bluuebunny/crossref_metadata_2025 huggingface dataset:
A Call to Action to Train Underrepresented Minorities in Surgical Subspecialties and Fellowships
Authors: Escobar Natalie , Keshinro Ajaratu , Hambrecht Amanda , Frangos Spiros , Berman Russell S , DiMaggio Charles , Joseph Kathie-Ann , Bukur Marko , Klein Michael J , Ude-Welcome Akuezunkpa , Berry Cherisse
Published: March 2023

Objective:

With each succession along the surgical career pathway, from medical school to faculty, the percentage of those who identify as Underrepresented in Medicine (URiM) decreases. We sought to evaluate the demographic trend of surgical fellowship applicants, matriculants, and graduates over time.

Methods:

The Electronic Residency Application Service (ERAS) and the Graduate Medical Education Survey for general surgery fellowships in colorectal surgery, surgical oncology, pediatric surgery, thoracic surgery, and vascular surgery were retrospectively analyzed (2005-2020). Data were stratified by race and gender, descriptive statistics were performed, and time series were evaluated. Race/ethnicity groups included White, Asian, Other, and Underrepresented in Medicine (URiM), defined as Black/African American, Hispanic/Latino(a), Alaskan or Hawaiian Native, and Native American.

Results:

From 2005 to 2020, there were 5,357 ERAS applicants, 4,559 matriculants, and 4,178 graduates to surgery fellowships. Whites, followed by Asians, represented the highest percentage of applicants (62.7% and 22.3%, respectively), matriculants (65.4% and 23.8% respectively), and graduates (65.4% and 24.0%, respectively). For URiMs, the applicants (13.4%), matriculants (9.1%), and graduates (9.1%) remained significantly low (p < 0.001). When stratified by both race and gender, only 4.6% of the applicants, 2.7% of matriculants, and 2.4% of graduates identified as both URiM and female compared to white female applicants (20.0%), matriculants (17.9%), and graduates (16.5%, p <0.001).

Conclusion:

Significant disparities exist for URiMs in general surgery subspecialty fellowships. These results serve as a call to action to re-examine and improve the existing processes to increase the number of URiMs in the surgery subspecialty fellowship training pathway.
Location, location, location: survival of Antarctic biota requires the best real estate
Authors: Stevens Mark I. , Mackintosh Andrew N.
Published: March 2023

The origin of terrestrial biota in Antarctica has been debated since the discovery of springtails on the first historic voyages to the southern continent more than 120 years ago. A plausible explanation for the long-term persistence of life requiring ice-free land on continental Antarctica has, however, remained elusive. The default
glacial eradication
scenario has dominated because hypotheses to date have failed to provide a mechanism for their widespread survival on the continent, particularly through the Last Glacial Maximum when geological evidence demonstrates that the ice sheet was more extensive than present. Here, we provide support for the alternative
nunatak refuge
hypothesis—that ice-free terrain with sufficient relief above the ice sheet provided refuges and was a source for terrestrial biota found today. This hypothesis is supported here by an increased understanding from the combination of biological and geological evidence, and we outline a mechanism for these refuges during successive glacial maxima that also provides a source for coastal species. Our cross-disciplinary approach provides future directions to further test this hypothesis that will lead to new insights into the evolution of Antarctic landscapes and how they have shaped the biota through a changing climate.
Beyond collective intelligence: Collective adaptation
Authors: Galesic Mirta , Barkoczi Daniel , Berdahl Andrew M. , Biro Dora , Carbone Giuseppe , Giannoccaro Ilaria , Goldstone Robert L. , Gonzalez Cleotilde , Kandler Anne , Kao Albert B. , Kendal Rachel , Kline Michelle , Lee Eun , Massari Giovanni Francesco , Mesoudi Alex , Olsson Henrik , Pescetelli Niccolo , Sloman Sabina J. , Smaldino Paul E. , Stein Daniel L.
Published: March 2023

We develop a conceptual framework for studying collective adaptation in complex socio-cognitive systems, driven by dynamic interactions of social integration strategies, social environments and problem structures. Going beyond searching for ‘intelligent’ collectives, we integrate research from different disciplines and outline modelling approaches that can be used to begin answering questions such as why collectives sometimes fail to reach seemingly obvious solutions, how they change their strategies and network structures in response to different problems and how we can anticipate and perhaps change future harmful societal trajectories. We discuss the importance of considering path dependence, lack of optimization and collective myopia to understand the sometimes counterintuitive outcomes of collective adaptation. We call for a transdisciplinary, quantitative and societally useful social science that can help us to understand our rapidly changing and ever more complex societies, avoid collective disasters and reach the full potential of our ability to organize in adaptive collectives.
Does artificial feeding impact neonate growth rates in a large free-ranging mammal?
Authors: Griffin Laura L. , Haigh Amy , Amin Bawan , Faull Jane , Corcoran Fiachra , Baker-Horne Connie , Ciuti Simone
Published: March 2023

Variation and disparity in resource access between individuals in an animal population within human-dominated landscapes require attention as artificial selection processes may be at work. Independent, recreational human–wildlife feeding interactions constitute an increasingly prevalent, yet understudied, food resource for birds and mammals living in our cities. However, only a limited number of risk-taking individuals may access it. Using urban fallow deer as our model species, we hypothesized that if these interactions result in positive effects for the engaging individual, e.g. increased milk quality and yield, then this would result in the increased growth rates of their offspring. Alternatively, if these individuals were prioritizing investing time in engagement with humans, resulting in decreased maternal care, then this would result in slower growth rates in their offspring. We found that the offspring of those females that regularly interacted with humans displayed significantly faster growth rates than their risk-adverse counterparts. This advantage for fearless mothers in terms of boosted neonatal growth rates could be mirrored in birds accessing garden feeders, seagulls or pigeons utilizing urban resources, or seals approaching city harbours. Here, we add a new piece to the complex puzzle of how humans are impacting wildlife living within human-dominated landscapes.
Metabolically active angiosperms survive passage through the digestive tract of a large-bodied waterbird
Authors: Paolacci Simona , Jansen Marcel A. K. , Stejskal Vlastimil , Kelly Thomas C. , Coughlan Neil E.
Published: March 2023

Avian vectors, such as ducks, swans and geese, are important dispersers of plant propagules. Until recently, it was thought that small vegetative propagules were reliant on adherence to vectors and are unlikely to survive passage through the avian digestive tract. Here, we conclusively demonstrate that metabolically active angiosperms can survive passage through the digestive tract of a large-bodied waterbird. In addition, we show that extended periods of air exposure for up to 7 days does not inhibit the survival of plantlets embedded in faecal matter. Following air exposure, plantlets (n= 3000) were recovered from 75 faecal samples of mute swans,Cygnus olor, with the survival of 203 plantlets. The number of recovered and surviving plantlets did not significantly differ among durations of air exposure. For recovered plantlets, the long-term viability and clonal reproduction of two duckweed species,Lemna minorandL. gibba, were confirmed following greater than eight months of growth. These data further amplify the key role of waterbirds as vectors for aquatic plant dispersal and demonstrate the internal transport (i.e. endozoochory) of metabolically active plantlets. These data suggest dispersal of vegetative plant propagules by avian vectors is likely to be a common occurrence, underpinning connectivity, range expansion and invasions of some aquatic plants.
Local supersymmetry: variations on a theme by Volkov and Soroka
Authors: Kuzenko Sergei M.
Published: March 2023

We revisit the work by Volkov and Soroka on spontaneously broken local supersymmetry. It is demonstrated for the first time that, for specially chosen parameters of the theory, the Volkov–Soroka action is invariant under two different local supersymmetries. One of them is present for arbitrary values of the parameters and acts on the Goldstino, while the other supersymmetry emerges only in a special case and leaves the Goldstino invariant. The former can be used to gauge away the Goldstino, and then the resulting action coincides with that proposed by Deser and Zumino for consistent supergravity in the first-order formalism. In this sense, pure

N

=
1

supergravity is a special case of the Volkov–Soroka theory, although it was not discovered by these authors. We also explain how the Volkov–Soroka approach allows one to naturally arrive at the 1.5 formalism. Our analysis provides a nonlinear realization approach to construct unbroken

N

=
1

Poincaré supergravity.
Advancing the quantitative characterization of farm animal welfare
Authors: Bartlett Harriet , Balmford Andrew , Holmes Mark A. , Wood James L. N.
Published: March 2023

Animal welfare is usually excluded from life cycle assessments (LCAs) of farming systems because of limited consensus on how to measure it. Here, we constructed several LCA-compatible animal-welfare metrics and applied them to data we collected from 74 diverse breed-to-finish systems responsible for 5% of UK pig production. Some aspects of metric construction will always be subjective, such as how different aspects of welfare are aggregated, and what determines poor versus good welfare. We tested the sensitivity of individual farm rankings, and rankings of those same farms grouped by label type (memberships of quality-assurance schemes or product labelling), to a broad range of approaches to metric construction. We found farms with the same label types clustered together in rankings regardless of metric choice, and there was broad agreement across metrics on the rankings of individual farms. We found woodland and
Organic
systems typically perform better than those with no labelling and
Red tractor
labelling, and that outdoor-bred and outdoor-finished systems perform better than indoor-bred and slatted-finished systems, respectively. We conclude that if our goal is to identify relatively better and worse farming systems for animal welfare, exactly how LCA welfare metrics are constructed may be less important than commonly perceived.
Parthenogenesis in dipterans: a genetic perspective
Authors: Sperling A. L. , Glover D. M.
Published: March 2023

Parthenogenesis has been documented in almost every phylum of animals, and yet this phenomenon is largely understudied. It has particular importance in dipterans since some parthenogenetic species are also disease vectors and agricultural pests. Here, we present a catalogue of parthenogenetic dipterans, although it is likely that many more remain to be identified, and we discuss how their developmental biology and interactions with diverse environments may be linked to different types of parthenogenetic reproduction. We discuss how the advances in genetics and genomics have identified chromosomal loci associated with parthenogenesis. In particular, a polygenic cause of facultative parthenogenesis has been uncovered inDrosophila mercatorum,allowing the corresponding genetic variants to be tested for their ability to promote parthenogenesis in another species,Drosophila melanogaster. This study probably identifies just one of many routes that could be followed in the evolution of parthenogenesis. We attempt to account for why the phenomenon has evolved so many times in the dipteran order and why facultative parthenogenesis appears particularly prevalent. We also discuss the significance of coarse genomic changes, including non-disjunction, aneuploidy, and polyploidy and how, together with changes to specific genes, these might relate to both facultative and obligate parthenogenesis in dipterans and other parthenogenetic animals.
Colonization order of bacterial isolates on treefrog embryos impacts microbiome structure in tadpoles
Authors: Jones Korin Rex , Hughey Myra C. , Belden Lisa K.
Published: March 2023

Priority effects, or impacts of colonization order, may have lasting influence on ecological community composition. The embryonic microbiome is subject to stochasticity in colonization order of bacteria. Stochasticity may be especially impactful for embryos developing in bacteria-rich environments, such as the embryos of many amphibians. To determine if priority effects experienced as embryos impacted bacterial community composition in newly hatched tadpoles, we selectively inoculated the embryos of laboratory-raised hourglass treefrogs,
Dendropsophus ebraccatus
, with bacteria initially isolated from the skin of wild
D. ebraccatus
adults over 2 days. First, embryos were inoculated with two bacteria in alternating sequences. Next, we evaluated the outcomes of priority effects in an
in vitro
co-culture assay absent of host factors. We then performed a second embryo experiment, inoculating embryos with one of three bacteria on the first day and a community of five target bacteria on the second. Through 16S rRNA gene amplicon sequencing, we observed relative abundance shifts in tadpole bacteria communities due to priority effects. Our results suggest that the initial bacterial source pools of embryos shape bacterial communities at later life stages; however, the magnitude of those changes is dependent on the host environment and the identity of bacterial colonists.
Co-segregation of recombinant chromatids maintains genome-wide heterozygosity in an asexual nematode
Authors: Blanc Caroline , Saclier Nathanaelle , Le Faou Ehouarn , Marie-Orleach Lucas , Wenger Eva , Diblasi Celian , Glemin Sylvain , Galtier Nicolas , Delattre Marie
Published: March 2023

In asexual animals, female meiosis is modified to produce diploid oocytes. Associated with recombination, this is expected to lead to a rapid loss of heterozygosity, with adverse effects on fitness. Many asexuals, however, have a heterozygous genome, the underlying mechanisms being most often unknown. Cytological and population genomic analyses in the nematodeMesorhabditis belarirevealed another case of recombining asexual being highly heterozygous genome-wide. We demonstrated that heterozygosity is maintained because the recombinant chromatids of each chromosome pair co-segregate during the unique meiotic division. A theoretical model confirmed that this segregation bias is necessary to account for the observed pattern and likely to evolve under a wide range of conditions. Our study uncovers a new type of cell division involving Directed Chromatid Assortment.

One sentence summary

Genome wide heterozygosity in the asexual nematodeMesorhabditis belariis achieved by directed assortment of recombinant chromatids during female meiosis
Ketogenic diet therapy for pediatric epilepsy is associated with alterations in the human gut microbiome that confer seizure resistance in mice
Authors: Lum Gregory R. , Ha Sung Min , Olson Christine A. , Blencowe Montgomery , Paramo Jorge , Reyes Beck , Matsumoto Joyce H. , Yang Xia , Hsiao Elaine Y.
Published: March 2023

The gut microbiome modulates seizure susceptibility and the anti-seizure effects of the ketogenic diet (KD) in animal models, but whether these relationships translate to KD therapies for human drug-resistant epilepsy is unclear. Herein, we find that the clinical KD shifts the function of the gut microbiome in children with refractory epilepsy. Colonizing mice with KD-associated human gut microbes confers increased resistance to 6-Hz psychomotor seizures, as compared to colonization with gut microbes from matched pre-treatment controls. Parallel analysis of human donor and mouse recipient metagenomic and metabolomic profiles identifies subsets of shared functional features that are seen in response to KD treatment in humans and preserved upon transfer to mice fed a standard diet. These include enriched representation of microbial genes and metabolites related to anaplerosis, fatty acid beta-oxidation, and amino acid metabolism. Mice colonized with KD-associated human gut microbes further exhibit altered hippocampal and frontal cortical transcriptomic profiles relative to colonized pre-treatment controls, including differential expression of genes related to ATP synthesis, glutathione metabolism, oxidative phosphorylation, and translation. Integrative co-occurrence network analysis of the metagenomic, metabolomic, and brain transcriptomic datasets identifies features that are shared between human and mouse networks, and select microbial functional pathways and metabolites that are candidate primary drivers of hippocampal expression signatures related to epilepsy. Together, these findings reveal key microbial functions and biological pathways that are altered by clinical KD therapies for pediatric refractory epilepsy and further linked to microbiome-induced alterations in brain gene expression and seizure protection in mice.
Age and diet modulate the insulin-sensitizing effects of exercise: a tracer-based oral glucose tolerance test
Authors: Vieira-Lara Marcel A. , Reijne Aaffien C. , Koshian Serj , Ciapaite Jolita , Abegaz Fentaw , Talarovicova Alzbeta , van Dijk Theo H. , Versloot Christian J. , Bandsma Robert H.J. , Wolters Justina C. , Groen Albert K. , Reijngoud Dirk-Jan , van Dijk Gertjan , Bakker Barbara M.
Published: March 2023

Diet modulates the development of insulin resistance during aging. This includes tissue-specific alterations in insulin signaling and mitochondrial function, which ultimately affect glucose homeostasis. Exercise stimulates glucose clearance, mitochondrial lipid oxidation and enhances insulin sensitivity. It is not well known how exercise interacts with age and diet in the development of insulin resistance. To investigate this, oral glucose tolerance tests (OGTT) with a tracer were conducted in mice ranging from 4 to 21 months of age, fed a low- (LFD) or high-fat diet (HFD), with or without life-long voluntary access to a running wheel (RW). We developed a computational model to derive glucose fluxes, which were commensurate with independent values from steady-state tracer infusions. Both insulin sensitivity indices derived for peripheral tissues and liver (IS-P and IS-L, respectively) were steeply decreased by aging and a HFD. This preceded the age-dependent decline in the mitochondrial capacity to oxidize lipids. In LFD young animals, RW access enhanced the IS-P concomitantly with the muscle β-oxidation capacity. Surprisingly, RW access completely prevented the age-dependent IS-L decrease, but only in LFD animals. This study indicates, therefore, that endurance exercise can improve the age-dependent decline in organ-specific IS mostly in the context of a healthy diet.
IGF2BP1 induces high-risk neuroblastoma and forms a druggable feedforward loop with MYCN promoting 17q oncogene expression
Authors: Hagemann Sven , Misiak Danny , Bell Jessica L. , Fuchs Tommy , Lederer Marcell I. , Bley Nadine , Hämmerle Monika , Ghazy Ehab , Sippl Wolfgang , Schulte Johannes H. , Hüttelmaier Stefan
Published: March 2023

Background

Neuroblastoma is the most common solid tumor in infants accounting for approximately 15% of all cancer-related deaths. Over 50% of high-risk neuroblastoma relapse, emphasizing the need of novel drug targets and therapeutic strategies. In neuroblastoma, chromosomal gains at chromosome 17q, includingIGF2BP1, andMYCNamplification at chromosome 2p are associated with adverse outcome. Recent, pre-clinical evidence indicates the feasibility of direct and indirect targeting of IGF2BP1 and MYCN in cancer treatment.

Methods

Candidate oncogenes on 17q were identified by profiling the transcriptomic/genomic landscape of 100 human neuroblastoma samples and public gene essentiality data. Molecular mechanisms and gene expression profiles underlying the oncogenic and therapeutic target potential of the 17q oncogeneIGF2BP1and its cross-talk withMYCNwere characterized and validated in human neuroblastoma cells, xenografts and PDX as well as novel IGF2BP1/MYCN transgene mouse models.

Results

We reveal a novel, druggable feedforward loop of IGF2BP1 (17q) and MYCN (2p) in high-risk neuroblastoma. This promotes 2p/17q chromosomal gains and unleashes an oncogene storm resulting in fostered expression of 17q oncogenes like BIRC5 (survivin). Conditional, sympatho- adrenal transgene expression of IGF2BP1 induces neuroblastoma at a 100% incidence. IGF2BP1- driven malignancies are reminiscent to human high-risk neuroblastoma, including 2p/17q-syntenic chromosomal gains and upregulation of Mycn, Birc5, as well as key neuroblastoma circuit factors like Phox2b. Co-expression of IGF2BP1/MYCN reduces disease latency and survival probability by fostering oncogene expression. Combined inhibition of IGF2BP1 by BTYNB, MYCN by BRD inhibitors or BIRC5 by YM-155 is beneficialin vitroand, for BTYNB, alsoin vivo.

Conclusion

We reveal a novel, druggable neuroblastoma oncogene circuit settling on strong, transcriptional/post-transcriptional synergy of MYCN and IGF2BP1. MYCN/IGF2BP1 feed-forward regulation promotes an oncogene storm harboring high therapeutic potential for combined, targeted inhibition of IGF2BP1, MYCN expression and MYCN/IGF2BP1-effectors like BIRC5.
Identification of annotation artifacts concerning theCHALCONE SYNTHASE(CHS)
Authors: Bartas Martin , Volna Adriana , Cerven Jiri , Pucker Boas
Published: March 2023

Objective

Chalcone synthase (CHS) catalyzes the initial step of the flavonoid biosynthesis. The CHS encoding gene is well studied in numerous plant species. Rapidly growing sequence databases contain hundreds of CHS entries that are the result of automatic annotation. In this study, we evaluated apparent multiplication of CHS domains inCHSgene models of four plant species.

Main findings

CHSgenes with an apparent triplication of the CHS domain encoding part were discovered through database searches. Such genes were found inMacadamia integrifolia, Musa balbisiana, Musa troglodytarum, andNymphaea colorata. A manual inspection of theCHSgene models in these four species with massive RNA-seq data suggests that these gene models are the result of artificial fusions in the annotation process. While there are hundreds of apparently correct CHS records in the databases, it is not clear why these annotation artifacts appeared.
Application of the ANDROMEDA Software for Prediction of the Human Pharmacokinetics of Modern Anticancer Drugs
Authors: Fagerholm Urban , Hellberg Sven , Alvarsson Jonathan , Spjuth Ola
Published: March 2023

The ANDROMEDA toolkit for prediction of human clinical pharmacokinetics, based on machine learning, conformal prediction and a new physiologically-based pharmacokinetic model, was used to predict and characterize the human clinical pharmacokinetics of 12 small anticancer drugs marketed in 2021 and 2022 (molecular weight 355 to 1326 g/mol). The study is part of a series of software validations. A majority of clinical pharmacokinetic data was missing. ANDROMEDA successfully filled this gap. Most drugs were predicted/measured to have relatively complex pharmacokinetics, with limited passive permeability+efflux, high degree of plasma protein binding, significant gut-wall elimination and food interaction, biliary excretion and/or limited dissolution potential. Median, mean and maximum prediction errors for steady state volume of distribution, unbound fraction in plasma, blood-to-plasma concentration ratio, hepatic, renal and total clearance, fraction absorbed, oral bioavailability, half-life and degree of food interaction were 1.6-, 2.4- and 17-fold, respectively. Less than 3-fold errors were found for 78 % of predictions. Results are consistent with those obtained in previous validation studies and are better than with the best laboratory-based prediction methods, which validates ANDROMEDA for predictions of human clinical pharmacokinetics of modern small anticancer drugs with multi-mechanistical and challenging pharmacokinetics.
Bacterial genome engineering using CRISPR RNA-guided transposases
Authors: Gelsinger Diego R. , Vo Phuc Leo H. , Klompe Sanne E. , Ronda Carlotta , Wang Harris , Sternberg Samuel H.
Published: March 2023

CRISPR-associated transposons (CASTs) have the potential to transform the technology landscape for kilobase-scale genome engineering, by virtue of their ability to integrate large genetic payloads with high accuracy, easy programmability, and no requirement for homologous recombination machinery. These transposons encode efficient, CRISPR RNA-guided transposases that execute genomic insertions inE. coliat efficiencies approaching ∼100%, generate multiplexed edits when programmed with multiple guides, and function robustly in diverse Gram-negative bacterial species. Here we present a detailed protocol for engineering bacterial genomes using CAST systems, including guidelines on the available homologs and vectors, customization of guide RNAs and DNA payloads, selection of common delivery methods, and genotypic analysis of integration events. We further describe a computational crRNA design algorithm to avoid potential off-targets and CRISPR array cloning pipeline for DNA insertion multiplexing. Starting from available plasmid constructs, the isolation of clonal strains containing a novel genomic integration event-of-interest can be achieved in 1 week using standard molecular biology techniques.
GD2 and its biosynthetic enzyme GD3 synthase promote tumorigenesis in prostate cancer by regulating cancer stem cell behavior
Authors: Bhat Aaqib M. , Mohapatra Bhopal C. , Luan Haitao , Mushtaq Insha , Chakraborty Sukanya , Kumar Siddhartha , Wu Wangbin , Nolan Ben , Dutta Samikshan , Storck Matthew D. , Schott Micah , Meza Jane L. , Lele Subodh M. , Lin Ming-Fong , Cook Leah M. , Corey Eva , Morrissey Colm , Coulter Donald W. , Rowley M. Jordan , Natarajan Amarnath , Datta Kaustubh , Band Vimla , Band Hamid
Published: March 2023

While better management of loco-regional prostate cancer (PC) has greatly improved survival, advanced PC remains a major cause of cancer deaths. Identification of novel targetable pathways that contribute to tumor progression in PC could open new therapeutic options. The di-ganglioside GD2 is a target of FDA-approved antibody therapies in neuroblastoma, but the role of GD2 in PC is unexplored. Here, we show that GD2 is expressed in a small subpopulation of PC cells in a subset of patients and a higher proportion of metastatic tumors. Variable levels of cell surface GD2 expression were seen on many PC cell lines, and the expression was highly upregulated by experimental induction of lineage progression or enzalutamide resistance in CRPC cell models. GD2highcell fraction was enriched upon growth of PC cells as tumorspheres and GD2highfraction was enriched in tumorsphere-forming ability. CRISPR-Cas9 knockout (KO) of the rate-limiting GD2 biosynthetic enzyme GD3 Synthase (GD3S) in GD2highCRPC cell models markedly impaired thein vitrooncogenic traits and growth as bone-implanted xenograft tumors and reduced the cancer stem cell (CSC) and epithelial-mesenchymal transition (EMT) marker expression. Our results support the potential role of GD3S and its product GD2 in promoting PC tumorigenesis by maintaining cancer stem cells and suggest the potential for GD2 targeting in advanced PC.
Reward prediction-errors weighted by cue salience produces addictive behaviors in simulations, with asymmetrical learning and steeper delay discounting
Authors: Kalhan Shivam , Garrido Marta I. , Hester Robert , David Redish A.
Published: March 2023

Dysfunction in learning and motivational systems are thought to contribute to addictive behaviours. Previous models have suggested that dopaminergic roles in learning and motivation could produce addictive behaviours through pharmacological manipulations that provide excess dopaminergic signalling towards these learning and motivational systems. Redish 2004 suggested a role based on dopaminergic signals of value prediction error, while Zhang et al. 2009 suggested a role based on dopaminergic signals of motivation. Both these models present significant limitations. They do not explain the reduced sensitivity to drug-related costs/negative consequences, the increased impulsivity generally found in people with a substance use disorder, craving behaviours, and non-pharmacological dependence, all of which are key hallmarks of addictive behaviours. Here, we propose a novel mathematical definition of salience, that combines aspects of dopamine’s role in both, learning and motivation, within the reinforcement learning framework. Using a single parameter regime, we simulated addictive behaviours that the Zhang et al. 2009 and Redish 2004 models also produce but we went further in simulating the downweighting of drug-related negative prediction-errors, steeper delay discounting of drug rewards, craving behaviours and aspects of behavioural/non-pharmacological addictions. The current salience model builds on our recently proposed conceptual theory that salience modulates internal representation updating and may contribute to addictive behaviours by producing misaligned internal representations (Kalhan et al., 2021). Critically, our current mathematical model of salience argues that the seemingly disparate learning and motivational aspects of dopaminergic functioning may interact through a salience mechanism that modulates internal representation updating.
Nasopharyngeal Angiotensin Converting Enzyme 2 (ACE2) Expression as a Risk-Factor for SARS-CoV-2 Transmission in Concurrent Hospital Associated Outbreaks
Authors: Nikiforuk Aidan M. , Kuchinski Kevin S. , Short Katy , Roman Susan , Irvine Mike A. , Prystajecky Natalie , Jassem Agatha N. , Patrick David M. , Sekirov Inna
Published: March 2023

Background

Widespread human-to-human transmission of the severe acute respiratory syndrome coronavirus two (SARS-CoV-2) stems from a strong affinity for the cellular receptor angiotensin converting enzyme two (ACE2). We investigate the relationship between a patient’s nasopharyngealACE2transcription and secondary transmission within a series of concurrent hospital associated SARS-CoV-2 outbreaks in British Columbia, Canada.

Methods

Epidemiological case data from the outbreak investigations was merged with public health laboratory records and viral lineage calls, from whole genome sequencing, to reconstruct the concurrent outbreaks using infection tracing transmission network analysis.ACE2transcription and RNA viral load were measured by quantitative real-time polymerase chain reaction. The transmission network was resolved to calculate the number of potential secondary cases. Bivariate and multivariable analyses using Poisson and Negative Binomial regression models was performed to estimate the association betweenACE2transcription the number of SARS-CoV-2 secondary cases.

Results

The infection tracing transmission network provided n = 76 potential transmission events across n = 103 cases. Bivariate comparisons found that on averageACE2transcription did not differ between patients and healthcare workers (P = 0.86). HighACE2transcription was observed in 98.6% of transmission events, either the primary or secondary case had above averageACE2. Multivariable analysis found that the association betweenACE2transcription and the number of secondary transmission events differs between patients and healthcare workers. In health care workers Negative Binomial regression estimated that a one unit change inACE2transcription decreases the number of secondary cases (B = −0.132 (95%CI: −0.255 to −0.0181) adjusting for RNA viral load. Conversely, in patients a one unit change inACE2transcription increases the number of secondary cases (B = 0.187 (95% CI: 0.0101 to 0.370) adjusting for RNA viral load. Sensitivity analysis found no significant relationship betweenACE2and secondary transmission in health care workers and confirmed the positive association among patients.

Conclusion

Our study suggests thatACE2transcription has a positive association with SARS-CoV-2 secondary transmission in admitted inpatients, but not health care workers in concurrent hospital associated outbreaks, and it should be further investigated as a risk-factor for viral transmission.
MIMOSA: A resource consisting of improved methylome imputation models increases power to identify DNA methylation-phenotype associations
Authors: Melton Hunter J. , Zhang Zichen , Deng Hong-Wen , Wu Lang , Wu Chong
Published: March 2023

Although DNA methylation has been implicated in the pathogenesis of numerous complex diseases, the exact methylation sites that play key roles in these processes remain elusive. One strategy to identify putative causal CpG sites and enhance disease etiology understanding is to conduct methylome-wide association studies (MWASs), in which predicted DNA methylation that is associated with complex diseases can be identified.However, current MWAS models are primarily trained by using the data from single studies, thereby limiting the methylation prediction accuracy and the power of subsequent association studies. Here, we introduce a new resource, MWAS Imputing Methylome Obliging Summary-level mQTLs and Associated LD matrices (MIMOSA), a set of models that substantially improve the prediction accuracy of DNA methylation and subsequent MWAS power through the use of a large, summary-level mQTL dataset provided by the Genetics of DNA Methylation Consortium (GoDMC). With the analyses of GWAS (genome-wide association study) summary statistics for 28 complex traits and diseases, we demonstrate that MIMOSA considerably increases the accuracy of DNA methylation prediction in whole blood, crafts fruitful prediction models for low heritability CpG sites, and determines markedly more CpG site-phenotype associations than preceding methods. Finally, we use MIMOSA to conduct a case study in high cholesterol, pinpointing 146 putatively causal CpG sites.
The Change of Screen Time and Screen Addiction, and their Association with Psychological Well-being During the COVID-19 Pandemic: An Analysis of US Country-Wide School-Age Children and Adolescents Between 2018 and 2020
Authors: Wu Helena T. , Li Jiandong , Tsurumi Amy
Published: March 2023

Previous studies on screen use and children’s mental health during the Coronavirus Disease 2019 (COVID-19) pandemic either focused only on the timeframe during the pandemic, or only on children previously reporting COVID-related severe family economic hardship or worries. Instead, we used a large sample (n=63,211) of the National Survey of Children’s Health (NSCH) years 2018-20 to analyze changes in the trends of recreational screen device use before, versus during the COVID-19 pandemic, and associations with psychological well-being, widely among school-age children (6-17 year-olds) across the US. We assessed recreational screen use, instead of overall use including both instructional and recreational use, and developed psychological well-being issue scores to evaluate the associations among the pandemic, recreational screen use, and psychological well-being states. We found an increase in the prevalence of screen overuse/addiction and psychological well-being issues during the pandemic compared to the years prior, detected an association between the pandemic and psychological well-being issue scores (p <0.01 across all models), and observed increased magnitude of association between recreational screen overuse/addiction and mental health during the pandemic year (p <0.01 across all models). Further studies on elucidating and addressing the specific aspects of the pandemic that contribute to these associations are critical.
Structural basis for functional properties of cytochromecoxidase
Authors: Ishigami Izumi , Sierra Raymond G. , Su Zhen , Peck Ariana , Wang Cong , Poitevin Frederic , Lisova Stella , Hayes Brandon , Moss Frank R. , Boutet Sébastien , Sublett Robert E. , Yoon Chun Hong , Yeh Syun-Ru , Rousseau Denis L.
Published: March 2023

Cytochromecoxidase (CcO) is an essential enzyme in mitochondrial and bacterial respiration. It catalyzes the four-electron reduction of molecular oxygen to water and harnesses the chemical energy to translocate four protons across biological membranes, thereby establishing the proton gradient required for ATP synthesis1. The full turnover of the CcO reaction involves an oxidative phase, in which the reduced enzyme (R) is oxidized by molecular oxygen to the metastable oxidizedOHstate, and a reductive phase, in whichOHis reduced back to theRstate. During each of the two phases, two protons are translocated across the membranes2. However, ifOHis allowed to relax to the resting oxidized state (O), a redox equivalent toOH, its subsequent reduction toRis incapable of driving proton translocation2,3. How theOstate structurally differs fromOHremains an enigma in modern bioenergetics. Here, with resonance Raman spectroscopy and serial femtosecond X-ray crystallography (SFX)4, we show that the hemea3iron and CuBin the active site of theOstate, like those in theOHstate5,6, are coordinated by a hydroxide ion and a water molecule, respectively. However, Y244, a residue covalently linked to one of the three CuBligands and critical for the oxygen reduction chemistry, is in the neutral protonated form, which distinguishesOfromOH, where Y244 is in the deprotonated tyrosinate form. These structural characteristics ofOprovide new insights into the proton translocation mechanism of CcO.
Mammals achieve common neural coverage of visual scenes using distinct sampling behaviors
Authors: Samonds Jason M. , Szinte Martin , Barr Carrie , Montagnini Anna , Masson Guillaume S , Priebe Nicholas J.
Published: March 2023

Most vertebrates use head and eye movements to quickly change gaze orientation and sample different portions of the environment with periods of stable fixation. Visual information must be integrated across several fixations to construct a more complete perspective of the visual environment. In concert with this sampling strategy, neurons adapt to unchanging input to conserve energy and ensure that only novel information from each fixation is processed. We demonstrate how adaptation recovery times and saccade properties interact, and thus shape spatiotemporal tradeoffs observed in the motor and visual systems of different species. These tradeoffs predict that in order to achieve similar visual coverage over time, animals with smaller receptive field sizes require faster saccade rates. Indeed, we find comparable sampling of the visual environment by neuronal populations across mammals when integrating measurements of saccadic behavior with receptive field sizes and V1 neuronal density. We propose that these mammals share a common statistically driven strategy of maintaining coverage of their visual environment over time calibrated to their respective visual system characteristics.
PTEN deletion in spinal pathways via retrograde transduction with AAV-rg enhances forelimb motor recovery after cervical spinal cord injury; sex differences and late-onset pathophysiologies
Authors: Metcalfe Mariajose , Steward Oswald
Published: March 2023

Spinal cord injuries (SCI) cause permanent functional impairments due to interruption of motor and sensory pathways. Regeneration of axons does not occur due to lack of intrinsic growth capacity of adult neurons and extrinsic inhibitory factors, especially at the injury site. However, some regeneration can be achieved via deletion of the phosphatase and tensin homolog (PTEN) in cells of origin of spinal pathways. Here, we deployed an AAV variant that is retrogradely transported (AAV-rg) to deliver gene modifying cargos to the cells of origin of multiple pathways interrupted by SCI, testing whether this promoted recovery of motor function. PTENf/f;RosatdTomatomice and control RosatdTomatomice received injections of different doses (number of genome copies, GCs) of AAV-rg/Cre into the cervical spinal cord at the time of a C5 dorsal hemisection injury. Forelimb grip strength was tested over time using a grip strength meter. PTENf/f;RosatdTomatomice with AAV-rg/Cre (PTEN-deleted) exhibited substantial improvements in forelimb gripping ability in comparison to controls. Of note, there were major sex differences in the extent of recovery, with male mice exhibiting greater recovery than females. However, at around 5-7 weeks post-injury/injection, many mice with SCI and AAV-rg-mediated PTEN deletion began to exhibit pathophysiologies involving excessive scratching of the ears and back of the neck and rigid forward extension of the hindlimbs. These pathophysiologies increased in incidence and severity over time. Our results reveal that although intra-spinal injections of AAV-rg/Cre in PTENf/f;RosatdTomatomice can enhance forelimb motor recovery after SCI, late-developing functional abnormalities occur with the experimental conditions used here. Mechanisms underlying late-developing pathophysiologies remain to be defined.
Depletion of bleomycin hydrolase (Blmh) downregulates histone demethylase Phf8, impairs mTOR signaling/autophagy, accelerates amyloid beta accumulation, and induces neurological deficits in mice
Authors: Witucki Łukasz , Borowczyk Kamila , Suszyńska-Zajczyk Joanna , Warzych Ewelina , Pawlak Piotr , Jakubowski Hieronim
Published: March 2023

Bleomycin hydrolase (BLMH), a homocysteine (Hcy)-thiolactone detoxifying enzyme, is attenuated in brains of Alzheimer’s disease patients. In mice, Blmh depletion causes astrogliosis and behavioral changes. Depletion of histone demethylase PHF8, which controls mTOR signaling by demethylating H4K20me1, causes neuropathy in humans and mice. Here we examined how Blmh depletion affects the Phf8/H4K20me1/mTOR signaling/autophagy pathway and amyloid beta (Aβ) accumulation and cognitive/neuromotor performance in mice. We found that Phf8 was significantly downregulated in brains ofBlmh-/-micevs.Blmh+/+sibling controls. H4K20me1, mTOR, phospho-mTOR, and App were upregulated while autophagy markers Bcln1, Atg5, and Atg7 were downregulated inBlmh-/-brains. Blmh depletion caused similar biochemical changes and significantly elevated Aβ inBlmh-/-5xFADvs.Blmh+/+5xFAD brains. Behavioral testing identified cognitive/neuromotor deficits inBlmh-/-andBlmh-/-5xFAD mice. In Blmh-depleted N2a-APPswecells, Phf8 was downregulated, while APP, total H4K20me1, and H4K20me1-mTORpromoter binding were elevated. This led to mTOR upregulation, autophagy downregulation, and significantly increased APP and Aβ levels. Phf8 depletion or treatments with Hcy-thiolactone orN-Hcy-protein, metabolites that are elevated in Blmh-depleted mice, induced similar biochemical changes in N2a-APPswecells, akin to those in induced by Blmh depletion. Taken together, our findings indicate that Blmh interacts with APP and the Phf8/H4K20me1/mTOR/autophagy pathway and show that disruption of these interactions lead to Aβ accumulation and cognitive and neuromotor deficits.
Nanograms of SARS-CoV-2 Spike Protein Delivered by Exosomes Induce Potent Neutralization of Both Delta and Omicron Variants
Authors: Cacciottolo Mafalda , Li Yujia , Nice Justin B , LeClaire Michael J. , Twaddle Ryan , Mora Ciana L. , Adachi Stephanie Y. , Young Meredith , Angeles Jenna , Elliott Kristi , Sun Minghao
Published: March 2023

Exosomes are emerging as potent and safe delivery carriers for use in vaccinology and therapeutics. A better vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed to provide improved, broader, longer lasting neutralization of SARS-CoV-2, a more robust T cell response, enable widespread global usage, and further enhance the safety profile of vaccines given the likelihood of repeated booster vaccinations. Here, we use Capricor’s StealthX™ platform to engineer exosomes to express native SARS-CoV-2 spike Delta variant (STX-S) protein on the surface for the delivery of a protein-based vaccine for immunization against SARS-CoV-2 infection. The STX-S vaccine induced a strong immunization with the production of a potent humoral immune response as demonstrated by high levels of neutralizing antibody not only against the delta SARS-CoV-2 virus but also two Omicron variants (BA.1 and BA.5), providing broader protection than current mRNA vaccines. Additionally, both CD4+and CD8+T cell responses were increased significantly after treatment. Quantification of spike protein by ELISA showed that only nanograms of protein were needed to induce a potent immune response. This is a significantly lower dose than traditional recombinant protein vaccines with no adjuvant required, which makes the StealthX™ exosome platform ideal for the development of multivalent vaccines with a better safety profile. Importantly, our exosome platform allows novel proteins, or variants in the case of SARS-CoV-2, to be engineered onto the surface of exosomes in a matter of weeks, comparable with mRNA vaccine technology, but without the cold storage requirements. The ability to utilize exosomes for cellular delivery of proteins, as demonstrated by STX-S, has enormous potential to revolutionize vaccinology by rapidly facilitating antigen presentation at an extremely low dose resulting in a potent, broad antibody response.
Nucleolar Essential Protein 1 (Nep1): Elucidation of Enzymatic Catalysis Mechanism by Combined Molecular Dynamics Simulation and Quantum Chemical Calculations
Authors: Jedrzejewski Mateusz , Bełza Barbara , Lewandowska Iwona , Sadlej Marta , Perlinska Agata P. , Augustyniak Rafal , Christian Thomas , Hou Ya–Ming , Kalek Marcin , Sulkowska Joanna I.
Published: March 2023

Nep1 is a protein essential for the formation of the eukaryotic and archaeal small ribosomal subunit. It is an enzyme responsible for the site–specific SAM–dependent methylation of pseudouridine (Ψ) during the pre–rRNA processing. It possesses a non–trivial topology, namely, a 31knot in the active site. Herein, we investigate the structure and mechanism of catalysis of Nep1 using a combination of bioinformatics, computational, and experimental methods. In particular, we address the issue of seemingly unfeasible deprotonation of Ψ nucleobase in the active site of Nep1 by a distant aspartate residue (e.g., D101 in Nep1 ofS. cerevisiae). Sequence alignment analysis across different organisms identifies a conserved serine/threonine residue that may play a role of a proton–transfer mediator (e.g., S233 in Nep1 fromS. cerevisiae), facilitating the reaction. Two enzyme–substrate complexes, one based on an available crystal structure and the other generated by molecular docking, of representative eukaryotic (fromS. cerevisiae) and archaeal (fromA. fulgidus) Nep1 homologs are subjected to molecular dynamics (MD) simulations. The resulting trajectories confirm that the hydroxyl–containing amino acid can indeed adopt a position suitable for proton–shuttling, with the OH group located in between the proton donor and acceptor. However, during the MD simulations, a water molecule emerges from arrangements of the active site, which can assume the role of the proton–transfer mediator instead. To discern between these two alternative pathways, we evaluate the possible methylation mechanisms by quantum–chemical calculations based on density functional theory, using the cluster approach. The obtained energy profiles indicate that the most facile course of the reaction for both the yeast and archaeal enzymes is to engage the water molecule. These results are corroborated by agreement of the computed energy barriers with experimentally measured enzyme kinetics. Moreover, mutational studies show that, while aspartate D101 is crucial for the catalytic activity, serine S233 is irrelevant in this context, indirectly supporting the water–mediated proton transfer. Our findings comprehensively elucidate the mode of action of Nep1 and provide implication for understanding the catalytic mechanisms of other enzymes that involve a proton transfer in the active site over extended distances.