis in mice. Elucidating how these competitive behavioral states are integral to adaptive behavior and change over time and experience to coordinate anxiogenesis should greatly benefit anxiety disorder research. Specifically, implementing this assay in mice will enable cell-type selective interrogation of these processes and further our understanding of the neural basis of anxiogenesis.
Unsupervised Clustering Applied to Electronic Health Record-derived Phenotypes in Patients with Heart Failure
Authors: Reza Nosheen , Yang Yifan , Bone William P. , Singhal Pankhuri , Verma Anurag , Denduluri Srinivas , Adusumalli Srinath , Ritchie Marylyn D. , Cappola Thomas P.
Published: November 2022

Background

High-dimensional electronic health records (EHR) data can be used to phenotype complex diseases. The aim of this study is to apply unsupervised clustering to EHR-based traits derived in a cohort of patients with heart failure (HF) from a large integrated health system.

Methods

Using the institutional EHR, we identified 8569 patients with HF and extracted 1263 EHR-based input features, including clinical, echocardiographic, and comorbidity data, prior to the time of HF diagnosis. Principal component analysis, Uniform Manifold Approximation and Projection, and spectral clustering were applied to the input features after sex stratification of the cohort. The optimal number of clusters for each sex-stratified group was selected by highest Silhouette score and by within-cluster and between-cluster sums of squares. Determinants of cluster assignment were evaluated.

Results

We identified four clusters in each of the female-only (44%) and male-only (56%) cohorts. Sex-specific cohorts differed significantly by age of HF diagnosis, left ventricular chamber size, markers of renal and hepatic function, and comorbidity burden (all p<0.001). Left ventricular ejection fraction was not a strong driver of cluster assignment.

Conclusion

Readily available EHR data collected in the course of routine care can be leveraged to accurately classify patients into major phenotypic HF subtypes using data driven approaches.
Negligible peptidome diversity of SARS-CoV-2 and its higher taxonomic ranks
Authors: Chong Li Chuin , Khan Asif M.
Published: November 2022

The unprecedented increase in SARS-CoV-2 sequence data limits the application of alignment-dependent approaches to study viral diversity. Herein, we applied our recently published UNIQmin, an alignment-free tool to study the protein sequence diversity of SARS-CoV-2 (sub-species) and its higher taxonomic lineage ranks (species, genus, and family). Only less than 0.5% of the reported SARS-CoV-2 protein sequences are required to represent the inherent viral peptidome diversity, which only increases to a mere ∼2% at the family rank. This is expected to remain relatively the same even with further increases in the sequence data. The findings have important implications in the design of vaccines, drugs, and diagnostics, whereby the number of sequences required for consideration of such studies is drastically reduced, short-circuiting the discovery process, while still providing for a systematic evaluation and coverage of the pathogen diversity.
Evaluation of GABAAR-mediated inhibition in the human brain using TMS-evoked potentials
Authors: Šulcová Dominika , Salatino Adriana , Ivanoiu Adrian , Mouraux André
Published: November 2022

GABAAreceptor (GABAAR) – mediated inhibition participates in the control of cortical excitability, and its impairment likely contributes to the pathologic excitability changes that have been associated with multiple neurological disorders. Therefore, there is a need for its direct evaluation in the human brain, and the combination of transcranial magnetic stimulation (TMS) and electroencephalography (EEG) might represent the optimal tool. TMS-evoked brain potentials (TEPs) capture the spread of activity across the stimulated brain network, and since this process at least partially depends on the GABAAR-mediated inhibition, TEPs may constitute relevant biomarkers of local GABAAergic function.

Here, we aimed to assess the effect of GABAARs activation using TEPs, and to identify TEP components that are sensitive to the state of GABAAergic inhibition. In 20 healthy subjects, we recorded TEPs evoked by sub- and supra-threshold stimulation of the primary motor cortex (M1), motor-evoked potentials (MEPs) and resting-state EEG (RS-EEG). GABAARs were activated (1) pharmacologically by oral administration of alprazolam compared to placebo within each subject, and (2) physiologically using a sub-threshold conditioning stimulus to characterize the effect of short-latency intracortical inhibition (SICI).

In supra-threshold TEPs, alprazolam suppressed the amplitude of components N17, N100 and P180, and increased component N45. The pharmacological modulation of N17 correlated with the change observed in MEPs and with the alprazolam-induced increase of lower β-band RS-EEG. Only a reduction of N100 and P180 was found in sub-threshold TEPs. TEP SICI manifested as a reduction of N17, P60 and N100, and its effect on N17 correlated with the alprazolam-induced N17 suppression and β increase. Our results indicate that N17 of supra-threshold TEPs could serve as a non-invasive biomarker of local cortical excitability reflecting the state of GABAAR-mediated inhibition in the sensorimotor network. Furthermore, the alprazolam-induced increase of β-band oscillations possibly corresponds to the increased inhibitory neurotransmission within this network.
A mesocorticolimbic signature of pleasure in the human brain
Authors: Kragel Philip A. , Treadway Michael T. , Admon Roee , Pizzagalli Diego A. , Hahn Emma C.
Published: November 2022

Pleasure is a fundamental driver of human behavior, yet its neural basis remains largely unknown. Rodent studies highlight opioidergic neural circuits connecting the nucleus accumbens, ventral pallidum, insula, and orbitofrontal cortex as critical for the initiation and regulation of pleasure, and human neuroimaging studies exhibit some translational parity. However, whether activation observed across these regions reflects a common, generalizable code for pleasure driven by opioidergic mechanisms remains unclear. Here we use pattern recognition techniques to develop a human functional magnetic resonance imaging signature of mesocorticolimbic activity unique to states of pleasure. In independent validation tests, we find this signature has high sensitivity to pleasant tastes and positive affect evoked by humor. The signature is spatially coextensive with mu-opioid receptor gene expression, and its response is attenuated by the opioid antagonist naloxone. These findings provide evidence of a basis for pleasure derived from primary and secondary rewards in humans that is distributed across brain systems, and suggest that similar mechanisms underlie hedonic impact across mammalian species.
Single cell CRISPR base editor engineering and transcriptional characterization of cancer mutations
Authors: Kim Heon Seok , Grimes Susan M. , Sathe Anuja , Lau Billy T. , Ji Hanlee P.
Published: November 2022

We developed a multiplexed single cell technology to genome engineer mutations, directly delineate their genotype among individual cells and determine each mutation’s transcriptional phenotype. This approach uses CRISPR base editors to introduce predesignated variants into a target gene. Long-read sequencing of the target gene’s transcript identifies the engineered mutations among individual cells. Simultaneously, we analyzed the transcriptome profile from the same set of cells by short-read sequencing. By integrating the two types of data, we determined the mutations’ genotype and expression phenotype at single cell resolution. Using cell lines, we engineered and evaluated the phenotype of more than 100TP53mutations. Based on the single cell gene expression, we classified the mutations as having a functionally significant phenotype versus the wild-type state. We validated these results on a subset of mutations using isolated clones analyzed with RNA-seq. Overall, we successfully demonstrated single cell mutation engineering and phenotypic assessment.
Developing an automated skeletal phenotyping pipeline to leverage biobank-level medical imaging databases
Authors: Cataldo-Ramirez Chelsea C. , Haddad David , Amenta Nina , Weaver Timothy D.
Published: November 2022

Objectives

Collecting skeletal measurements from medical imaging databases remains a tedious task, limiting the research utility of biobank-level data. Here we present an automated phenotyping pipeline for obtaining skeletal measurements from DXA scans and compare its performance to manually collected measurements.

Materials and Methods

A pipeline that extends and modifies the Advanced Normalization Tools (ANTs) framework was developed on 341 whole-body DXA scans of UK Biobank South Asian participants. A set of 10 measurements throughout the skeleton was automatically obtained via this process, and the performance of the method was tested on 20 additional DXA images by calculating percent error and concordance correlation coefficients (CCC) for manual and automated measurements. Stature was then regressed on the automated femoral and tibia lengths and compared to published stature regressions to further assess the reliability of the automated measurements.

Results

Based on percent error and CCC, the performance of the automated measurements falls into three categories: poor (sacral and acetabular breadths), variable (trunk length, upper thoracic breadth, and innominate height), and high (maximum pelvic aperture breadth, bi-iliac breadth, femoral maximum length, and tibia length). Stature regression plots indicate that the automated measurements reflect realistic body proportions and appear consistent with published data reflecting these relationships in South Asian populations.

Discussion

Based on the performance of this pipeline, a subset of measurements can be reliably extracted from DXA scans, greatly expanding the utility of biobank-level data for biological anthropologists and medical researchers.
Axon guidance pathways modulate neurotoxicity of ALS-associated UBQLN2
Authors: Kim Sang Hwa , Nichols Kye D. , Anderson Eric N. , Liu Yining , Ramesh Nandini , Jia Weiyan , Kuerbis Connor J. , Scalf Mark , Smith Lloyd M. , Pandey Udai Bhan , Tibbetts Randal S.
Published: November 2022

Mutations in the ubiquitin (Ub) chaperoneUbiquilin 2 (UBQLN2)cause X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) through unknown mechanisms. Here we show that aggregation-prone, ALS-associated mutants of UBQLN2 (UBQLN2ALS) trigger heat stress-dependent neurodegeneration in Drosophila. A genetic modifier screen implicated endolysosomal and axon guidance genes, including the netrin receptor, Unc-5, as key modulators of UBQLN2 toxicity. Reduced gene dosage ofUnc-5or its coreceptorDcc/frazzleddiminished neurodegenerative phenotypes, including motor dysfunction, neuromuscular junction defects, and shortened lifespan, in flies expressing UBQLN2ALSalleles. Induced pluripotent stem cells (iPSCs) harboring UBQLN2ALSknockin mutations exhibited lysosomal defects while inducible motor neurons (iMNs) expressing UBQLN2ALSalleles exhibited cytosolic UBQLN2 inclusions, reduced neurite complexity, and growth cone defects that were partially reversed by silencing of UNC5B and DCC. The combined findings suggest that altered growth cone dynamics are a conserved pathomechanism in UBQLN2-associated ALS/FTD.