bluuebunny/crossref_metadata_2025 huggingface dataset:
Age-Invariant Genes: Multi-Tissue Identification and Characterization of Murine Reference Genes
Authors: González John T. , Thrush Kyra , Meer Margarita , Levine Morgan E. , Higgins-Chen Albert T.
Published: April 2024

Studies of the aging transcriptome focus on genes that change with age. But what can we learn from age-invariant genes—those that remain unchanged throughout the aging process? These genes also have a practical application: they serve as reference genes (often called housekeeping genes) in expression studies. Reference genes have mostly been identified and validated in young organisms, and no systematic investigation has been done across the lifespan. Here, we build upon a common pipeline for identifying reference genes in RNA-seq datasets to identify age-invariant genes across seventeen C57BL/6 mouse tissues (brain, lung, bone marrow, muscle, white blood cells, heart, small intestine, kidney, liver, pancreas, skin, brown, gonadal, marrow, and subcutaneous adipose tissue) spanning 1 to 21+ months of age. We identify 9 pan-tissue age-invariant genes and many tissue-specific age-invariant genes. These genes are stable across the lifespan and are validated in independent bulk RNA-seq datasets and RT-qPCR. We find age-invariant genes have shorter transcripts on average and are enriched for CpG islands. Interestingly, pathway enrichment analysis for age-invariant genes identifies an overrepresentation of molecular functions associated with some, but not all, hallmarks of aging. Thus, though hallmarks of aging typically involve changes in cell maintenance mechanisms, select genes associated with these hallmarks resist fluctuations in expression with age. Finally, our analysis concludes no classical reference gene is appropriate for aging studies in all tissues. Instead, we provide tissue-specific and pan-tissue genes for assays utilizing reference gene normalization (i.e., RT-qPCR) that can be applied to animals across the lifespan.
Meta-analysis: a quantitative model of adult neurogenesis in the rodent hippocampus
Authors: Arellano Jon I. , Rakic Pasko
Published: April 2024

Contrary to humans, adult neurogenesis in rodents is not controversial. And in the last three decades, multiple studies in rodents have deemed adult neurogenesis essential for most hippocampal functions. The functional relevance of new neurons relies on their distinct physiological properties during their maturation before they become indistinguishable from mature granule cells. Most functional studies have used very young animals with robust neurogenesis. However, this trait declines dramatically with age, questioning its functional relevance in aging animals, a caveat that has been mentioned repeatedly, but rarely analyzed quantitatively. In this meta-analysis, we use data from published studies to determine the critical functional window of new neurons and to model their numbers across age in both mice and rats. Our model shows that new neurons with distinct functional profile represent about 3% of the total granule cells in young adult 3-month-old rodents, and their number decline following a power function to reach less than 1% in middle aged animals and less than 0.5% in old mice and rats. These low ratios pose an important logical and computational caveat to the proposed essential role of new neurons in the dentate gyrus, particularly in middle aged and old animals, a factor that needs to be adequately addressed when defining the relevance of adult neurogenesis in hippocampal function.
Three years of insecticide resistance evolution and associated mechanisms inAedes aegyptipopulations of Ouagadougou, Burkina Faso
Authors: Yaméogo Félix , Sombié Aboubacar , Oté Manabu , Saiki Erisha , Sakurai Tatsuya , Wangrawa Dimitri W. , McCall Philip J. , Weetman David , Kanuka Hirotaka , Badolo Athanase
Published: April 2024

Background

Resistance to insecticides is spreading among populations ofAedes aegypti, the primary vector of important human arboviruses. The escalating insecticide resistance poses a significant threat to dengue vector control, with an expanding number of countries affected by the disease.

To gain a deeper insight into the evolution of insecticide resistance, it is essential to have longitudinal surveillance results, which are currently lacking, particularly from AfricanAe. aegyptipopulations.

Here we report on three-years of surveillance ofAe. aegyptisusceptibility to insecticide resistance phenotypes and associated kdr mutations in Burkina Faso, a country with regular dengue outbreaks.

Methods

Ae.aegyptisusceptibility to insecticides and the V410L, V1016I, and F1534Ckdrtarget site mutations linked to pyrethroid insecticide resistance were monitored in Ouagadougou from 2016 to 2018. Larvae were collected from artificial containers at two sites and reared to adulthood in an insectary. Bioassays were conducted on female adults, alongside with a laboratory-susceptible strain, following standard WHO protocols. Allele-specific PCR genotyping assays were utilized to identify the V410L, V1016I, and F1534Ckdrpyrethroid target site mutations.

Results

Bioassays revealed a high level of resistance to permethrin and deltamethrin that progressively increased over the three-year period in both localities. The 1534C mutation was nearly fixed throughout the three years at each locality, and while the closely related 410L and 1016I mutations did not vary between localities, their frequency notably increased from 2016 to 2018. Interestingly,Ae. aegyptipopulations in both areas remained susceptible to bendiocarb, fenitrothion, and malathion. Modeling the mortality data further confirmed the escalating resistance trend over the years and emphasized the significant role played by the three kdr mutations in conferring resistance to pyrethroids.

Conclusion

Mortality rates indicate thatAe. aegyptipopulations from Ouagadougou are becoming increasingly resistant to pyrethroid insecticides, likely due to an increase in the frequencies of the 410L and 1016Ikdr mutations. Organophosphate insecticides are likely to be better alternative options for control.
An inferotemporal coding strategy robust to partial object occlusion
Authors: Cheng Andrew , Sokol Sach , Connor Charles E.
Published: April 2024

Object coding in primate ventral pathway cortex progresses in sparseness/compression/efficiency, from many orientation signals in V1, to fewer 2D/3D part signals in V4, to still fewer multi-part configuration signals in AIT (anterior inferotemporal cortex).1–11This progression could lead to individual neurons exclusively selective for unique objects, the sparsest code for identity, especially for highly familiar, important objects.12–18To test this, we trained macaque monkeys to discriminate 8 simple letter-like shapes in a match-to-sample task, a design in which one-to-one coding of letters by neurons could streamline behavior. Performance increased from chance to >80% correct over a period of weeks, after which AIT neurons showed clear learning effects, with increased selectivity for multi-part configurations within the trained alphabet shapes. But these neurons were not exclusively tuned for unique letters based on training, since their responsiveness generalized to different, non-trained shapes containing the same configurations. This multi-part configuration coding limit in AIT is not maximally sparse, but it could explain the robustness of primate vision to partial object occlusion, which is common in the natural world and problematic for computer vision. Multi-part configurations are highly diagnostic of identity, and neural signals for various partial object structures can provide different but equally sufficient evidence for whole object identity across most occlusion conditions.
A dataset containing speciation rates, uncertainty, and presence-absence matrices for more than 34,000 vertebrate species
Authors: Vásquez-Restrepo Juan D.
Published: April 2024

The increasing availability of phylogenetic data has facilitated the exploration of macroecological and macroevolutionary patterns across diverse spatial and temporal scales. However, calculating some model-based diversification metrics often requires significant computational power and time. To address this, I present a comprehensive dataset of Bayesian diversification rates for over 34,000 vertebrate species, spanning five major groups: amphibians, birds, mammals, reptiles, and sharks. This is the first large-scale dataset of its kind, providing both continuous and binary data for speciation rates and presence-absence matrices, respectively, with global coverage. The dataset not only enables analyses of evolutionary and spatial diversity patterns but also democratizes access to data-intensive studies. Additionally, as it is based on Markov chains, the dataset can be customized and extended without the need to start from scratch, offering flexibility for future research on diversification dynamics.
Inhibiting CRF Projections from the Central Amygdala to Lateral Hypothalamus and Amygdala Deletion of CRF Alters Binge-Like Ethanol Drinking in a Sex-Dependent Manner
Authors: Bendrath Sophie C. , Méndez Hernán G. , Dankert Anne M. , Lerma-Cabrera Jose Manuel , Carvajal Francisca , Dornellas-Loper Ana Paula , Lee Sophia , Neira Sofia , Haun Harold , Delpire Eric , Navarro Montserrat , Kash Thomas L. , Thiele Todd E.
Published: April 2024

Background

Binge alcohol drinking is a dangerous pattern of consumption that can contribute to the development of more severe alcohol use disorders (AUDs). Importantly, the rate and severity of AUDs has historically differed between men and women, suggesting that there may be sex differences in the central mechanisms that modulate alcohol (ethanol) consumption. Corticotropin releasing factor (CRF) is a centrally expressed neuropeptide that has been implicated in the modulation of binge-like ethanol intake, and emerging data highlight sex differences in central CRF systems.

Methods

In the present report we characterized CRF+ neurocircuitry arising from the central nucleus of the amygdala (CeA) and innervating the lateral hypothalamus (LH) in the modulation of binge-like ethanol intake in male and female mice.

Results

Using chemogenetic tools we found that silencing the CRF+ CeA to LH circuit significantly blunted binge-like ethanol intake in male, but not female, mice. Consistently, genetic deletion of CRF from neurons of the CeA blunted ethanol intake exclusively in male mice. Furthermore, pharmacological blockade of the CRF type-1 receptor (CRF1R) in the LH significantly reduced binge-like ethanol intake in male mice only, while CRF2R activation in the LH failed to alter ethanol intake in either sex. Finally, a history of binge-like ethanol drinking blunted CRF mRNA in the CeA regardless of sex.

Conclusions

These observations provide novel evidence that CRF+ CeA to LH neurocircuitry modulates binge-like ethanol intake in male, but not female mice, which may provide insight into the mechanisms that guide known sex differences in binge-like ethanol intake.
All-trans retinoic acid induces durable tumor immunity in IDH-mutant gliomas by rescuing transcriptional repression of the CRBP1-retinoic acid axis
Authors: Rao Aparna , Zhang Xiaoran , Cillo Anthony R. , Sussman Jonathan H. , Sandlesh Poorva , Tarbay Antonio Corral , Mallela Arka N. , Cardello Carly , Krueger Katharine , Xu Jessica , Li Alex , Xu Jason , Patterson Jonathan , Akca Ebrar , Angione Angelo , Jaman Emade , Kim Wi Jin , Allen Jordan , Venketeswaran Abhishek , Zinn Pascal O. , Parise Robert , Beumer Jan , Duensing Anette , Holland Eric C. , Ferris Robert , Bagley Stephen J. , Bruno Tullia C. , Vignali Dario A.A. , Agnihotri Sameer , Amankulor Nduka M.
Published: April 2024

Diffuse gliomas are epigenetically dysregulated, immunologically cold, and fatal tumors characterized by mutations in isocitrate dehydrogenase (IDH). Although IDH mutations yield a uniquely immunosuppressive tumor microenvironment, the regulatory mechanisms that drive the immune landscape of IDH mutant (IDHm) gliomas remain unknown. Here, we reveal that transcriptional repression of retinoic acid (RA) pathway signaling impairs both innate and adaptive immune surveillance in IDHm glioma through epigenetic silencing of retinol binding protein 1 (RBP1) and induces a profound anti-inflammatory landscape marked by loss of inflammatory cell states and infiltration of suppressive myeloid phenotypes. Restorative retinoic acid therapy in murine glioma models promotes clonal CD4+T cell expansion and induces tumor regression in IDHm, but not IDH wildtype (IDHwt), gliomas. Our findings provide a mechanistic rationale for RA immunotherapy in IDHm glioma and is the basis for an ongoing investigator-initiated, single-center clinical trial investigating all-trans retinoic acid (ATRA) in recurrent IDHm human subjects.
Major Metabolites fromHypericum PerforatumL., Hyperforin and Hypericin, are both active against Human Coronaviruses
Authors: Raczkiewicz I. , Rivière C. , Bouquet P. , Desmarets L. , Tarricone A. , Camuzet C. , François N. , Lefèvre G. , Samaillie J. , Silva Angulo F. , Robil C. , Trottein F. , Sahpaz S. , Dubuisson J. , Belouzard S. , Goffard A. , Séron K.
Published: April 2024

COVID-19 pandemic has highlighted the need of antiviral molecules against coronaviruses. Plants are an endless source of active compounds. In the current study, we investigated the potential antiviral effects ofHypericum perforatumL.. Its extract contained two major metabolites belonging to distinct chemical classes, hypericin (HC) and hyperforin (HF). First, we demonstrated that HC inhibited HCoV-229E at the entry step by directly targeting the viral particle in a light-dependent manner. While antiviral properties have already been described for HC, the study here showed for the first time that HF has pan-coronavirus antiviral capacity. Indeed, HF was highly active against Alphacoronavirus HCoV-229E (IC50value of 1.10 µM), and Betacoronaviruses SARS-CoV-2 (IC50value of of 0.24 to 0.98 µM), SARS-CoV (IC50value of 1.01 µM) and MERS-CoV (IC50value of 2.55 µM). Unlike HC, HF was active at a post-entry step, most likely the replication step. Antiviral activity of HF on HCoV-229E and SARS-CoV-2 was confirmed in primary human respiratory epithelial cells. Furthermore,in vitrocombination assay of HF with remdesivir showed that their association was additive, which was encouraging for a potential therapeutical association. As HF was active on both Alpha- and Betacoronaviruses, a cellular target was hypothesized. Heme oxygenase 1 (HO-1) pathway, a potential target of HF, has been investigated but the results showed that HF antiviral activity against HCoV-229E was not dependent on HO-1. Collectively, HF is a promising antiviral candidate in view of our results and pharmacokinetics studies already published in animal models or in human.
Loss of age-accumulatedcrh-1circRNAs ameliorate amyloid β-induced toxicity in aC. elegansmodel for Alzheimer’s disease
Authors: Alshareef Hussam , Ballinger Thomas , Rojas Everett , van der Linden Alexander M.
Published: April 2024

Circular RNAs (circRNAs) are non-coding RNAs mostly derived from exons of protein-coding genes via a back-splicing process. The expression of hundreds of circRNAs accumulates during healthy aging and is associated with Alzheimer’s disease (AD), characterized by the accumulation of amyloid-beta (Aβ) proteins. InC. elegans, many circRNAs were previously found to accumulate during aging, with loss of age-accumulated circRNAs derived from the CREB gene (circ-crh-1) to increase mean lifespan. Here, we usedC. elegansto study the effects of age-accumulated circRNAs on the age-related onset of Aβ-toxicity. We found that circ-crh-1mutations delayed Aβ-induced muscle paralysis and lifespan phenotypes in a transgenicC. elegansstrain expressing a full-length human Aβ-peptide (Aβ1-42) selectively in muscle cells (GMC101). The delayed Aβ phenotypic defects were associated with inhibiting the deposition of Aβ aggregates, and thus, genetic removal of circ-crh-1provides protection against Aβ-induced toxicity. Consistent with a detrimental role for age-accumulated circRNAs in AD, circ-crh-1expression level is elevated after induction of Aβ during aging, whereas linearcrh-1mRNA expression remains unchanged. Finally, we show that a circ-crh-1upregulated collagen gene,col-49, promotes Aβ-induced paralysis. Taken together, our results show that the loss of an age-accumulated circRNA exerts a protective role on Aβ-induced toxicity, demonstrating the utility ofC. elegansfor studying circRNAs in AD and its relationship to aging.
The Effects of Bipolar Disorder Granule Cell Hyperexcitability and Lithium Therapy on Pattern Separation in a Computational Model of the Dentate Gyrus
Authors: Singh Selena , Khayachi Anouar , Stern Shani , Trappenberg Thomas , Alda Martin , Nunes Abraham
Published: April 2024

Induced pluripotent stem cell (iPSC) derived hippocampal dentate granule cell-like neurons from individuals with bipolar disorder (BD) are hyperexcitable and more spontaneously active relative to healthy control (HC) neurons. These abnormalities are normalised after the application of lithium in neurons derived from lithium responders (LR) only. How these abnormalities impact hippocampal microcircuit computation is not understood. We aimed to investigate the impacts of BD-associated abnormal granule cell (GC) activity on pattern separation (PS) using a computational model of the dentate gyrus (DG). We used parameter optimization to fit the parameters of biophysically realistic granule cell (GC) models to electrophysiological data from iPSC GCs from patients with BD. These cellular models were incorporated into DG networks to assess impacts on PS using an adapted spatiotemporal task. Relationships between BD, lithium and spontaneous activity were analysed using linear mixed effects modelling. Lithium and BD negatively impacted PS, consistent with clinical reports of cognitive slowing and memory impairment during lithium therapy. By normalising spontaneous activity levels, lithium improved PS performance in LRs only. Improvements in PS after lithium therapy in LRs may therefore be attributable to the normalisation of spontaneous activity levels, rather than reductions in GC intrinsic excitability as we hypothesised. Our results agree with a hypothesised relationship between behavioural mnemonic discrimination and DG PS, as previous research has suggested that mnemonic discrimination improves after lithium therapy in lithium responders only. Our work can be expanded on in the future by simulating the effects of lithium-induced neurogenesis on PS.
Electrophysiological correlates of lucid dreaming: sensor and source level signatures
Authors: Demirel Çağatay , Gott Jarrod , Appel Kristoffer , Lüth Katharina , Fischer Christian , Raffaelli Cecilia , Westner Britta , Wang Xinlin , Zavecz Zsófia , Steiger Axel , Erlacher Daniel , LaBerge Stephen , Mota-Rolim Sérgio , Ribeiro Sidarta , Zeising Marcel , Adelhöfer Nico , Dresler Martin
Published: April 2024

Lucid dreaming (LD) is a state of conscious awareness of the current dream state, predominantly associated with REM sleep. Research progress in uncovering the neurobiological basis of LD has been hindered by low sample sizes, diverse EEG setups, and specific artifact issues like saccadic eye movements and signal non-stationarity. To address these matters, we developed a multi-stage preprocessing pipeline that integrates standardized early-stage preprocessing, artifact subspace reconstruction, and signal-space projection. This approach enhanced data quality by precisely removing saccadic potential effects even in setups with minimal channels. To robustly identify the electrophysiological correlates of LD, we applied this methodology to LD data collected across laboratories (pooled N = 44) and explored sensor-and source-level markers hypothesized to underlie LD. Compared to non-lucid REM sleep, we observed few robust differences on the EEG sensor level, which is in line with recent findings. In contrast, on the source level, gamma1 power (30-36 Hz) showed increases during LD in left-hemispheric temporal areas, which might reflect verbal insight processes. Gamma1 power also increased around the onset of LD eye signaling in right temporo-occipital regions including the right precuneus, in line with its involvement in self-referential thinking. Reductions in beta power (12-30 Hz) during LD in right central and parietal areas including the temporo-parietal junction are potentially associated with a conscious reassessment of the veridicality of the currently perceived reality. Notably, functional connectivity in alpha band (8-12 Hz) increased during LD, in contrast to the reductions typically seen in psychedelic states, highlighting enhanced self-awareness. Taken together, these findings illuminate the electrophysiological correlates of LD state, and may serve as a basis to uncover neural mechanisms at the time point of lucid dream insight.
Human Cells for Human Proteins: Isotope Labeling in Mammalian Cells for Functional NMR Studies of Disease-Relevant Proteins
Authors: Rößler Philip , Ruckstuhl Marco , Löbbert Arnelle , Stühlinger Timo , Franchini Lucia R. , Tsai Ching-Ju , Lichtenecker Roman , Shrestha Binesh , Rüdisser Simon H. , Konrat Robert , Schertler Gebhard F. X. , Gossert Alvar D.
Published: April 2024

In biological and biomedical research the focus progressively moves towards difficult human proteins, which often can only be expressed in higher eukaryotic cells. Nuclear magnetic resonance (NMR) could contribute significantly to the understanding of important proteins as it is one of the most information-rich methods: it allows studying structure, function and dynamics of biomolecules and, importantly, their interactions with natural ligands or drugs. However, to exploit the full potential of NMR, proteins must be isotope labeled. Although expression protocols in e.g. HEK293 cells are often established, isotope labeling is difficult and very expensive. To resolve this disparity, we have developed a comprehensive suite of protocols for isotope labeling in HEK293 cells. We demonstrate uniform 15N and 13C labeling, as well as specific labeling, with special focus on methyl bearing amino acids, including the popular ILV 13C-methyl labeling pattern. Labeling is achieved with a simple laboratory setup and affordable labeling media. These are based on either labeled amino acids, their precursors or amino extracts from microorganisms, like yeast, algae or bacteria.

This enables NMR studies of important, but difficult to produce proteins, like receptors. We therefore expect that these new methods make many highly important proteins accessible to NMR studies and allow exploiting the high information content of this method for accelerating biological and pharmaceutical research.
Rescuing Photoreceptors in RPE Dysfunction-Driven Retinal Degeneration: The Role of Small Extracellular Vesicles Secreted from Retinal Pigment Epithelium
Authors: Pollalis Dimitrios , Georgescu Constantin , Wren Jonathan D. , Tombulyan Grigor , Leung Justin M. , Lo Pein-An , Bloemhof Clarisa Marie , Lee Ryang Hwa , Bae EunHye , Bailey Jeffrey K. , Pennington Britney O. , Khan Amir I. , Kelly Kaitlin R. , Yeh Ashley K. , Sundaram Kartik S. , Humayun Mark , Louie Stain , Clegg Dennis O. , Lee Sun Young
Published: April 2024

Dysfunction of the retinal pigment epithelium (RPE) is a common shared pathology in major degenerative retinal diseases despite variations in the primary etiologies of each disease. Due to their demanding and indispensable functional roles throughout the lifetime, RPE cells are vulnerable to genetic predisposition, external stress, and aging processes. Building upon recent advancements in stem cell technology for differentiating healthy RPE cells and recognizing the significant roles of small extracellular vesicles (sEV) in cellular paracrine and autocrine actions, we investigated the hypothesis that the RPE-secreted sEV alone can restore essential RPE functions and rescue photoreceptors in RPE dysfunction-driven retinal degeneration. Our findings support the rationale for developing intravitreal treatment of sEV. We demonstrate that intravitreally delivered sEV effectively penetrate the full thickness of the retina. Xenogenic intraocular administration of human-derived EVs did not induce acute immune reactions in rodents. sEV derived from human embryonic stem cell (hESC)-derived fully differentiated RPE cells, but not sEV-depleted conditioned cell culture media (CCM minus sEV), rescued photoreceptors and their function in a Royal College of Surgeons (RCS) rat model. This model is characterized by photoreceptor death and retinal degeneration resulting from a mutation in theMerTKgene in RPE cells. From the bulk RNA sequencing study, we identified 447 differently expressed genes in the retina after hESC-RPE-sEV treatment compared with the untreated control. Furthermore, 394 out of 447 genes (88%) showed a reversal in expression toward the healthy state in Long-Evans (LE) rats after treatment compared to the diseased state. Particularly, detrimental alterations in gene expression in RCS rats, including essential RPE functions such as phototransduction, vitamin A metabolism, and lipid metabolism were partially reversed. Defective photoreceptor outer segment engulfment due to intrinsicMerTKmutation was partially ameliorated. These findings suggest that RPE-secreted sEV may play a functional role similar to that of RPE cells. Our study justifies further exploration to fully unlock future therapeutic interventions with sEV in a broad array of degenerative retinal diseases.
Comparative modeling reveals the molecular determinants of aneuploidy fitness cost in a wild yeast model
Authors: Rojas Julie , Hose James , Dutcher H. Auguste , Place Michael , Wolters John F , Hittinger Chris Todd , Gasch Audrey P
Published: April 2024

Although implicated as deleterious in many organisms, aneuploidy can underlie rapid phenotypic evolution. However, aneuploidy will only be maintained if the benefit outweighs the cost, which remains incompletely understood. To quantify this cost and the molecular determinants behind it, we generated a panel of chromosome duplications inSaccharomyces cerevisiaeand applied comparative modeling and molecular validation to understand aneuploidy toxicity. We show that 74-94% of the variance in aneuploid strains’ growth rates is explained by the additive cost of genes on each chromosome, measured for single-gene duplications using a genomic library, along with the deleterious contribution of snoRNAs and beneficial effects of tRNAs. Machine learning to identify properties of detrimental gene duplicates provided no support for the balance hypothesis of aneuploidy toxicity and instead identified gene length as the best predictor of toxicity. Our results present a generalized framework for the cost of aneuploidy with implications for disease biology and evolution.
Quantitative Models for Distinguishing Punctuated and Continuous-Time Models of Character Evolution and Their Implications for Macroevolutionary Theory
Authors: Wright April M. , Wagner Peter J.
Published: April 2024

The recent proliferation of quantitative models for assessing anatomical character evolution all assume that character change happens continuously through time. However, punctuated equilibrium model posits that character change should be coincide with cladogenetic events, and thus should be tied to origination rates. Rates of cladogenesis are important to quantitative phylogenetics, but typically only for establishing prior probabilities of phylogenetic topologies. Here, we modify existing character likelihood models to use the local cladogenesis rates from Bayesian analyses to generate the amounts of character change over time dependent on origination rates, as expected under the punctuated equilibrium model. In the case of strophomenoid brachiopods strop from the Ordovician, we find that Bayesian analyses strongly favor punctuated models over continuous-time models, with elevated rates of cladogenesis early in the clade’s history inducing frequencies of change despite constant rates of change per speciation event. This corroborates prior work proposing that the early burst in strophomenoid disparity reflects simply elevated speciation rates,which in turnhas implications for seemingly unrelated macroevolutionary theory about whether early bursts reflect shifts in intrinsic constraints or empty ecospace. Future development of punctuated character evolution models should account for the full durations of species, which will provide a test of continuous change rates. Ultimately, continuous change vs. punctuated change should become part of phylogenetic paleobiology in the same way that other tests of character evolution currently are.

Non-technical Summary

Punctuated Equilibrium predicts a distribution of anatomical change that is fundamentally different from the models used in studies of relationships among species. We present a model to assess relationships that assumes punctuated change. We apply this model to a dataset of strophomenoid brachiopods to demonstrate that a model of punctuated change fits better than a model of continuous-time (“phyletic gradualism”) change in this group. Notably, because the punctuated model posits elevated speciation rates early in the strophomenoid history, the model also posits elevated rates of change among the early strophomenoids relative to later ones. This corroborates notions for what causes bursts of anatomical evolution rooted in ecological theory rather than evolutionary developmental theory. More basically, it emphasizes that paleontologists should consider both punctuated and continuous-time models when assessing relationships and other aspects of macroevolutionary theory.
Feeding a low-carbohydrate and high-protein diet diminishes working memory in healthy mice: possible involvement of miR-539-3p/Lrp6/Igf1raxis in the hippocampus
Authors: Shima Takeru , Onishi Hayate , Terashima Chiho
Published: April 2024

A low-carbohydrate and high-protein (LC-HP) diet demonstrates favorable impacts on metabolic parameters, albeit it leads to a decline in hippocampal function among healthy mice. The reduction in working memory induced by LC-HP diets is attributed to the decreased expression of hippocampal IGF-1 receptor (IGF-1R). However, the precise mechanisms underlying this phenomenon remain unexplored. Here, we investigated that by analyzing alterations in hippocampal miRNA profiles. C57BL/6 mice were divided into the LC-HP diet-fed group (25.1% carbohydrate, 57.2% protein, and 17.7% fat as percentages of calories) and the control diet-fed group (58.9% carbohydrate, 24.0% protein, and 17.1% fat as percentages of calories). After four weeks, all mice underwent the Y-maze test, followed by analyses of mRNA and miRNA expressions in the hippocampus. Our investigation revealed that feeding the LC-HP diet suppressed working memory function and hippocampalIgf1rmRNA levels in mice. Sequencing of miRNA demonstrated 17 upregulated and 27 downregulated miRNAs in the hippocampus of LC-HP diet-fed mice. Notably, upregulation of miR-539-3p, predicted to modulateIgf1rgene expression, was observed. Consequently, we found decreased hippocampal mRNA levels of low-density lipoprotein receptor-related protein 6 (Lrp6), a gene modulated by miR-539-3p, in mice fed the LC-HP diet. Furthermore, a significant positive correlation was observed betweenLrp6andIgf1rmRNA levels in the hippocampus. These findings suggest that LC-HP diets may suppress hippocampal function via the miR-539-3p/Lrp6/Igf1raxis, offering a potential target for nutritional strategies to preserve hippocampal health.
SIEVE: One-stop differential expression, variability, and skewness analyses using RNA-Seq data
Authors: Li Hongxiang , Khang Tsung Fei
Published: April 2024

Motivation

RNA-Seq data analysis is commonly biased towards detecting differentially expressed genes and insufficiently conveys the complexity of gene expression changes between biological conditions. This bias arises because discrete models of RNA-Seq count data cannot fully characterize the mean, variance, and skewness of gene expression distribution using independent model parameters. A unified framework that simultaneously tests for differential expression, variability, and skewness is needed to realize the full potential of RNA-Seq data analysis in a systems biology context.

Results

We present SIEVE, a statistical methodology that provides the desired unified framework. SIEVE embraces a compositional data analysis framework that transforms discrete RNA-Seq counts to a continuous form with a distribution that is well-fitted by a skew-normal distribution. Simulation results show that SIEVE controls the false discovery rate and probability of Type II error better than existing methods for differential expression analysis. Analysis of the Mayo RNA-Seq dataset for Alzheimer’s disease using SIEVE reveals that a gene set with significant expression difference in mean, standard deviation and skewness between the control and the Alzheimer’s disease group strongly predicts a subject’s disease state. Furthermore, functional enrichment analysis shows that relying solely on differentially expressed genes detects only a segment of a much broader spectrum of biological aspects associated with Alzheimer’s disease. The latter aspects can only be revealed using genes that show differential variability and skewness. Thus, SIEVE enables fresh perspectives for understanding the intricate changes in gene expression that occur in complex diseases

Availability

The SIEVE R package and source codes are available athttps://github.com/Divo-Lee/SIEVE.
The recombination efficiency of the bacterial integron depends on the mechanical stability of the synaptic complex
Authors: Vorobevskaia Ekaterina , Loot Céline , Mazel Didier , Schlierf Michael
Published: April 2024

The predominant tool for adaptation in Gram-negative bacteria is a genetic system called integron. Under conditions of stress, it rearranges gene cassettes, ensuring their sampling through expression, to offer a solution for overcoming the initial stress. Integrons are a major actor of multiple antibiotic resistances, a recognized major global health threat. Cassettes are recombined by a unique recombination process involving a tyrosine recombinase – the IntI integrase – and folded single-stranded DNA hairpins – theattCsites which terminate each cassette. Four recombinases and twoattCsites form a macromolecular synaptic complex, which is key to the recombination process and the focus of our study. The bottom strand of allattCsites shows highest recombination efficiencyin vivothan the top one, however, the efficiency still varies several orders of magnitude and the underlying reason remains unclear. Here, we established an optical tweezers force-spectroscopy assay that allows us to probe the synaptic complex stability. We found for seven combinations ofattCsites great variability in the mechanical stability. Two protein variants also showed a strong influence on the mechanical stability. We then determined thein vivorecombination efficiencies of the differentattCsite combinations and protein variants and discovered a strong correlation between recombination efficiency and mechanical stability of the synaptic complex, indicating a regulatory mechanism from the DNA sequence to the macromolecular complex stability. Taking into account known forces during DNA metabolism, we suggest that the variation of thein vivorecombination efficiency is mediated strongly by the synaptic complex stability.
Repeatability of gait of children with spastic cerebral palsy in different walking conditions
Authors: Everaert Laure , Dewit Tijl , Huenaerts Catherine , Van Campenhout Anja , Labey Luc , Desloovere Kaat
Published: April 2024

Objectives

Three-dimensional gait analysis is the ‘gold standard’ for measurement and description of gait. Gait variability can arise from intrinsic and extrinsic factors and may vary between walking conditions. This study aimed to define the inter-trial and inter-session repeatability in gait analysis data of children with cerebral palsy (CP) who were walking in four conditions, namely barefoot or with ankle-foot orthosis (AFO), and overground or treadmill.

Design

Test-retest repeatability study.

Setting

Rehabilitation facility with a human motion analysis laboratory.

Participants

Ten ambulatory children with spastic CP (age=5-15years). In addition, two control datasets (N=56; N=18) of typically developing children were used as a reference.

Interventions

Not applicable.

Main Outcome Measures

Inter-trial and inter-session variability was measured using intra-class correlations (ICC’s) with accompanying confidence intervals, standard error of measurement (SEM), as well as the SEM expressed as percentage (%SEM) of the total joint-range-of-motion of typically developed children.

Results

Overall we found good to excellent ICC-values and favourable SEM-values for the inter-session Gait Profile Score (ICC=0.85-0.98, SEM=0.45°-0.91°) and Gait Variable Scores (ICC=0.85-0.99, SEM=0.22-1.11°) for the lower-limb joints. The %SEM was the highest for the ankle joint (%SEM=0.8%–3.0%). For the continuous waveform data, only in the ankle joint, differences were observed. Namely, smaller SEM-values for the AFO-condition (mean inter-trial=0.14°; mean inter-session=1.121°) in comparison to the barefoot-condition (mean inter-trial= 0.55°; mean inter-session=2.22°). For all the kinetic parameters, the treadmill conditions showed smaller SEM-values in comparison to the overground condition.

Conclusions

All conditions proved to be repeatable, showing good to excellent ICC-values. The ankle kinematics were more repeatable when the participants were walking with their AFOs in comparison to barefoot walking. Taking the total joint-range-of-motion into account, the knee joint showed the most repeatable motion, while ankle motions showed the lowest repeatability. For kinetics, treadmill conditions showed better repeatability than the overground conditions.
Temporo-spatial cellular atlas of the regenerating alveolar niche in idiopathic pulmonary fibrosis
Authors: Weeratunga Praveen , Hunter Bethany , Sergeant Martin , Bull Joshua , Clelland Colin , Denney Laura , Vuppusetty Chaitanya , Burgoyne Rachel , Woo Jeongmin , Hu Tian , Borthwick Lee , Shaw James , Antanaciuvete Agne , Filby Andrew , Byrne Helen , Fisher Andrew , Ho Ling-Pei
Published: April 2024

Abstract

Healthy repair of the alveoli requires alveolar stem cells to differentiate into cells designed for gas exchange. In chronic lung fibrotic disease like idiopathic pulmonary fibrosis (IPF), alveolar epithelial cells regenerate abnormally. The cause of this is unknown but its highly cellular, inflamed and structurally altered regenerating niche is likely to be relevant. Here, in unique sets of human lung tissues capturing advancing fibrosis, and with a 33-plex single cell imaging mass cytometry (IMC), we provide a high resolution and comprehensive temporo-spatial cell atlas of the regenerating alveolar niches. Using a suite of mathematical tools, we expose an organized immune network and identify CD206hialveolar macrophages as a central immune cell in the immune-alveolar epithelial interactome. A spatially-directed receptor-ligand analysis offers an in-silico mechanism by which these macrophages influenced alveolar regeneration. Our study unravels a complex cellular environment and identifies key interactions that influence alveolar regeneration in a fibrotic lung.
Simulated Misuse of Large Language Models and Clinical Credit Systems
Authors: Anibal James , Huth Hannah , Gunkel Jasmine , Gregurick Susan , Wood Bradford
Published: April 2024

Large language models (LLMs) have been proposed to support many healthcare tasks, including disease diagnostics and treatment personalization. While AI may be applied to assist or enhance the delivery of healthcare, there is also a risk of misuse. LLMs could be used to allocate resources via unfair, unjust, or inaccurate criteria. For example, a social credit system uses big data to assess “trustworthiness” in society, penalizing those who score poorly based on evaluation metrics defined only by a power structure (e.g., a corporate entity or governing body). Such a system may be amplified by powerful LLMs which can evaluate individuals based on multimodal data - financial transactions, internet activity, and other behavioral inputs. Healthcare data is perhaps the most sensitive information which can be collected and could potentially be used to violate civil liberty or other rights via a “clinical credit system”, which may include limiting access to care. The results of this study show that LLMs may be biased in favor of collective or systemic benefit over protecting individual rights, potentially enabling this type of future misuse. Moreover, experiments in this report simulate how clinical datasets might be exploited with current LLMs, demonstrating the urgency of addressing these ethical dangers. Finally, strategies are proposed to mitigate the risk of developing large AI models for healthcare.
Polygenic scores for autism are associated with neurite density in adults and children from the general population
Authors: Gu Yuanjun , Maria-Stauffer Eva , Bedford Saashi A. ,   APEX consortium,   iPSYCH-autism consortium, Romero-Garcia Rafael , Grove Jakob , Børglum Anders D. , Martin Hilary , Baron-Cohen Simon , Bethlehem Richard A.I. , Warrier Varun
Published: April 2024

Genetic variants linked to autism are thought to change cognition and behaviour by altering the structure and function of the brain. Although a substantial body of literature has identified structural brain differences in autism, it is unknown whether autism-associated common genetic variants are linked to changes in cortical macro- and micro-structure. We investigated this using neuroimaging and genetic data from adults (UK Biobank, N = 31,748) and children (ABCD, N = 4,928). Using polygenic scores and genetic correlations we observe a robust negative association between common variants for autism and a magnetic resonance imaging derived phenotype for neurite density (intracellular volume fraction) in the general population. This result is consistent across both children and adults, in both the cortex and in white matter tracts, and confirmed using polygenic scores and genetic correlations. There were no sex differences in this association. Mendelian randomisation analyses provide no evidence for a causal relationship between autism and intracellular volume fraction, although this should be revisited using better powered instruments. Overall, this study provides evidence for shared common variant genetics between autism and cortical neurite density.
Effectiveness of the 2023-2024 Omicron XBB.1.5-containing mRNA COVID-19 vaccine (mRNA-1273.815) in preventing COVID-19-related hospitalizations and medical encounters among adults in the United States: An interim analysis
Authors: Kopel Hagit , Araujo Andre B. , Bogdanov Alina , Zeng Ni , Winer Isabelle , Winer-Jones Jessamine , Lu Tianyi , Marks Morgan A. , Bonafede Mac , Nguyen Van Hung , Martin David , Mansi James A.
Published: April 2024

Background/Objectives

COVID-19 continues to pose a significant burden that impacts public health and the healthcare system as the SARS-CoV-2 virus continues to evolve. Regularly updated vaccines are anticipated to boost waning immunity and provide protection against circulating variants. This study evaluated vaccine effectiveness (VE) of mRNA-1273.815, a 2023-2024 Omicron XBB.1.5-containing mRNA COVID-19 vaccine, at preventing COVID-19-related hospitalizations and any medically attended COVID-19 in adults ≥18 years, overall, and by age and underlying medical conditions.

Methods

This retrospective cohort study used the Veradigm Network EHR linked to claims data to identify US adults ≥18 years of age who received the mRNA-1273.815 vaccine (exposed) matched 1:1 to individuals who did not receive a 2023-2024 updated COVID-19 vaccine (unexposed). Patients in the unexposed cohort were randomly matched to eligible mRNA-1273.815 recipients. Inverse probability of treatment weighting was used to adjust for differences between the two cohorts. The exposed cohort was vaccinated between September 12, 2023, and December 15, 2023, and individuals in both cohorts were followed up for COVID-19-related hospitalizations and medically attended COVID-19 until December 31, 2023. A Cox regression model was used to estimate the hazard ratio (HR). VE of the mRNA-1273.815 vaccine in preventing COVID-19-related hospitalizations and any medically attended COVID-19 was estimated as 100*(1-HR). Subgroup analyses were performed for adults ≥50, adults ≥65, and individuals with underlying medical conditions associated with severe COVID-19 outcomes.

Results

Overall, 859,335 matched pairs of mRNA-1273.815 recipients and unexposed adults were identified. The mean age was 63 years, and 80% of the study population was ≥50 years old. 61.5% of the mRNA-1273.815 cohort and 66.4% of the unexposed cohort had an underlying medical condition. Among the overall adult population (≥18 years), VE was 60.2% (53.4–66.0%) against COVID-19-related hospitalization and 33.1% (30.2%–35.9%) against medically attended COVID-19 over a median follow-up of 63 (IQR: 44–78) days. VE estimates by age and underlying medical conditions were similar.

Conclusions

These results demonstrate the significant protection provided by mRNA-1273.815 against COVID-19-related hospitalizations and any medically attended COVID-19 in adults 18 years and older, regardless of their vaccination history, and support CDC recommendations for vaccination with the 2023-2024 Omicron XBB.1.5-containing COVID-19 vaccine to prevent COVID-19-related outcomes, including hospitalizations.
Utilizing Large Language Models for Enhanced Clinical Trial Matching: A Study on Automation in Patient Screening
Authors: Beattie Jacob , Neufeld Sarah , Yang Daniel , Chukwuma Christian , Gul Ahmed , Desai Neil , Jiang Steve , Dohopolski Michael
Published: April 2024

Background

Clinical trial matching, essential for advancing medical research, involves detailed screening of potential participants to ensure alignment with specific trial requirements. Research staff face challenges due to the high volume of eligible patients and the complexity of varying eligibility criteria. The traditional manual process, both time-consuming and error-prone, often leads to missed opportunities. Utilizing Artificial Intelligence (AI) and Natural Language Processing (NLP) can significantly enhance the accuracy and efficiency of this process through automated patient screening against established criteria.

Methods

Utilizing data from the National NLP Clinical Challenges (n2c2) 2018 Challenge, we utilized 202 longitudinal patient records. These records were annotated by medical professionals and evaluated against 13 selection criteria encompassing various health assessments. Our approach involved embedding medical documents into a vector database to determine relevant document sections, then using a large language model (GPT-3.5 Turbo and GPT-4 OpenAI API) in tandem with structured and chain-of-thought prompting techniques for systematic document assessment against the criteria. Misclassified criteria were also examined to identify classification challenges.

Results

This study achieved an accuracy of 0.81, sensitivity of 0.80, specificity of 0.82, and a micro F1 score of 0.79 using GPT-3.5 Turbo, and an accuracy of 0.87, sensitivity of 0.85, specificity of 0.89, and micro F1 score of 0.86 using GPT-4 Turbo. Notably, some criteria in the ground truth appeared mislabeled, an issue we couldn’t explore further due to insufficient label generation guidelines on the website.

Conclusion

Our findings underscore the significant potential of AI and NLP technologies, including large language models, in the clinical trial matching process. The study demonstrated strong capabilities in identifying eligible patients and minimizing false inclusions. Such automated systems promise to greatly alleviate the workload of research staff and improve clinical trial enrollment, thus accelerating the process and enhancing the overall feasibility of clinical research.