bluuebunny/crossref_metadata_2025 huggingface dataset:
Vulnerability to Decubitus Ulcers and Their Association With Healthcare Utilization: Evidence From Nationwide Inpatient Sample Dataset From 2016 to 2020 in US Hospitals
Authors: Kim Sun Jung , Medina Mar , Hotz Kaci , Kim Juliy , Chang Jongwha
Published: December 2023

Objective

The aim of the study is to identify vulnerable populations at risk of developing decubitus ulcers and their resultant increase in healthcare utilization to promote the use of early prevention methods.

Methods

The National Inpatient Sample of the United States was used to identify hospitalized patients across the country who had a length of stay of 5 or more days (N = 9,757,245, weighted N = 48,786,216) from 2016 to 2020. We examined the characteristics of the entire inpatient sample based on the presence of decubitus ulcers, temporal trends, risk of decubitus ulcer development, and its association with healthcare utilization, measured by discounted hospital charges and length of stay. The multivariate survey logistic regression model was used to identify predictors for decubitus ulcer occurrence, and the survey linear regression model was used to measure how decubitus ulcers are associated with healthcare utilization.

Results

Among 48,786,216 nationwide inpatients, 3.9% had decubitus ulcers. The percentage of inpatients with decubitus ulcers who subsequently experienced increased healthcare utilization rose with time. The survey logistic regression results indicate that patients who were Black, older, male, or those reliant on Medicare/Medicaid had a statistically significant increased risk of decubitus ulcers. The survey linear regression results demonstrate that inpatients with decubitus ulcers were associated with increased hospital charges and longer lengths of stay.

Conclusions

Patients with government insurance, those of minority races and ethnicities, and those treated in the Northeast and West may be more vulnerable to pressure ulcers and subsequent increased healthcare utilization. Implementation of early prevention methods in these populations is necessary to minimize the risk of developing decubitus ulcers, even if upfront costs may be increased. For example, larger hospitals were found to have a lower risk of decubitus ulcer development but an increased cost of preventative care. Hence, it is imperative to explore and use universal, targeted preventative methods to improve patient safety.
Urine tenofovir and dried blood spot tenofovir diphosphate concentrations and viraemia in people taking efavirenz and dolutegravir-based antiretroviral therapy
Authors: Dorward Jienchi , Govender Katya , Moodley Pravikrishnen , Lessells Richard , Samsunder Natasha , Sookrajh Yukteshwar , Fanshawe Thomas R. , Turner Philip J. , Butler Christopher C. , Drain Paul K. , Hayward Gail N. , Garrett Nigel
Published: December 2023

Objective:

We aimed to determine whether urine tenofovir (TFV) and dried blood spot (DBS) tenofovir diphosphate (TFV-DP) concentrations are associated with concurrent HIV viraemia.

Design:

Cross-sectional study among people with HIV (PWH) receiving tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy (ART).

Methods:

We used dual tandem liquid chromatography and mass spectrometry to measure urine TFV and DBS TFV-DP concentrations, and evaluated their associations with concurrent viraemia at least 1000 copies/ml using logistic regression models. In exploratory analyses, we used receiver operating curves (ROCs) to estimate optimal urine TFV and DBS TFV-DP thresholds to predict concurrent viraemia.

Results:

Among 124 participants, 68 (54.8%) were women, median age was 39 years [interquartile range (IQR) 34–45] and 74 (59.7%) were receiving efavirenz versus 50 (40.3%) receiving dolutegravir. Higher concentrations of urine TFV [1000 ng/ml increase, odds ratio (OR) 0.97 95% CI 0.94–0.99, P = 0.005] and DBS TFV-DP (100 fmol/punch increase, OR 0.76, 95% CI 0.67–0.86, P < 0.001) were associated with lower odds of viraemia. There was evidence that these associations were stronger among people receiving dolutegravir than among people receiving efavirenz (urine TFV, P = 0.072; DBS TFV-DP, P = 0.003). Nagelkerke pseudo-R
2 for the DBS TFV-DP models was higher for the urine TFV models, demonstrating a stronger relationship between DBS TFV-DP and viraemia. Among people receiving dolutegravir, a DBS TFV-DP concentration of 483 fmol/punch had 88% sensitivity and 85% specificity to predict concurrent viraemia ≥1000 copies/ml.

Conclusion:

Among PWH receiving TDF-based ART, urine TFV concentrations, and in particular DBS TFV-DP concentrations, were strongly associated with concurrent viraemia, especially among people receiving dolutegravir.
Incidence, description, predictors, and consequences of persistent taxane-induced peripheral neuropathy
Authors: Hertz Daniel L.
Published: December 2023

Purpose of review

This review aims to provide insights into persistent taxane-induced peripheral neuropathy (TIPN). The primary objective is to describe the incidence, predictors, and consequences of TIPN lasting at least 1 year after the end of taxane treatment.

Recent findings

Studies show varying rates of TIPN persistence, with an estimated 30–40% and 40–60% resolving by 1- and 3-year post-treatment. TIPN in the feet and motor symptoms show less resolution post-treatment. Patients who are older or have higher body weight may experience less TIPN resolution, but results may be confounded by TIPN development during treatment. Persistent TIPN negatively impacts long-term functional ability, including gait, balance, and the ability to work. It also reduces overall quality of life (QOL), particularly affecting physical and social aspects.

Clinicians should be aware of the potential for persistent TIPN and its impact on patients’ function and QOL. Future research should focus on large prospective studies with systematic TIPN assessments during and after treatment to better understand which symptoms and patient characteristics predict resolution. This information can guide treatment decisions, balancing the need for effective chemotherapy with minimizing long-term impairments in function and QOL.
Proportion of Hospitalizations Preventable with Increased Oral SARS-CoV-2 Antiviral Treatment
Authors: Levy Matthew E. , Chilunda Vanessa , Heaton Phillip R. , Grzymski Joseph , Pawloski Pamala A. , Goldman Jason D. , Luo Shishi
Published: December 2023

We estimated the proportion of hospitalizations that could have been averted had all eligible high-risk adults with SARS-CoV-2 infection in a clinical cohort been treated with an oral SARS-CoV-2 antiviral agent early in infection. Among 3,037 patients with risk factors for progressing to severe COVID-19, 946 (31.1%) received an oral antiviral prescription (834 nirmatrelvir and 112 molnupiravir). Only 3.0% of treated patients vs 9.1% of untreated patients were hospitalized (adjusted risk ratio [RR]=0.27; 95% confidence interval [CI]: 0.18-0.41). If all patients had been treated, an estimated 63.3% (95% CI: 50.4-75.1) of hospitalizations within 30 days could have been prevented. This finding is attributed to large gaps in treatment and a strong protective association of antiviral treatment with subsequent hospitalization.
“Fire! Do Not Fire!”: A new paradigm testing how autonomous systems affect agency and moral decision-making
Authors: Salatino Adriana , Prével Arthur , Caspar Émilie , Bue Salvatore Lo
Published: December 2023

Autonomous systems have pervaded many aspects of human activities. However, research suggest that the interaction with those machines may influence human decision-making processes. These effects raise ethical concerns in moral situations. We created an ad hoc setup to investigate the effects of system autonomy on moral decision-making and human agency in a trolley-like dilemma. In a battlefield simulation, participants had to decide whether to initiate an attack depending on conflicting moral values. Our results suggest that our paradigm is suitable for future research aimed at understanding the effects of system autonomy on moral decision -making and human agency.
Predicting the Trend of SARS-CoV-2 Mutation Frequencies Using Historical Data
Authors: Zhou Xinyu , Hu Kevin , Pan Minmin , Li Yajie , Zhang Chi , Cao Sha
Published: December 2023

As the SARS-CoV-2 virus rapidly evolves, predicting the trajectory of viral variations has become a critical yet complex task. A deep understanding of future mutation patterns, in particular the mutations that will prevail in the near future, is vital in steering diagnostics, therapeutics, and vaccine strategies in the coming months.

In this study, we developed a model to forecast future SARS-CoV-2 mutation surges in real-time, using historical mutation frequency data from the USA. To improve upon the accuracy of traditional time-series models, we transformed the prediction problem into a supervised learning framework using a sliding window approach. This involved breaking the time series of mutation frequencies into very short segments. Considering the time-dependent nature of the data, we focused on modeling the first-order derivative of the mutation frequency. We predicted the final derivative in each segment based on the preceding derivatives, employing various machine learning methods, including random forest, XGBoost, support vector machine, and neural network models, in this supervised learning setting. Empowered by the novel transformation strategy and the high capacity of machine learning models, we witnessed low prediction error that is confined within 0.1% and 1% when making predictions for future 30 and 80 days respectively. In addition, the method also led to a notable increase in prediction accuracy compared to traditional time-series models, as evidenced by lower MAE, and MSE for predictions made within different time horizons. To further assess the method’s effectiveness and robustness in predicting mutation patterns for unforeseen mutations, we categorized all mutations into three major patterns. The model demonstrated its robustness by accurately predicting unseen mutation patterns when training on data from two pattern categories while testing on the third pattern category, showcasing its potential in forecasting a variety of mutation trajectories.

To enhance accessibility and utility, we built our methodology into an R-shiny app (https://swdatpredicts.shinyapps.io/rshiny_predict/), a tool with potential applicability in studying other infectious diseases, thus extending its relevance beyond the current pandemic.
Genome-wide characterization of 54 urinary metabolites reveals molecular impact of kidney function
Authors: Valo Erkka , Richmond Anne , Mutter Stefan , Campbell Archie , Porteous David , Wilson James F ,   FinnDiane Study Group, Groop Per-Henrik , Hayward Caroline , Sandholm Niina
Published: December 2023

Dissecting the genetic mechanisms underlying urinary metabolite concentrations can provide molecular insights into kidney function and open possibilities for causal assessment of urinary metabolites with risk factors and disease outcomes. Proton nuclear magnetic resonance metabolomics provides a high-throughput means for urinary metabolite profiling, as widely applied for blood biomarker studies. Here we report a genome-wide association study meta-analysed for 3 European cohorts comprising 8,026 individuals, covering both people with type 1 diabetes and general population settings. We identified 52 associations (p<9.3×10-10) for 19 of 54 studied metabolite concentrations. Out of these, 32 were not reported previously for relevant urinary or blood metabolite traits. Subsequent two-sample Mendelian randomization analysis suggests that estimated glomerular filtration rate (eGFR) causally affects 13 urinary metabolite concentrations whereas urinary ethanolamine, an initial precursor for phosphatidylcholine and phosphatidylethanolamine, was associated with higher eGFR lending support for a potential protective role.
Prevalence study of cellular capsid-specific immune responses to AAV2, 4, 5, 8, 9 and rh10 in healthy donors
Authors: Xicluna Rebecca , Avenel Allan , Vandamme Céline , Devaux Marie , Jaulin Nicolas , Couzinie Célia , Le Duff Johanne , Charrier Alicia , Guilbaud Mickaël , Adjali Oumeya , Gernoux Gwladys
Published: December 2023

Recombinant adeno-associated virus (rAAV) vectors appear, more than ever, to be efficient viral vectors forin vivogene transfer as illustrated by the approvals of 7 drugs across Europe and the USA. Nevertheless, pre-existing immunity to AAV capsid in humans remains one of the major limits for a successful clinical translation. Whereas pre-existing humoral response to AAV capsid is well documented, the prevalence of pre-existing capsid-specific T cell responses still needs to be studied and characterized. Here, we investigated the prevalence of AAV-specific circulating T cells towards AAV2, 4, 5, 8, 9 and rh10 in a large cohort of healthy donors using the standard IFNγ ELISpot assay. We observed the highest prevalence of pre-existing cellular immunity to AAV9 serotype followed by AAV8, AAV4, AAV2, AAVrh10 and AAV5 independently of the donors’ serological status. An in-depth analysis of T cell responses towards the 2 most prevalent serotypes 8 and 9 shows that IFNγ secretion is mainly mediated by CD8 T cells for both serotypes. A polyfunctional analysis reveals different cytokine profiles between AAV8 and AAV9. Surprisingly, no IL-2 secretion was mediated by anti-AAV9 immune cells suggesting that these cells may rather be exhausted or terminally differentiated than cytotoxic T cells. Altogether, these results suggest that pre-existing immunity to AAV may vary depending on the serotype and support the necessity of using multiparametric monitoring methods to better characterize anti-capsid cellular immunity and foresee its impact in rAAV-mediated clinical trials.
Spatial propagation of temperate phages within and among biofilms
Authors: Winans James B. , Garcia Sofia L. , Zeng Lanying , Nadell Carey D.
Published: December 2023

Bacteria form groups comprised of cells and a secreted polymeric matrix that controls their spatial organization. These groups – termed biofilms – can act as refuges from environmental disturbances and from biotic threats, including phages. Despite the ubiquity of temperate phages and bacterial biofilms, live propagation of temperate phages within biofilms has never been characterized on cellular spatial scales. Here, we leverage several approaches to track temperate phages and distinguish between lytic and lysogenic host infections. We determine that lysogeny withinE. colibiofilms initially occurs within a predictable region of cell group packing architecture on the biofilm periphery. Because lysogens are generally found on the periphery of large cell groups, where lytic viral infections also reduce local biofilm cell packing density, lysogens are predisposed to disperse into the passing liquid and are over-represented in biofilms formed from the dispersal pool of the original biofilm-phage system. Comparing our results with those for virulent phages reveals that temperate phages have previously unknown advantages in propagating over long spatial and time scales within and among bacterial biofilms.
Nanotopography boosts cellular uptake by inducing macropinocytosis
Authors: Aramesh Morteza , Yu Di , Essand Magnus , Persson Cecilia
Published: December 2023

Efficient cellular uptake of biomolecules, including genetic material, mRNA, proteins, and nanoparticles, requires novel approaches to overcome inherent cellular barriers. This study investigates how nanotopographical cues from nanoporous surfaces impact the uptake efficiency of diverse molecules by cells. The results demonstrate that cellular uptake efficiency increases significantly on nanoporous surfaces compared to flat surfaces. Notably, this process is found to be dependent on the size and morphology of the nanopores, reaching its peak efficacy with blind pores of 400 nm in size. Enhanced genetic transduction on nanoporous surfaces were observed for multiple vectors, including lentiviruses, baculoviruses, and mRNA molecules. The versatile nature of this approach allows co-transfection of cells with multiple mRNA vectors. Moreover, the nanoporous platform was used for efficient and fast manufacturing of CAR-T cells through lentiviral transduction. Furthermore, we pinpoint macropinocytosis as the predominant mechanism driving increased cellular uptake induced by the nanoporous surfaces. The method introduced here for enhancing genetic transduction of cells has applications in immunotherapy research, drug delivery, and cell engineering.
Rewriting regulatory DNA to dissect and reprogram gene expression
Authors: Martyn Gabriella E. , Montgomery Michael T. , Jones Hank , Guo Katherine , Doughty Benjamin R. , Linder Johannes , Chen Ziwei , Cochran Kelly , Lawrence Kathryn A. , Munson Glen , Pampari Anusri , Fulco Charles P. , Kelley David R. , Lander Eric S. , Kundaje Anshul , Engreitz Jesse M.
Published: December 2023

Regulatory DNA sequences within enhancers and promoters bind transcription factors to encode cell type-specific patterns of gene expression. However, the regulatory effects and programmability of such DNA sequences remain difficult to map or predict because we have lacked scalable methods to precisely edit regulatory DNA and quantify the effects in an endogenous genomic context. Here we present an approach to measure the quantitative effects of hundreds of designed DNA sequence variants on gene expression, by combining pooled CRISPR prime editing with RNA fluorescencein situhybridization and cell sorting (Variant-FlowFISH). We apply this method to mutagenize and rewrite regulatory DNA sequences in an enhancer and the promoter ofPPIFin two immune cell lines. Of 672 variant-cell type pairs, we identify 497 that affectPPIFexpression. These variants appear to act through a variety of mechanisms including disruption or optimization of existing transcription factor binding sites, as well as creation ofde novosites. Disrupting a single endogenous transcription factor binding site often led to large changes in expression (up to –40% in the enhancer, and –50% in the promoter). The same variant often had different effects across cell types and states, demonstrating a highly tunable regulatory landscape. We use these data to benchmark performance of sequence-based predictive models of gene regulation, and find that certain types of variants are not accurately predicted by existing models. Finally, we computationally design 185 small sequence variants (≤10 bp) and optimize them for specific effects on expressionin silico. 84% of these rationally designed edits showed the intended direction of effect, and some had dramatic effects on expression (–100% to +202%). Variant-FlowFISH thus provides a powerful tool to map the effects of variants and transcription factor binding sites on gene expression, test and improve computational models of gene regulation, and reprogram regulatory DNA.
Mitochondria-derived nuclear ATP surge protects against confinement-induced proliferation defects
Authors: Ghose Ritobrata , Pezzano Fabio , Kourtis Savvas , Sheraj Ilir , Das Shubhamay , Zapater Antoni Gañez , Ghose Upamanyu , Espinar Lorena , Parapatics Katja , Venturini Valeria , Müller André C , Ruprecht Verena , Sdelci Sara
Published: December 2023

The physical microenvironment regulates cell behaviour. However, whether physical confinement rewires the subcellular localisation of organelles and affect metabolism is unknown. Proteomics analysis revealed that cellular confinement induces a strong enrichment of mitochondrial proteins within the nuclear compartment. High-resolution microscopy confirmed that mechanical cell confinement leads to a rapid re-localisation of mitochondria to the nuclear periphery. This nuclear-mitochondrial proximity is mediated by an endoplasmic reticulum-based net that entraps the mitochondria in an actin-dependent manner. Functionally, the mitochondrial proximity results in a nuclear ATP surge, which can be reverted by the pharmacological inhibition of mitochondrial ATP production or via actin depolymerisation. Inhibition of the confinement-derived nuclear ATP surge reveals long-term effects on cell fitness which arise from alterations of chromatin states, delayed DNA damage repair, and impaired cell cycle progression. Together, our data describe a confinement-induced metabolic adaptation that is required to enable prompt DNA damage repair and cell cycle progression by allowing chromatin state transitions.
Sculpting conducting nanopore size and shape throughde novoprotein design
Authors: Berhanu Samuel , Majumder Sagardip , Müntener Thomas , Whitehouse James , Berner Carolin , Bera Asim K. , Kang Alex , Liang Binyong , Khan G Nasir , Sankaran Banumathi , Tamm Lukas K. , Brockwell David J. , Hiller Sebastian , Radford Sheena E. , Baker David , Vorobieva Anastassia A.
Published: December 2023

Transmembrane β-barrels (TMBs) are widely used for single molecule DNA and RNA sequencing and have considerable potential for a broad range of sensing and sequencing applications. Current engineering approaches for nanopore sensors are limited to naturally occurring channels such as CsgG, which have evolved to carry out functions very different from sensing, and hence provide sub-optimal starting points. In contrast,de novoprotein design can in principle create an unlimited number of new nanopores with any desired properties. Here we describe a general approach to the design of transmembrane β-barrel pores with different diameter and pore geometry. NMR and crystallographic characterization shows that the designs are stably folded with structures close to the design models. We report the first examples ofde novodesigned TMBs with 10, 12 and 14 stranded β-barrels. The designs have distinct conductances that correlate with their pore diameter, ranging from 110 pS (∼0.5 nm pore diameter) to 430 pS (∼1.1 nm pore diameter), and can be converted into sensitive small-molecule sensors with high signal to noise ratio. The capability to generate on demand β-barrel pores of defined geometry opens up fundamentally new opportunities for custom engineering of sequencing and sensing technologies.

One sentence summary

De novo design enables the generation of stable and quite transmembrane beta-barrel nanopores with tailored sizes, shapes and properties.
Low land-use intensity buffers grasslands against future climate and inter-annual climate variability in a large field experiment
Authors: Korell Lotte , Andrzejak Martin , Berger Sigrid , Durka Walter , Haider Sylvia , Hensen Isabell , Herion Yva , Höfner Johannes , Kindermann Liana , Klotz Stefan , Knight Tiffany M. , Linstädter Anja , Madaj Anna-Maria , Merbach Ines , Michalski Stefan , Plos Carolin , Roscher Christiane , Schädler Martin , Welk Erik , Auge Harald
Published: December 2023

Climate and land-use change are key drivers of global change. Full-factorial field experiments in which both drivers are manipulated are essential to understand and predict their potentially interactive effects on the structure and functioning of grassland ecosystems. Here, we present eight years of data on grassland dynamics from the Global Change Experimental Facility (GCEF) in Central Germany. On large experimental plots, temperature and seasonal patterns of precipitation are manipulated by superimposing regional climate model projections onto background climate variability. Climate manipulation is factorially crossed with agricultural land-use scenarios, including intensively used meadows and extensively used (i.e. low-intensity) meadows and pastures. Inter-annual variation of background climate during our study years was high, including three of the driest years on record for our region. The effects of this temporal variability far exceeded the effects of the experimentally imposed climate change on plant species diversity and productivity, especially in the intensively used, species-poor grasslands. These changes in productivity and diversity in response to alterations in climate were due to immigrant species replacing the target forage cultivars. This shift from forage cultivars to immigrant species may impose additional economic costs in terms of a decreasing fodder value and the need for more frequent management measures. In contrast, the extensively used, species-rich grasslands showed weaker responses to both experimentally manipulated future climate and inter-annual climate variability, suggesting that these diverse grasslands are more resistant to climate change than intensively used, species-poor grasslands. We therefore conclude that an extensive management of agricultural grasslands, together with other measures to increase species diversity, can stabilize primary productivity under climate change.
MUT-7 exoribonuclease activity and localisation are mediated by an ancient domain
Authors: Busetto Virginia , Pshanichnaya Lizaveta , Lichtenberger Raffael , Hann Stephan , Ketting René F. , Falk Sebastian
Published: December 2023

The MUT-7 family of 3’-5’ exoribonucleases is evolutionarily conserved across the animal kingdom and plays essential roles in small RNA production in the germline. Most MUT-7 homologs carry a C-terminal domain of unknown function named MUT7-C appended to the exoribonuclease domain. Our analysis shows that the MUT7-C is evolutionary ancient, as a minimal version of the domain exists as an individual protein in prokaryotes. In animals, MUT7-C has acquired an insertion that diverged during evolution, expanding its functions.C. elegansMUT-7 contains a specific insertion within MUT7-C, which allows binding to MUT-8 and, consequently, MUT-7 recruitment to germ granules. In addition, inC. elegansand human MUT-7, the MUT7-C domain contributes to RNA binding and is thereby crucial for nuclease activity. This RNA-binding function most likely represents the ancestral function of the MUT7-C domain. Overall, this study sheds light on MUT7-C and assigns two functions to this previously uncharacterised domain.
The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1
Authors: Honzejkova Karolina , Košek Dalibor , Obsilova Veronika , Obsil Tomas
Published: December 2023

Apoptosis signal-regulating kinase 1 (ASK1) is a crucial stress sensor, directing cells towards apoptosis, differentiation and senescence via the p38 and JNK signaling pathways. ASK1 dysregulation has been associated with cancer and inflammatory, cardiovascular and neurodegenerative diseases, among others. However, our limited knowledge of the underlying structural mechanism of ASK1 regulation hampers our ability to target this member of the MAP3K protein family towards developing therapeutic interventions for these disorders. Nevertheless, as a multidomain Ser/Thr protein kinase, ASK1 is regulated by a complex mechanism involving dimerization and interactions with several other proteins, including thioredoxin 1 (TRX1). Thus, the present study aims at structurally characterizing ASK1 and its complex with TRX1 using several biophysical techniques. As shown by cryo-EM analysis, in a state close to its active form, ASK1 is a compact and asymmetric dimer, which enables extensive interdomain and interchain interactions. These interactions stabilize the active conformation of the ASK1 kinase domain. In turn, TRX1 functions as a negative allosteric effector of ASK1, modifying the structure of the TRX1-binding domain and changing its interaction with the tetratricopeptide repeats domain. Consequently, TRX1 reduces access to the activation segment of the kinase domain. Overall, our findings not only clarify the role of ASK1 dimerization and inter-domain contacts but also provide key mechanistic insights into its regulation, thereby highlighting the potential of ASK1 protein-protein interactions as targets for antiinflammatory therapy.
Genetic drift drives faster-Z evolution in the salmon louseLepeophtheirus salmonis
Authors: Mongue Andrew J. , Baird Robert B.
Published: December 2023

Sex chromosome evolution is a particularly complex sub-field of population genetics and there are still unresolved questions about how quickly and adaptively these chromosomes should evolve compared to autosomes. One key limitation to existing knowledge is an intense focus on only a handful of taxa in existing literature, resulting in uncertainty about whether observed patterns reflect general processes or are idiosyncratic to the more widely studied clades. In particular, the Z chromosomes of female heterogametic (ZW) systems tend to be quickly but not adaptively evolving in birds, while in butterflies and moths Z chromosomes tend to be evolving adaptively, but not always faster than autosomes. To understand how these two observations fit into broader evolutionary patterns, we explore, for the first time, patterns of Z chromosome evolution outside of these two well-studied clades. We utilize a publicly available high quality genome, gene expression, population, and outgroup data for the salmon louseLepeophtheirus salmonis, an important aquacultural pest copepod. We find that the Z chromosome is faster evolving than the autosomes, but that this increased effect is driven by drift rather than adaptive evolution. This faster-Z effect seems to be a result of a very low effective population size of the Z chromosome, as well as high rates of female reproductive failure contributing to decreased efficiency of hemizygous selection acting on the Z. These results highlight the usefulness of organismal life history in calibrating population genetic expectations and demonstrate the usefulness of the ever-expanding wealth of modern publicly available genomic data to help resolve outstanding evolutionary questions.
L-Glyceraldehyde inhibits neuroblastoma cell growth via a multi-modal mechanism on metabolism and signaling
Authors: Forbes Martin , Kempa Richard , Mastrobuoni Guido , Rayman Liam , Pietzke Matthias , Bayram Safak , Arlt Birte , Spruessel Annika , Deubzer Hedwig , Kempa Stefan
Published: December 2023

Glyceraldehyde (GA) is a 3-carbon monosaccharide that can be present in cells as a by-product of fructose metabolism. Bruno Mendel and Otto Warburg showed that the application of GA to cancer cells inhibits glycolysis and their growth. This phenomenon was extensively studied up until the 1970’s. However, the molecular mechanism by which this occurred was not clarified. We describe a novel multi-modal mechanism by which the L-isomer of GA (L-GA) inhibits cancer cell growth. L-GA induces significant changes in the metabolic profile, promotes oxidative stress and hinders nucleotide biosynthesis. GC-MS and13C-labelling was employed to measure the flow of carbon through glycolytic intermediates under L-GA treatment. It was found that L-GA is a potent inhibitor of glycolysis due to its proposed targeting of NAD(H)-dependent reactions. This results in growth inhibition, apoptosis and a redox crisis in the cancer cell. It was confirmed that the redox mechanisms were modulated via L-GA by proteomic analysis. This elucidated a specific subset of proteins harbouring oxidoreductase and antioxidant activity. Analysis of nucleotide pools in L-GA treated cells depicted a remarkable and previously unreported phenotype. Nucleotide biosynthesis in neuroblastoma cells is significantly inhibited upon L-GA treatment. Through the application of the antioxidant N-acetyl-cysteine in conjunction with L-GA, metabolic inhibition was partially relieved. We present novel evidence for the multi-modal mechanism of L-GA action in neuroblastoma cells. Specifically, a simple sugar that inhibits the growth of cancer via dysregulating the fragile homeostatic environment inherent to the cancerous cell.
Early transcriptional similarities between two distinct neural lineages during ascidian embryogenesis
Authors: Copley Richard R , Buttin Julia , Arguel Marie-Jeanne , Williaume Géraldine , Lebrigand Kevin , Barbry Pascal , Hudson Clare , Yasuo Hitoyoshi
Published: December 2023

In chordates, the central nervous system arises from precursors that have distinct developmental and transcriptional trajectories. Anterior nervous systems are ontogenically associated with ectodermal lineages while posterior nervous systems are associated with mesoderm. Taking advantage of the well-documented cell lineage of ascidian embryos, we asked how the transcriptional states of the different neural lineages become similar during the course of progressive lineage restriction. We performed single-cell RNA sequencing (scRNA-seq) analyses on hand-dissected neural precursor cells of the two distinct lineages, together with those of their sister cell lineages, with a high temporal resolution covering five successive cell cycles from the 16-cell to neural plate stages. A transcription factor binding site enrichment analysis of neural specific genes at the neural plate stage revealed limited evidence for shared transcriptional control between the two neural lineages, consistent with their different ontogenies. Nevertheless, PCA analysis and hierarchical clustering showed that, by neural plate stages, the two neural lineages cluster together. Consistent with this, we identified a set of genes enriched in both neural lineages at the neural plate stage, includingmiR-124, CELF3/5/6, Zic.r-b,andEts1/2.
The role of satellite cell-derived TRIM28 in mechanical load- and injury-induced myogenesis
Authors: Lin Kuan-Hung , Hibbert Jamie E , Lemens Jake L , Torbey Melissa M. , Steinert Nathaniel D. , Flejsierowicz Philip M. , Melka Kiley M. , Lares Marcos , Setaluri Vijayasaradhi , Hornberger Troy A.
Published: December 2023

Satellite cells are skeletal muscle stem cells that contribute to postnatal muscle growth, and they endow skeletal muscle with the ability to regenerate after a severe injury. Here we discovered that this myogenic potential of satellite cells requires a protein called tripartite motif-containing 28 (TRIM28). Unexpectedly, multiple lines of both in vitro and in vivo evidence revealed that the myogenic function of TRIM28 is not dependent on changes in the phosphorylation of its serine 473 residue. Moreover, the functions of TRIM28 were not mediated through the regulation of satellite cell proliferation or differentiation. Instead, our findings indicate that TRIM28 regulates the ability of satellite cells to progress through the process of fusion. Specifically, we discovered that TRIM28 controls the expression of a fusogenic protein called myomixer and concomitant fusion pore formation. Collectively, the outcomes of this study expose the framework of a novel regulatory pathway that is essential for myogenesis.
Model-Based Closed-Loop Control of Thalamic Deep Brain Stimulation
Authors: Tian Yupeng , Saradhi Srikar , Bello Edward , Johnson Matthew , D’Eleuterio Gabriele , Popovic Milos R. , Lankarany Milad
Published: December 2023

Closed-loop control of deep brain stimulation (DBS) is crucial for effective and automatic treatments of various neurological disorders like Parkinson’s disease (PD) and essential tremor (ET). Manual (open-loop) DBS programming solely based on clinical observations relies on neurologists’ expertise and patients’ experience. The continuous stimulation in open-loop DBS may decrease battery life and cause side effects. On the contrary, a closed-loop DBS system utilizes a feedback biomarker/signal to track worsening (or improving) patient’s symptoms and offers several advantages compared to open-loop DBS. Existing closed-loop DBS control systems do not incorporate physiological mechanisms underlying the DBS or symptoms, for example how DBS modulates dynamics of synaptic plasticity. In this work, we proposed a computational framework for development of a model-based DBS controller where a biophysically-reasonable model can describe the relationship between DBS and neural activity, and a polynomial-based approximation can estimate the relationship between the neural and behavioral activity. A controller is utilized in our model in a quasi-real-time manner to find DBS patterns that significantly reduce the worsening of symptoms. These DBS patterns can be tested clinically by predicting the effect of DBS before delivering it to the patient. We applied this framework to the problem of finding optimal DBS frequencies for essential tremor given EMG recordings solely. Building on our recent network model of ventral intermediate nuclei (Vim), the main surgical target of the tremor, in response to DBS, we developed a biophysically-reasonable simulation in which physiological mechanisms underlying Vim-DBS are linked to symptomatic changes in EMG signals. By utilizing a PID controller, we showed that a closed-loop system can track EMG signals and adjusts the stimulation frequency of Vim-DBS so that the power of EMG in [2, 200] Hz reaches a desired target. We demonstrated that our model-based closed-loop control system of Vim-DBS finds an appropriate DBS frequency that aligns well with clinical studies. Our model-based closed-loop system is adaptable to different control targets, highlighting its potential usability for different diseases and personalized systems.
DNA barcoding reveals an increased diversity within the genusCulex(Diptera: Culicidae) in Ireland
Authors: Curran Thomas G. , O’Hanlon Aidan , Gallagher Finán , Pedersen Rasmus S. , Zintl Annetta , Isiye Elsie , Olmeda Angela Valcarcel , O’Neill David , McDevitt Allan D. , O’Reilly Catherine , O’Meara Denise B.
Published: December 2023

Arthropod populations are changing globally due to the combined impacts of climate change, land-use transformation, globalisation and trade. Changes in arthropod populations can potentially result in the decline and extinction of some native and/or endemic species, while other species that potentially pose threats may increase. Such dynamics lead to weakened ecosystem resilience, which can facilitate the establishment and spread of species with vector capabilities, such as mosquitoes. While many of the mosquito species present in Ireland possess vector capabilities, populations have not been nationally surveyed since 1991. At that time, species identification relied on morphological examination, a method that was even then recognised as inadequate for differentiating certain species within complexes. In this study, we present the first DNA barcoding investigation of Irish mosquito populations and reveal species and hidden diversity not previously recognised in Ireland. These include two potential new species/ecotypes,Culex torrentiumandCulex pipiensformpipiens, which were recorded for the first time in Ireland. We demonstrate that barcoding with Cytochrome C Oxidase Subunit 1 (COI) based primers is suitable for the majority of species-level identifications. However, additional primer sets targeting the Internal Transcribed Spacer regions 1 and 2 (ITS1 and ITS2) were necessary to differentiate species within theCulex pipienscomplex. The multi-locus approach employed in this study can enhance national surveillance efforts, especially in monitoring mosquitoes that may transmit vector-borne diseases, and in recognising increased species diversity from a biodiversity perspective.
Estimating Genome-wide Phylogenies Using Probabilistic Topic Modeling
Authors: Khodaei Marzieh , Edwards Scott V. , Beerli Peter
Published: December 2023

Abstract

Methods for rapidly inferring the evolutionary history of species or populations with genome-wide data are progressing, but computational constraints still limit our abilities in this area. We developed an alignment-free method to infer genome-wide phylogenies and implemented it in the Python package TopicContml. The method uses probabilistic topic modeling (specifically, Latent Dirichlet Allocation or LDA) to extract ‘topic’ frequencies fromk-mers, which are derived from multilocus DNA sequences. These extracted frequencies then serve as an input for the program Contmlin the PHYLIP package, which is used to generate a species tree. We evaluated the performance of TopicContmlon simulated datasets with gaps and three biological datasets: (1) 14 DNA sequence loci from two Australian bird species distributed across nine populations, (2) 5162 loci from 80 mammal species, and (3) raw, unaligned, non-orthologous PacBiosequences from 12 bird species. Our empirical results and simulated data suggest that our method is efficient and statistically robust. We also assessed the uncertainty of the estimated relationships among clades using a bootstrap procedure.
Assembly and analysis of the genome ofNotholithocarpus densiflorus
Authors: Cai Ying , Anderson Ellis , Xue Wen , Wong Sylvia , Cui Luman , Cheng Xiaofang , Wang Ou , Mao Qing , Liu Sophie Jia , Davis John T. , Magalang Paulo R. , Schmidt Douglas , Kasuga Takao , Garbelotto Matteo , Drmanac Radoje , Kua Chai-Shian , Cannon Charles , Maloof Julin N. , Peters Brock A.
Published: December 2023

Tanoak (Notholithocarpus densiflorus) is an evergreen tree in the Fagaceae family found in California and southern Oregon. Historically, tanoak acorns were an important food source for Native American tribes and the bark was used extensively in the leather tanning process. Long considered a disjunct relictual element of the Asian stone oaks (Lithocarpus spp.), phylogenetic analysis has determined that the tanoak is an example of convergent evolution. Tanoaks are deeply divergent from oaks (Quercus) of the Pacific Northwest and comprise a new genus with a single species. These trees are highly susceptible to ‘sudden oak death’ (SOD), a plant pathogen (Phytophthora ramorum) that has caused widespread mortality of tanoaks. Here, we set out to assemble the genome and perform comparative studies among a number of individuals that demonstrated varying levels of susceptibility to SOD. First, we sequenced andde novoassembled a draft reference genome ofN. densiflorususing co-barcoded library processing methods and an MGI DNBSEQ-G400 sequencer. To increase the contiguity of the final assembly, we also sequenced Oxford Nanopore (ONT) long reads to 30X coverage. To our knowledge, the draft genome reported here is one of the more contiguous and complete genomes of a tree species published until now, with a contig N50 of ∼1.2 Mb and a scaffold N50 of ∼2.1 Mb. In addition, we sequenced 11 genetically distinct individuals and mapped these onto the draft reference genome enabling the discovery of almost 25 million single nucleotide polymorphisms and ∼4.4 million small insertions and deletions. Finally, using co-barcoded data we were able to generate complete haplotype coverage of all 11 genomes.
Systematic cross-species comparison of prefrontal cortex functional networks targeted via Transcranial Magnetic Stimulation
Authors: Berger Taylor , Xu Ting , Opitz Alexander
Published: December 2023

Transcranial Magnetic Stimulation (TMS) is a non-invasive brain stimulation method that safely modulates neural activity in vivo. Its precision in targeting specific brain networks makes TMS invaluable in diverse clinical applications. For example, TMS is used to treat depression by targeting prefrontal brain networks and their connection to other brain regions. However, despite its widespread use, the underlying neural mechanisms of TMS are not completely understood. Non-human primates (NHPs) offer an ideal model to study TMS mechanisms through invasive electrophysiological recordings. As such, bridging the gap between NHP experiments and human applications is imperative to ensure translational relevance. Here, we systematically compare the TMS-targeted functional networks in the prefrontal cortex in humans and NHPs. To conduct this comparison, we combine TMS electric field modeling in humans and macaques with resting-state functional magnetic resonance imaging (fMRI) data to compare the functional networks targeted via TMS across species. We identified distinct stimulation zones in macaque and human models, each exhibiting variations in the impacted networks (macaque: Frontoparietal Network, Somatomotor Network; human: Frontoparietal Network, Default Network). We identified differences in brain gyrification and functional organization across species as the underlying cause of found network differences. The TMS-network profiles we identified will allow researchers to establish consistency in network activation across species, aiding in the translational efforts to develop improved TMS functional network targeting approaches.
Synaptic mechanisms modulate the spatiotemporal dynamics of striatal direct pathway neurons and motor output
Authors: Marshall John J , Xu Jian , Yeh Nai-Hsing , Yun Seongsik , Nomura Toshihiro , Armstrong John N , Parker Jones G , Contractor Anis
Published: December 2023

Striatal spiny-projection neurons (SPNs) integrate glutamatergic inputs from the motor cortex and thalamus with neuromodulatory signals to regulate motor output.In vivoCa2+imaging has demonstrated that ensembles of direct and indirect pathway SPNs (dSPNs, iSPNs) are coactive during spontaneous movement. Co-activity is statistically greater among nearby neurons, correlates with behavioral state, and undergoes plasticity in an SPN-type-specific manner under pathological conditions. This spatially clustered co-activity could reflect shared excitatory inputs. However, whether and how synaptic mechanisms generate this distinctive spatiotemporal activity is unknown. Here, we show that the Group I metabotropic glutamate receptor 5 (mGluR5), which regulates synaptic strength at corticostriatal synapses, is a key mediator of spatially clustered SPN co-activity. Pharmacological modulation of mGluR5 signaling bidirectionally altered movement and spatially clustered dynamics, but not the absolute level of activity of dSPNs. Targeted deletion of mGluR5 in dSPNs recapitulated the effects on spatiotemporal neural dynamics and movement demonstrating a striatum-specific effect of mGluR5. Targeted deletion of mGluR5 also produced changes in the synaptic properties of dSPNs. These results show that properties of excitatory synapses influence motor function by shaping the characteristic spatially clustered patterns of co-activity that typify dSPN activationin vivo.
Cohesin and CTCF do not assemble TADs inXenopussperm and male pronuclei
Authors: Jessberger Gregor , Várnai Csilla , Stocsits Roman R. , Tang Wen , Stary Georg , Peters Jan-Michael
Published: December 2023

Paternal genomes are compacted during spermiogenesis and decompacted following fertilization. These processes are fundamental for inheritance but incompletely understood. We analyzed these processes in the frogXenopus laevis, whose sperm can be assembled into functional pronuclei in egg extracts in vitro. In such extracts, cohesin extrudes DNA into loops, but in vivo cohesin only assembles topologically associating domains (TADs) at the mid-blastula transition (MBT). Why cohesin assembles TADs only at this stage is unknown. We first analyzed genome architecture in frog sperm and compared it to human and mouse. Our results indicate that sperm genome organization is conserved between frogs and humans and occurs without formation of TADs. TADs can be detected in mouse sperm samples, as reported, but these structures might originate from somatic chromatin contaminations. We therefore discuss the possibility that the absence of TADs might be a general feature of vertebrate sperm. To analyze sperm genome remodeling upon fertilization, we reconstituted male pronuclei inXenopusegg extracts. In pronuclei, chromatin compartmentalization increases, but cohesin does not accumulate at CTCF sites and assemble TADs. However, if pronuclei are formed in the presence of exogenous CTCF, CTCF binds to its consensus sites, and cohesin accumulates at these and forms short-range chromatin loops, which are preferentially anchored at CTCF's N terminus. These results indicate that TADs are only assembled at MBT because before this stage CTCF sites are not occupied and cohesin only forms short-range chromatin loops.