bluuebunny/crossref_metadata_2025_split huggingface dataset:
ANDROMEDA by Prosilico Software Successfully Predicts Human Clinical Pharmacokinetics of 300 Drugs Out of Reach forIn VitroMethods
Authors: Fagerholm Urban , Hellberg Sven , Alvarsson Jonathan , Spjuth Ola 
Published: October 2022

AbstractIntroductionIn vitromeasurements and predictions of human clinical pharmacokinetics (PK) are sometimes hindered and made impossible due to factors such as extensive binding to materials, low methodological sensitivity and large variability.MethodsThe objective was to find compounds out of reach forin vitroPK-methods and (if possible) predict corresponding human clinical estimates using the ANDROMEDA by Prosilico software.In vitromethods selected for the investigation were human microsomes and hepatocytes for measuring and predicting intrinsic hepatic metabolic clearance (CLint), Caco-2 and Ralph Russ canine kidney cells (RRCK) cells for measuring apparent intestinal permeability (Papp) for prediction of fraction absorbed (fa), plasma for measurement and estimation of unbound fraction (fu), and water and buffers for measuring solubility (S) for prediction ofin vivodissolution potential (fdiss).Results and ConclusionAs many as 329 non-quantifiablein vitroPK-measurements for 300 compounds were found in the literature: 191 for CLint, 101 for Papp, 11 for fuand 26 for S. ANDROMEDA was successful in predicting all corresponding clinical PK-estimates for the selection of compounds with non-quantifiablein vitroPK, and predicted estimates (1.6-fold median prediction error; n=159) were generally in line with observedin vivodata and results/problems atin vitrolaboratories. Thus, ANDROMEDA is applicable for predicting human clinical PK for compounds out of reach for laboratory methods.
Sprague-Dawley rats differ in responses to medial perforant path paired pulse and tetanic activation as a function of sex and age
Authors: Walling Susan G. , Harley Carolyn W. , Martin Gerard M , Dutton Olivia DE , Burke Alexander T , Chirinos Ella A 
Published: October 2022

ABSTRACTNetwork plasticity in the medial perforant path (MPP) of adult (5-9 mo) and aged (18-20 mo) urethane-anesthetized male and female Sprague-Dawley rats was characterized. Paired pulses probed recurrent networks before and after a moderate tetanic protocol.Adult females exhibited greater EPSP-spike coupling suggesting greater intrinsic excitability than adult males. Aged rats did not differ in EPSP-spike coupling but aged females had larger spikes at high currents than males. Paired pulses suggested lower GABA-B inhibition in females.Absolute population spike measures were larger post-tetani in female rats than male rats. Relative population spike increases were greatest in adult males relative to females and to aged males. EPSP slope potentiation was detected with normalization in some post-tetanic intervals for all groups except aged males. Tetani shortened spike latency across groups.Tetani-associated NMDA-mediated burst depolarizations were larger for the first two trains in each tetanus in adult males than other groups. EPSP slopes over 30 min post-tetani predicted spike size in female rats, but not in males.Replicating newer evidence MPP plasticity in adult males was mediated by increased intrinsic excitability. Female MPP plasticity was related to synaptic drive increases, not excitability increases. Aged male rats were deficient in MPP plasticity.
Ketone body metabolism declines with age in mice in a sex-dependent manner
Authors: Eap Brenda , Nomura Mitsunori , Panda Oishika , Garcia Thelma Y , King Christina D , Rose Jacob P , Leone Teresa C , Kelly Daniel P , Schilling Birgit , Newman John C 
Published: October 2022

AbstractUnderstanding how our cells maintain energy homeostasis has long been a focus of aging biology. A decline in energy metabolism is central to many age-related diseases such as Alzheimer’s disease, heart failure, frailty, and delirium. Intervening on pathways involved in energy homeostasis can extend healthy lifespan. When the primary energy substrate glucose is scarce, mice and humans can partially switch cellular energetic needs to fat-derived ketone bodies (i.e., beta-hydroxybutyrate (BHB), acetoacetate, acetone). Aging is associated with glucose intolerance and insulin insensitivity, yet, surprisingly, what role ketone body metabolism might play in compensating for impaired glucose utilization in age-related diseases is understudied. Here, we investigate how endogenous ketone body production and utilization pathways are modulated by age across the lifespan of male and female C57BL/6N mice (3 mo old, 12 mo old, 22 mo old). We show how different ages have different metabolic and gene expression responses to 1-week ketogenic diet (KD). We hypothesized that there would be a compensatory ketogenic response with age but instead saw declines in plasma BHB concentrations under fasting and non-fasting conditions with strong sexual dimorphism. Under KD, both sexes increased BHB concentrations at all ages, but only males showed strong gene expression induction. We also observed tissue-specific changes with age in baseline ketone metabolism, and surprising induction of extrahepatic ketogenic genes under KD. We found significant residual blood concentrations of BHB in KD even after a knockout of liver BHB production. Overall, these findings show that older mice have impaired non-fasting ketogenesis but are capable of increasing their ketogenic capacity under stimulation (i.e., KD) to meet energetic demands in aging. Therapies to augment non-fasting ketogenesis or provide exogenous ketones may be useful to improve energy homeostasis in diseases and conditions of aging.
LapTrack: Linear assignment particle tracking with tunable metrics
Authors: Fukai Yohsuke T. , Kawaguchi Kyogo 
Published: October 2022

MotivationParticle tracking is an important step of analysis in a variety of scientific fields, and is particularly indispensable for the construction of cellular lineages from live images. Although various supervised machine learning methods have been developed for cell tracking, the diversity of the data still necessitates heuristic methods that require parameter estimations from small amounts of data. For this, solving tracking as a linear assignment problem (LAP) has been widely applied and demonstrated to be efficient. However, there has been no implementation that allows custom connection costs, parallel parameter tuning with ground truth annotations, and the functionality to preserve ground truth connections, limiting the application to datasets with partial annotations.ResultsWe developed LapTrack, a LAP-based tracker which allows including arbitrary cost functions and inputs, parallel parameter tuning, and ground-truth track preservation. Analysis of real and artificial datasets demonstrates the advantage of custom metric functions for tracking score improvement. The tracker can be easily combined with other Python-based tools for particle detection, segmentation, and visualization.Availability and implementationLapTrack is available as a Python package on PyPi, and the notebook examples are shared athttps://github.com/yfukai/laptrack. The data and code for this publication are hosted athttps://github.com/NoneqPhysLivingMatterLab/laptrack-optimization.Contactysk@yfukai.net
Direct estimation of genome mutation rates from pedigrees in free-ranging baleen whales
Authors: Suárez-Menéndez Marcos , Bérubé Martine , Furni Fabrício , Rivera-León Vania E. , Heide-Jørgensen Mads-Peter , Larsen Finn , Sears Richard , Ramp Christian , Eriksson Britas Klemens , Etienne Rampal S. , Robbins Jooke , Palsbøll Per J. 
Published: October 2022

AbstractCurrent low germline mutation rate (μ) estimates in baleen whales have greatly influenced research ranging from assessments of whaling impacts to evolutionary cancer biology. However, the reported rates were subject to methodological errors and uncertainty. We estimated μ directly from pedigrees in natural populations of four baleen whale species and the results were similar to primates. The implications of revised μ values include pre-exploitation population sizes at 14% of previous genetic diversity-based estimates and the conclusion that μ in itself is insufficient to explain low cancer rates in gigantic mammals (i.e., Peto’s Paradox). We demonstrate the feasibility of estimating μ from whole genome pedigree data in natural populations, which has wide-ranging implications for the many ecological and evolutionary inferences that rely on μ.
Environmental transcriptomics under heat stress: Can environmental RNA reveal changes in gene expression of aquatic organisms?
Authors: Hechler Robert M. , Yates Matthew C. , Chain Frédéric J. J. , Cristescu Melania E. 
Published: October 2022

AbstractTo safeguard biodiversity in a changing climate, we require taxonomic information about species turnover and insights into the health of organisms. Environmental DNA approaches are increasingly used for species identification, but cannot provide functional insights. Transcriptomic methods reveal the physiological states of macroorganisms, but are currently species specific and require tissue sampling or animal sacrifice, making community-wide assessments challenging. Here, we test if broad functional information (expression level of the transcribed genes) can be harnessed from environmental RNA (eRNA), which includes extra-organismal RNA from macroorganisms along with whole microorganisms. We exposedDaphnia pulexas well as phytoplankton prey and microorganism colonizers to control (20 °C) and heat stress (28 °C) conditions for seven days. We sequenced eRNA from tank water (after complete removal ofDaphnia) as well as RNA fromDaphniatissue, enabling comparisons of extra-organismal and organismal RNA based gene expression profiles. Both RNA types detected similar heat stress responses ofDaphnia. Using eRNA, we identified 32Daphniagenes to be differentially expressed following heat stress. Of these, 17 were also differentially expressed and exhibited similar levels of relative expression in organismal RNA. In addition to the extra-organismalDaphniaresponse, eRNA detected community-wide heat stress responses consisting of distinct functional profiles and 121 differentially expressed genes across 8 taxa. Our study demonstrates that environmental transcriptomics based on eRNA can non-invasively reveal gene expression responses of macroorganisms following environmental changes, with broad potential implications for the biomonitoring of ecological health across the trophic chain.
Nicotine enhances intravenous self-administration of cannabinoids in adult rats
Authors: Stringfield Sierra J. , Sanders Bryson E. , Suppo Jude A. , Sved Alan F. , Torregrossa Mary M. 
Published: October 2022

ABSTRACTIntroductionNicotine and cannabis are commonly used together, yet few studies have investigated the effects of concurrent administration of both drugs. Nicotine exhibits reinforcement enhancing effects by promoting the reinforcing properties of stimuli including other drugs. As many studies of this effect have used non-contingent nicotine, we implemented a dual-self-administration model where rats are given simultaneous access to two drugs and choose which to self-administer throughout a session. Here, we investigated the effect of self-administered or non-contingently delivered nicotine on cannabinoid self-administration.MethodsAdult male rats were allowed to self-administer the synthetic cannabinoid WIN 55,212-2 (WIN) intravenously, with or without subcutaneous nicotine injections before each session. A separate group of animals were allowed to self-administer WIN, nicotine, or saline using a dual-catheter procedure, where each solution was infused independently and associated with a separate operant response. A third group of male and female rats were allowed to self-administer delta-9-tetrahydrocannabinol (THC) with or without pre-session injections of nicotine.ResultsNicotine injections increased self-administration of WIN and THC. During dual self-administration, nicotine availability increased saline and WIN infusions but nicotine intake was not changed by WIN or saline availability. Rats preferred nicotine over saline, but preferred nicotine and WIN equally when both were available. The effect of nicotine on cannabinoid self-administration was acute and reversible when nicotine was no longer present.ConclusionsThese results expand our understanding of the ability of nicotine to enhance reinforcement of other drugs of abuse and suggest that co-use of nicotine and cannabinoids promotes cannabinoid use in excess of what would be taken alone.ImplicationsThis study utilizes a dual intravenous self-administration model to investigate the ability of nicotine to enhance cannabinoid intake. Our results demonstrate that the reinforcement enhancing properties of nicotine on drug use extend to include cannabinoids, but that this effect occurs specifically when nicotine is administered alongside the cannabinoid. Interestingly, cannabinoid use did not promote nicotine intake, suggesting this mechanism of reinforcement is specific to nicotine.
A switch in jaw form-function coupling during the evolution of mammals
Authors: Tseng Z. Jack , Garcia-Lara Sergio , Flynn John J. , Holmes Emily , Rowe Timothy B. , Dickson Blake V. 
Published: October 2022

AbstractThe evolutionary shift from a single-element ear, multi-element jaw to a multi-element ear, single-element jaw during the transition to crown mammals marks one of the most dramatic structural transformations in vertebrates. Research on this transformation has focused on mammalian middle-ear evolution, but a mandible comprised of only the dentary is equally emblematic of this evolutionary radiation. Here we show that the remarkably diverse jaw shapes of crown mammals are coupled with surprisingly stereotyped jaw stiffness. This strength-based morphofunctional regime has a genetic basis and allowed mammalian jaws to effectively resist deformation as they radiated into highly disparate forms with markedly distinct diets. The main functional consequences for the mandible of decoupling hearing and mastication were a trade-off between higher jaw stiffness versus decreased mechanical efficiency and speed compared to non-mammals. This fundamental and consequential shift in jaw form-function underpins the ecological and taxonomic diversification of crown mammals.
Indigenous Cultural Safety Training for Applied Health, Social Work and Education Professionals: A PRISMA Scoping Review
Authors: MacLean Tammy , Qiang Jinfan , Henderson Lynn , Bowra Andrea , Howard Lisa , Pringle Victoria , Butsang Tenzin , Rice Emma , Di Ruggiero Erica , Mashford-Pringle Angela 
Published: October 2022

ABSTRACTBackgroundAnti-Indigenous racism is a widespread social problem in health, social work, and education systems in English-speaking Colonized countries such as Canada, with profound negative impacts to the health and education of Indigenous peoples. In 2015, Canada’s Truth and Reconciliation Commission recognized the legacy and impact of Colonization and recommended training programs for these professions on cultural competency and curricula, and on the colonial history of Canada. Yet there is little evidence on best practices for such training, highlighting the need to synthesize existing findings on how these training programs are developed, implemented, and evaluated.MethodsThis scoping review explored the academic literature on Indigenous cultural safety and competence training in the health, social work, and education fields. Medline, EMBASE, CINAHL, ERIC and ASSIA were searched for articles published between 1996-2020 in Canada, United States, Australia, and New Zealand. The Joanna Briggs Institute’s three-step search strategy was used as was the PRISMA extension for Scoping Reviews. Data was charted and synthesized in three stages.Results134 were included in this review. Data was extracted on four themes: 1) Article Characteristic; 2) Cultural Safety Concepts, Critiques and Rationale; 3) Characteristics of Cultural Safety Training; and 4) Evaluation Details of Cultural Safety Training. Findings suggest that research on cultural safety training programs in health, social work and education has grown significantly. Nursing and medicine professions have received a significant proportion of cultural training programs, compared with general/allied health, social work, and education. Across fields, professionals and students were targeted equally by training programs. Only half of evaluations of cultural safety and related intervention identified methodological limitations.ImplicationsConsidering, comparing, and contrasting literature on cultural safety and related concepts and how they are applied in practice would advance this scholarly work, as would more robust evaluations of cultural safety and similar training interventions to understand their impact at the individual level. Finally, commitment to meaningfully engage Indigenous communities to develop, implement and evaluate such programs is urgently needed.
Effects of high pCO2on snow crab larvae: Carryover effects from embryogenesis and oogenesis reduce direct effects on larval survival
Authors: Long W. Christopher , Swiney Katherine M. , Foy Robert J. 
Published: October 2022

AbstractOcean acidification, a decrease in ocean pH with increasing anthropogenic CO2concentrations, is expected to affect many marine animals. We determined the effects of ocean acidification on the economically important snow crab,Chionoecetes opilio. By holding females in treatment pH for two brooding cycles and using the resulting larvae, we assessed carryover effects from oogenesis and embryogenesis. Ovigerous females were held at three pHs: ~8.1 (Ambient), 7.8, and 7.5. Larvae were exposed to the same pH treatments in a fully crossed experimental design. Starvation-survival, morphology, condition, and calcium/magnesium content were assessed for larvae. In the first year, starvation-survival of larvae reared at ambient pH but hatched from embryos reared at reduced pH was lowered; however, the negative effect was eliminated when the larvae were reared at reduced pH. In the second year, there was no direct effect of either embryo or larval pH treatment, but larvae reared as embryos at reduced pH survived longer if reared at reduced pH. Larvae hatched from embryos held at pH 7.5 had lower calcium content right after hatching, but the effect was transitory in the second year. There was no effect of larval treatment on calcium content or effect of embryo or larval treatment on magnesium content. Larval morphometrics were slightly altered, though effect sizes were small smaller in the second year. These results suggest both that larvae are highly tolerant of reduced pH, and that embryos are able to acclimate to low pH and this effect carries over to the larval stage.
Host body size, not host population size, predicts genome-wide effective population size of parasites
Authors: Doña Jorge , Johnson Kevin P. 
Published: October 2022

AbstractThe effective population size (Ne) of an organism is expected to be generally proportional to the total number of individuals in a population. In parasites, we might expect the effective population size to be proportional to host population size and host body size, because both are expected to increase the number of parasite individuals. However, among other factors, parasite populations are sometimes so extremely subdivided that high levels of inbreeding may distort these predicted relationships. Here, we used whole-genome sequence data from dove parasites (71 feather louse species of the genusColumbicola) and phylogenetic comparative methods to study the relationship between parasite effective population size and host population size and body size.We found that parasite effective population size is largely explained by host body size but not host population size. These results suggest the potential local population size (infrapopulation or deme size) is more predictive of the long-term effective population size of parasites than is the total number of potential parasite infrapopulations (i.e., host individuals).Impact SummaryParasites, among Earth’s most diverse, threatened, and under-protected animals, play a central role in ecosystem function. The effective population size (Ne) of an organism has a profound impact on evolutionary processes, such as the relative contributions of selection and genetic drift to genomic change. Population size is also one of the most important parameters in conservation biology. For free-living organisms, it is expected thatNeis generally proportional to the total number of individuals in a population. However, for parasites, among other factors, populations are sometimes so extremely subdivided that high levels of inbreeding may distort these relationships. In this study, we used whole-genome sequence data from dove parasites and phylogenetic comparative methods to investigate the relationship between parasite effective population size (Ne) and host population size and body size. Our results revealed a positive relationship between parasite effective population size (Ne) and host body size, but not host population size. These results suggest that the size of parasite infrapopulations may be the most important factor when considering parasite effective population size, and have important implications for conservation.
Rapamycin not Dietary Restriction improves resilience against pathogens: a meta-analysis
Authors: Phillips Eleanor J , Simons Mirre J P 
Published: October 2022

AbstractDietary Restriction (DR) and rapamycin both increase lifespan across a number of taxa. Despite this positive effect on lifespan and other aspects of health, reductions in some physiological functions have been reported for DR and rapamycin has been used as an immunosuppressant. Perhaps surprisingly, both interventions have been suggested to improve immune function and delay immunosenescence. The immune system is complex and consists of many components. Therefore, arguably, the most holistic measurement of immune function is survival from an acute pathogenic infection. We reanalysed published post-infection short-term survival data of mice (n=1223 from 23 studies comprising 46 effect sizes involving DR (n=17) and rapamycin treatment (n=29) and analysed these results using meta-analysis. Rapamycin treatment significantly increased post infection survival rate (lnHR=-0.72; CI=-1.17, -0.28; p=0.0015). In contrast, DR reduced post-infection survival (lnHR=0.80; CI=0.08, 1.52; p=0.03). Importantly, the overall effect size of rapamycin treatment was significantly lower (P<0.001) than the estimate from DR studies, suggesting opposite effects on immune function. Our results show that immunomodulation caused by rapamycin treatment is beneficial to the survival from acute infection. For DR our results are based on a smaller number of studies, but do warrant caution as they indicate possible immune costs of DR. Our quantitative synthesis suggests that the geroprotective effects of rapamycin extend to the immune system and warrants further clinical trials of rapamycin to boost immunity in humans.