bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive machine learning boosts structure-based virtual screening for PARP1 inhibitors
Authors: Caba Klaudia , Tran-Nguyen Viet-Khoa , Rahman Taufiq , Ballester Pedro J.
Published: March 2024

Poly ADP-ribose polymerase 1 (PARP1) is an attractive therapeutic target for cancer treatment. Machine-learning scoring functions constitute a promising approach to discovering novel PARP1 inhibitors. Cutting-edge PARP1-specific machine-learning scoring functions were investigated using semi-synthetic training data from docking activity-labelled molecules: known PARP1 inhibitors, hard-to-discriminate decoys property-matched to them with generative graph neural networks and confirmed inactives. We further made test sets harder by including only molecules dissimilar to those in the training set. Comprehensive analysis of these datasets using five supervised learning algorithms, and protein-ligand fingerprints extracted from docking poses and ligand only features revealed two highly predictive scoring functions. The PARP1-specific support vector machine-based regressor, when employing PLEC fingerprints, achieved a high Normalized Enrichment Factor at the top 1% on the hardest test set (NEF1% = 0.588, median of 10 repetitions), and was more predictive than any other investigated scoring function, especially the classical scoring function employed as baseline.

Scientific Contribution

We present the first PARP1-specific machine-learning scoring functions for structure-based virtual screening. A particularly rigorous evaluation, including test sets with novel molecules and a much higher proportion of challenging property-matched decoys, reveals the most predictive scoring function for this important therapeutic target. Typically, narrow machine learning analyses would have likely missed this promising PARP1-specific scoring function, which is now released with this paper so that others can use it for prospective virtual screening.

Key Points

A new scoring tool based on machine-learning was developed to predict PARP1 inhibitors for potential cancer treatment.

The majority of PARP1-specific machine-learning models performed better than generic and classical scoring functions.

Augmenting the training set with ligand-only Morgan fingerprint features generally resulted in better performing models, but not for the best models where no further improvement was observed.

Employing protein-ligand-extracted fingerprints as molecular descriptors led to the best-performing and most-efficient model for predicting PARP1 inhibitors.

Deep learning performed poorly on this target in comparison with the simpler ML models.
Imprinting and DNA methylation in water lily endosperm: implications for seed evolution
Authors: Povilus Rebecca A. , Martin Caroline A. , Gehring Mary
Published: March 2024

Endosperm is a key evolutionary innovation associated with the origin of angiosperms (flowering plants). This altruistic seed tissue supports the growth and development of the embryo by mediating the relationship of the mother plant as a nutrient source to the compatriot embryo as a nutrient sink. The endosperm is the primary site of gene imprinting in plants (where expression of an allele depends on which parent it was inherited from) and of parent-specific epigenetic modifications like DNA methylation, which are differentially patterned during male and female gamete development1,2,3,4. Knowledge of endosperm gene imprinting and epigenetic patterning is derived from experiments performed in a phylogenetically-wide array of monocot and eudicot plants5,6. However, information from angiosperm lineages whose origins predate the monocot-eudicot divergence (such as Nymphaeales, water lilies) is extremely limited. Additionally, Nymphaeales are an intriguing lineage to investigate seed genetic and epigenetic phenomena, as it is characterized by diploid endosperm and a maternal storage tissue (perisperm), both of which are unusual across angiosperm diversity7,8,9,10,11,12. Here, we examined DNA methylation and genetic imprinting using two reproductively compatible water lily sister-species,Nymphaea thermarumandN. dimorpha. Our results suggest that endosperm hypomethylation and maternally-expressed imprinted genes are an ancestral condition for endosperm, and that other seed characters like seed provisioning strategies, endosperm ploidy, and paternally-expressed imprinted genes might have evolved as coinciding, opposing strategies in the evolutionary dialogue over parental control of offspring development.
Characterising tandem repeat complexities across long-read sequencing platforms with TREAT and otter
Authors: Tesi Niccolo , Salazar Alex , Zhang Yaran , van der Lee Sven , Hulsman Marc , Knoop Lydian , Wijesekera Sanduni , Krizova Jana , Schneider Anne-Fleur , Pennings Maartje , Sleegers Kristel , Kamsteeg Erik-Jan , Reinders Marcel , Holstege Henne
Published: March 2024

Tandem repeats (TR) play important roles in genomic variation and disease risk in humans. Long-read sequencing allows for the accurate characterisation of TRs, however, the underlying bioinformatics perspectives remain challenging. We present otter and TREAT: otter is a fast targeted local assembler, cross-compatible across different sequencing platforms. It is integrated in TREAT, an end-to-end workflow for TR characterisation, visualisation and analysis across multiple genomes. In a comparison with existing tools based on long-read sequencing data from both Oxford Nanopore Technology (ONT, Simplex and Duplex) and PacBio (Sequel 2 and Revio), otter and TREAT achieved state-of-the-art genotyping and motif characterisation accuracy. Applied to clinically relevant TRs, TREAT/otter significantly identified individuals with pathogenic TR expansions. When applied to a case-control setting, we significantly replicated previously reported associations of TRs with Alzheimer's Disease, including those near or within APOC1 (p=2.63x10-9), SPI1 (p=6.5x10-3) and ABCA7 (p=0.04) genes. We finally used TREAT/otter to systematically evaluate potential biases when genotyping TRs using diverse ONT and PacBio long-read sequencing datasets. We showed that, in rare cases (0.06%), long-read sequencing suffers from coverage drops in TRs, including the disease-associated TRs in ABCA7 and RFC1 genes. Such coverage drops can lead to TR mis-genotyping, hampering the accurate characterisation of TR alleles. Taken together, our tools can accurately genotype TR across different sequencing technologies and with minimal requirements, allowing end-to-end analysis and comparisons of TR in human genomes, with broad applications in research and clinical fields.
In-gel protein digestion using acidic methanol produces a highly selective methylation of glutamic acid residues
Authors: Lozano-Prieto Marta , Camafeita Emilio , Jorge Inmaculada , Laguillo-Gómez Andrea , Barrero-Rodríguez Rafael , Devesa Cristina A. , Pertusa Clara , Calvo Enrique , Sánchez-Madrid Francisco , Vázquez Jesús , Martin-Cofreces Noa B.
Published: March 2024

Mass-tolerant open search methods allow the high-throughput analysis of modified peptides by mass spectrometry. These techniques have paved the way to unbiased analysis of post-translational modifications (PTMs) in biological contexts, as well as of chemical modifications produced during the manipulation of protein samples. In this work, we have analyzed in-depth a wide variety of samples of different biological origin, including cells, extracellular vesicles, secretomes, centrosomes and tissue preparations, using Comet-ReCom, a recently improved version of the open search engine Comet-PTM. Our results demonstrate that glutamic acid residues undergo intensive methyl esterification when protein digestion is performed using in-gel techniques, but not using gel-free approaches. This effect was highly specific to Glu and was not found for other methylable residues such as Asp.
Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells
Authors: Brennan Patrick J. , Saunders Rebecca E. , Spanou Mary , Serafini Marta , Sun Liang , Heger Guillaume P. , Konopacka Agnieszka , Beveridge Ryan D. , Gordon Laurie , Bunally Shenaz B. , Saudemont Aurore , Benowitz Andrew B. , Martinez-Fleites Carlos , Queisser Markus A. , An Heeseon , Deane Charlotte M. , Hann Michael M. , Brayshaw Lewis L. , Conway Stuart J.
Published: March 2024

Immunomodulatory imide drugs (IMiDs) including thalidomide, lenalidomide, and pomalidomide, can be used to induce degradation of a protein of interest that is fused to a short zinc finger (ZF) degron motif. These IMiDs, however, also induce degradation of endogenous neosubstrates, including IKZF1 and IKZF3. To improve degradation selectivity, we took a bump-and-hole approach to design and screen bumped IMiD analogs against 8380 ZF mutants. This yielded a bumped IMiD analog that induces efficient degradation of a mutant ZF degron, while not affecting other cellular proteins, including IKZF1 and IKZF3. In proof-of-concept studies, this system was applied to induce efficient degradation of TRIM28, a disease-relevant protein with no known small molecule binders. We anticipate that this system will make a valuable addition to the current arsenal of degron systems for use in target validation.

One-Sentence Summary

Engineered zinc-finger-based degrons enable targeted protein degradation induced by selective molecular glues.
Multiscale Correlations between Joint and Tissue-Specific Biomechanics and Anatomy in Postmortem Ovine Stifles
Authors: Chatterjee Aritra , Davis Zachary Robert , Lescun Timothy , Chan Deva D.
Published: March 2024

The stability of the knee joint is an important indicator of its overall health and function. Joint stability depends on multiple structural and functional properties that include the anatomy of the underlying bones, the geometry and stiffness of the joint capsule and the soft tissues within like tendon, ligaments, cartilage and meniscus. The multiscale biomechanical relationships between the form and function of the whole joint and individual tissues can provide useful insights on the physiological condition of the knee and require further exploration. To better understand these relationships, in this study we compare multiple structural and mechanical parameters in healthy ovine stifles (n = 6). Specifically, we have evaluated joint laxity, joint morphology, individual tissueT2*relaxation and mechanical properties of the anterior and posterior cruciate ligaments (ACL, PCL), medial and lateral collateral ligaments (MCL, LCL), the patellar tendon, menisci, and cartilage from the femoral condyles. Using mechanical testing at two length scales along with anatomical and quantitative magnetic resonance imaging (MRI) scans, we investigate the correlation between individual tissue and whole joint mechanical properties. We also performed statistical tests to measure the strength of correlation coefficients between the measured metrics at multiple levels among whole joint mechanics, joint size, and individual tissue properties. We observe positive correlations between the joint laxity forces and the epicondyle-to-epicondyle distance measured as an anatomical marker. We also find that the viscoelastic properties of the tendons and ligaments correlate positively with joint laxity forces. No such correlations were observed between the cartilage and meniscus properties and the joint laxity forces. Further, we found a weak inverse correlation between the tissue viscoelastic properties andT2*for MCL; strong and moderately positive correlations for cartilage samples from both femoral condyles and the menisci, LCL and PCL respectively. These results provide useful insights into the differential role of individual tissue properties that can be used to predict the whole joint responses that are key indicators of knee health and performance.
The reduction of sleep-like perilesional cortical dynamics underlies clinical recovery in stroke
Authors: Sarasso S. , D’Ambrosio S. , Russo S. , Bernardelli L. , Hassan G. , Comanducci A. , De Giampaulis P. , Dalla Vecchia L. , Lanzone J. , Massimini M.
Published: March 2024

Introduction

Recent studies have shown that, following brain injury, sleep-like cortical dynamics intrude into wakefulness, potentially contributing to brain network disruption and behavioral deficits.

Aim

We employ TMS in combination with EEG to detect these dynamics and assess their impact on brain networks and clinical evolution in awake stroke patients.

Methods

Twelve patients with subacute unilateral ischemic cortical stroke underwent a longitudinal study with two assessments (t0 and t1), including clinical evaluation using the National Institutes of Health Stroke Scale (NIHSS) and TMS-EEG recordings targeting perilesional and contralesional cortical sites. Parameters such as slow wave amplitude (SWa), high-frequency power (HFp) suppression, and the Perturbational Complexity Index-state transition (PCIst) were analyzed to quantify sleep-like cortical dynamics and their network-level consequences.

Results

Results demonstrated a significant clinical improvement (NIHSS score: 7.16±0.73 at t0, 4.33±0.74 at t1; W=78, P<0.001). Perilesional SWa and HFp suppression decreased significantly at t1 compared to t0 (T(11)=3.05, P=0.01 and T(11)=-3.39, P<0.01, respectively), along with recovery of PCIst values (T(11)=-2.35, P=0.04). Importantly, both the dissipation of sleep-like perilesional cortical dynamics and the recovery of network-level interactions correlated with patients’ clinical improvement (Spearman ρ=0.62, P=0.03; ρ=-0.68, P=0.01, respectively).

Conclusion

These findings underscore the potential of TMS-EEG as an objective measure of neurological evolution and suggest targeting sleep-like cortical dynamics as a viable strategy for post-stroke neuromodulation and rehabilitation.
Multi-omics discovery of hallmark protein and lipid features of circulating small extracellular vesicles in humans
Authors: Rai Alin , Huynh Kevin , Poh Qi Hui , Fang Haoyun , Claridge Bethany , Cross Jonathon , Duong Thy , Duarte Carla , Marwick Thomas H , Meikle Peter , Greening David W
Published: March 2024

Extracellular vesicles (EVs) are now being increasingly recognized as an essential signaling entity in human plasma, linking them to health and various diseases. Still, their core protein and lipid componentry, which lie at the center of EV form and function, remains poorly defined. Achieving this unmet milestone remains greatly hindered by abundant non-vesicular extracellular plasma components (non-EVs) in mass spectrometry-based analyses. Here, we performed high-resolution density gradient fractionation of over 110 human plasma samples to isolate circulating EVs, and systematically construct their quantitative proteome (4500 proteins) and lipidome (829 lipids) landscapes. This led to the discovery of a highly conserved panel of 182 proteins (ADAM10, STEAP23, STX7) and 52 lipids (PS, PIPs, Hex2Cer, PAs), providing a deep survey of hallmark molecular features and biological pathways intrinsic to circulating EVs. Our efforts also mapped the surfaceome diversity, identifying 151 proteins on EV surface. We further establish a set of 42 proteins and 114 lipids features that served as hallmark features of non-EV particles in plasma. We submit ADAM10 and PS(36:1) as conserved EV biological markers that precisely differentiates between EV and non-EV particles. Our findings, which can be explored via open-source Shiny web tool (evmap.shinyapps.io/evmap/) will serve as a valuable repository to the research community for a clearer understanding of circulating EV biology.
Bumblebee visual learning: simple solutions for complex stimuli
Authors: Guiraud Marie-Geneviève , Gallo Vince , Quinsal-Keel Emily , MaBouDi HaDi
Published: March 2024

Natural visual stimuli are typically complex. This presents animals with the challenge of learning the most informative aspects of these stimuli while not being confused by variable elements. How animals might do this remains unclear. Here, we tested bumblebees’ ability to learn multicomponent visual stimuli composed of a simple constant bar element and a grating element that was consistent in orientation but varied in width and number of gratings. Bees rapidly and successfully learned these compound stimuli. Tests revealed learning of the single bar element was more robust than learning of the grating element. Our study highlights how even small-brained invertebrates can rapidly learn multicomponent stimuli and prioritise the most consistent elements within them. We discuss how the learning phenomena of generalisation and overshadowing may be sufficient to explain these findings, and caution that complex cognitive concepts are not necessary to explain the learning of complex stimuli.

Highlights

Bumblebees are highly efficient in prioritising the most consistent elements in multicomponent visual stimuli.

Bees trained on horizontal and vertical cues exhibit differences in how they memorise visual cues.

Two phenomena can explain how bees preferentially select, memorise and use visual cues in this experiment: generalisation and overshadowing.

Bumblebees as generalist foragers are well-suited to study visual cognition.
The growth-driven penetration strategy of plant roots is mechanically more efficient than pushing
Authors: Koren Yoni , Perilli Alessia , Tchaicheeyan Oren , Lesman Ayelet , Meroz Yasmine
Published: March 2024

Plant roots are considered highly efficient soil explorers. As opposed to the push-driven penetration strategy commonly used by many digging organisms, roots penetrate by growing, adding new cells at the tip, and elongating over a well-defined growth zone. However, a comprehensive understanding of the mechanical aspects associated with root penetration is currently lacking. We perform penetration experiments followingArabidopsis thalianaroots growing into an agar gel environment, and a needle of similar dimensions pushed into the same agar. We measure and compare the environmental deformations in both cases by following the displacement of fluorescent beads embedded within the gel, combining confocal microscopy and Digital Volume Correlation (DVC) analysis. We find that deformations are generally smaller for the growing roots. To better understand the mechanical differences between the two penetration strategies we develop a computational model informed by experiments. Simulations show that, compared to push-driven penetration, grow-driven penetration reduces frictional forces and mechanical work, with lower propagation of displacements in the surrounding medium. These findings shed light on the complex interaction of plant roots with their environment, providing a quantitative understanding based on a comparative approach.
An arrayed CRISPR/Cas9 screen identifies mTORC1 as a regulator of lipid droplet accumulation in APOE E3 and APOE KO iPSC-derived microglia
Authors: Meier Sonja , Larsen Anne Sofie Gry , Wanke Florian , Mercado Nicolas , Mei Arianna , Takacs Livia , Mracsko Eva Suszanna , Collin Ludovic , Kampmann Martin , Roudnicky Filip , Jagasia Ravi
Published: March 2024

Variants of the Apolipoprotein E (APOE) gene, particularly the E4 allele, are significantly associated with an increased risk of Alzheimer’s Disease and have been implicated in neuroinflammatory processes due to disrupted lipid metabolism. Lipid alterations can manifest in glial cells as an excessive buildup of lipids, potentially contributing to neuroinflammation. In this study, we observed a heightened lipid load in APOE-deficient human induced pluripotent stem cell (iPSC)-derived microglia relative to cells with other APOE isoforms. To explore the mechanisms governing lipid handling within microglia, we established a technique for the nucleofection of CRISPR/Cas9 ribonucleoprotein complexes into iPSC-derived myeloid cells. Utilizing this method, we performed a targeted screen to identify key upstream modifiers in lipid droplet formation. Our findings highlight the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway as a pivotal influence on lipid storage in microglia with both APOE3 and APOE knockout genotypes, underscoring its role in lipid dysregulation associated with Alzheimer’s Disease and neuroinflammation.
See-Star: a versatile hydrogel-based protocol for clearing large, opaque and calcified marine invertebrates
Authors: Clarke D. N. , Formery L. , Lowe C. J.
Published: March 2024

Studies of morphology and developmental patterning in adult stages of many invertebrates are hindered by opaque structures, such as shells, skeletal elements, and pigment granules that block or refract light and necessitate sectioning for observation of internal features. An inherent challenge in studies relying on surgical approaches is that cutting tissue is semi-destructive, and delicate structures, such as axonal processes within neural networks, are computationally challenging to reconstruct once disrupted. To address this problem, we developed See-Star, a hydrogel-based tissue clearing protocol to render the bodies of opaque and calcified invertebrates optically transparent while preserving their anatomy in an unperturbed state, facilitating molecular labeling and observation of intact organ systems. The resulting protocol can clear large (>1 cm3) specimens to enable deep-tissue imaging, and is compatible with molecular techniques, such as immunohistochemistry andin situhybridization to visualize protein and mRNA localization. To test the utility of this method, we performed a whole mount imaging study of intact nervous systems in juvenile echinoderms and molluscs, and demonstrate that See-Star allows for comparative studies to be extended far into development facilitating insights into the anatomy of juveniles and adults that are usually not amenable to whole mount imaging.
Internal monitoring of whisking and locomotion in the superior colliculus
Authors: Chinta Suma , Pluta Scott R.
Published: March 2024

To localize objects using active touch, our brain must merge its map of the body surface with an ongoing representation of self-motion. While such computations are often ascribed to the cerebral cortex, we examined the midbrain superior colliculus (SC), due to its close relationship with the sensory periphery as well as higher, motor-related brain regions. We discovered that active whisking kinematics and locomotion speed accurately predict the firing rate of mouse SC neurons. Kinematic features occurring either in the past, present, or future best predicted spiking, indicating that the SC population continuously estimates the trajectory of self-motion. Half of all self-motion encoding neurons displayed a touch response as an object entered the active whisking field. Trial-to-trial variation in the size of this response was explained by the position of the whisker upon touch. Taken together, these data indicate that SC neurons linearly combine an internal estimate of self-motion with external stimulation to enable active tactile localization.
Robust and Accurate Bayesian Inference of Genome-Wide Genealogies for Large Samples
Authors: Deng Yun , Nielsen Rasmus , Song Yun S.
Published: March 2024

The Ancestral Recombination Graph (ARG), which describes the full genealogical history of a sample of genomes, is a vital tool in population genomics and biomedical research. Recent advancements have increased ARG reconstruction scalability to tens or hundreds of thousands of genomes, but these methods rely on heuristics, which can reduce accuracy, particularly in the presence of model misspecification. Moreover, they reconstruct only a single ARG topology and cannot quantify the considerable uncertainty associated with ARG inferences. To address these challenges, we here introduce SINGER, a novel method that accelerates ARG sampling from the posterior distribution by two orders of magnitude, enabling accurate inference and uncertainty quantification for large samples. Through extensive simulations, we demonstrate SINGER’s enhanced accuracy and robustness to model misspecification compared to existing methods. We illustrate the utility of SINGER by applying it to African populations within the 1000 Genomes Project, identifying signals of local adaptation and archaic introgression, as well as strong support of trans-species polymorphism and balancing selection in HLA regions.
The distribution of particulate organic matter in the heterogeneous soil matrix - balancing between aerobic respiration and denitrification
Authors: Lucas Maik , Rohe Lena , Apelt Bernd , Stange Claus Florian , Vogel Hans-Jörg , Well Reinhard , Schlüter Steffen
Published: March 2024

Denitrification, a key process in soil nitrogen cycling, occurs predominantly within microbial hotspots, such as those around particulate organic matter (POM), where denitrifiers use nitrate as an alternative electron acceptor. For accurate prediction of dinitrogen (N2) and nitrous oxide (N2O) emissions from denitrification, a precise quantification of these microscale hotspots is required. The distribution of POM is of crucial importance in this context, as the local oxygen (O2) balance is governed not only by its high O2demand but also by the local O2availability.

Employing a unique combination of X-ray CT imaging, microscale O2measurements, and15N labeling, we were able to quantify hotspots of aerobic respiration and denitrification. We analyzed greenhouse gas (GHG) fluxes, soil oxygen supply, and the distribution of POM in intact soil samples from grassland and cropland under different moisture conditions. Our findings reveal that both proximal and distal POM, identified through X-ray CT imaging, contribute to GHG emissions. The distal POM, i.e. POM at distant locations to air-filled pores, emerged as a primary driver of denitrification within structured soils of both land uses. Thus, the higher denitrification rates in the grassland could be attributed to the higher content of distal POM. Conversely, despite possessing compacted areas that could favor denitrification, the cropland had only small amounts of distal POM to stimulate denitrification in it. This underlines the complex interaction between soil structural heterogeneity, organic carbon supply, and microbial hotspot formation and thus contributes to a better understanding of soil-related GHG emissions.

In summary, our study provides a holistic understanding of soil-borne greenhouse gas emissions and emphasizes the need to refine predictive models for soil denitrification and N2O emissions by incorporating the microscale distribution of POM.

Highlights

N2O originates from hotspots at the microscale and thus is largely unpredictable

We combined X-ray CT imaging, microscale O2sensors, and15N labeling to map hotspots

The position of the POM separates enhanced aerobic respiration and denitrification

Distal POM (to air-filled pores) as driver of denitrification (N2O+N2) in soils

Including POM distribution in models will enhance accuracy for soil GHG predictions

Abstract Figure
Evaluation of methods for RNA-Seq analysis for uncovering key components of estrogen receptor-alpha signaling pathway in breast cancer
Authors: Guo Wanru
Published: March 2024

Breast cancer is the most common female cancer worldwide. Higher estrogen receptor (ER) expression is often associated with poor prognosis in ER positive breast cancer, however the exact mechanism is unknown. RNA-Seq data of three different experiments of ER knockdown (siE1, siE2, siE3) was used by researchers previously to identify TNFAIP1/BACURD2 as the mediator of ER induced increase in cell migration typical of breast cancer. We herein present a more comprehensive analysis of the data using DESEq2, along with comparison of results using a non-parametric approach, SAM-Seq, in order to cover the low sample size used in the study, and compared the results. We have found that, SAM-Seq uncovers more significant genes and is as robust as DESeq2 in discovering genes deemed significant by DESeq2. Excitingly, our approach was able to uncover three most significantly DE genes among the three independent experiments, namely, UHMK1, ACLY and CLIC4. The fact that they are involved in cancer regulation, metabolism and cell signaling, but so far has barely been studied, serves as additional exciting avenues of targeting ER pathway in breast cancer. Lastly, neither of our DESeq2 nor SAM-Seq analysis results showed consistent downregulation of TNPAIP1 upon ERR-alpha knockout across three independent experiments. Since our analysis approaches are both more conservative and robust in situations of model assumption violations, we came to the conclusion that further experiments are needed to ascertain the involvement of TNFAIP1 in the ER signaling pathway in breast cancer.
The Impact of Model Assumptions in Interpreting Cell Kinetic Studies
Authors: Yan Ada , Sadreev Ildar , Mackerodt Jonas , Zhang Yan , Macallan Derek , Busch Robert , Asquith Becca
Published: March 2024

Author summary

Stable isotope labelling is one of the best available methods for quantifying cell dynamics in vivo, particularly in humans where the absence of toxicity makes it preferable over other techniques such as CFSE or BrdU. Interpretation of stable isotope labelling data necessitates simplifying assumptions. Here we investigate the impact of three of the most commonly used simplifying assumptions (that the cell population of interest is closed, that the population of interest is kinetically homogeneous, and that the population is spatially homogeneous) and suggest pragmatic ways in which the resulting errors can be reduced.
Endopiriform neurons projecting to ventral CA1 are a critical node for recognition memory
Authors: Yamawaki Naoki , Login Hande , Feld-Jakobsen Solbjørg Østergaard , Molnar Bernadett Mercedesz , Kirkegaard Mads Zippor , Moltesen Maria , Okrasa Aleksandra , Radulovic Jelena , Tanimura Asami
Published: March 2024

The claustrum complex is viewed as fundamental for higher order cognition; however, the circuit organization and function of its neuroanatomical subregions are not well understood. We demonstrated that some of the key roles of the CLA complex can be attributed to the connectivity and function of a small group of neurons in its ventral subregion, the endopiriform (EN). We identified a subpopulation of EN neurons by their projection to the ventral CA1 (ENvCA1-proj.neurons), embedded in recurrent circuits with other EN neurons and the piriform cortex. Although the ENvCA1-proj.neuron activity was biased toward novelty across stimulus categories, their chemogenetic inhibition selectively disrupted the memory-guided but not innate responses of mice to novelty. Based on our functional connectivity analysis, we suggest that ENvCA1-proj.neurons serve as an essential node for recognition memory through recurrent circuits mediating sustained attention to novelty, and through feed forward inhibition of distal vCA1 neurons shifting memory-guided behavior from familiarity to novelty.
Map of epigenetic age acceleration: a worldwide meta-analysis
Authors: Yusipov Igor , Kalyakulina Alena , Franceschi Claudio , Ivanchenko Mikhail
Published: March 2024

This study is the first systematic meta-analysis of epigenetic age acceleration of the largest publicly available DNA methylation data for healthy samples (93 datasets, 23K samples), focusing on geographic and ethnic aspects of different countries (25 countries) and populations (31 ethnicities) around the world. The most popular epigenetic tools for assessing age acceleration were examined in detail, their quality metrics were analyzed, and their ability to extrapolate to epigenetic data from different tissue types and age ranges different from the training data of these models was explored. In most cases, the models are not consistent with each other and show different signs of age acceleration, with the PhenoAge model tending to systematically underestimate and different versions of the GrimAge model tending to systematically overestimate the age prediction of healthy subjects. Although GEO is the largest open-access epigenetic database, most countries and populations are not represented, and different datasets use different criteria for determining healthy controls. Because of this, it is difficult to fully isolate the contribution of “geography/environment”, “ethnicity” and “healthiness” to epigenetic age acceleration. However, the DunedinPACE metric, which measures aging rate, adequately reflects the standard of living and socioeconomic indicators in countries, although it can be applied only to blood methylation data. When comparing epigenetic age acceleration, males age faster than females in most of the countries and populations considered.
Effects of arbuscular mycorrhizal fungi on nitrogen uptake in cotton (Gossypium hirsutumL.) under low-nitrogen conditions
Authors: Wang Hushan , Wang Yijian , Cheng Xiaojiao , He Yunzhu , Shen Zihui , Zhang Wangfeng , Pu Xiaozhen
Published: March 2024

Cotton is an important global cash crop whose yield and quality are highly influenced by soil nitrogen. Therefore, examining the interactions between roots and arbuscular mycorrhizal fungi (AMF) under reduced nitrogen conditions is of great significance.

We investigated the effects of nitrogen application (0, 250, and 375 kg· hm-2) on the AMF infection rate of cotton, the nitrogen content of each organ, root morphological characteristics and biomass, soil extracellular enzyme activity, and soil carbon and nitrogen content using a compartmentalized culture system.

The contribution of AMF to plant nitrogen was 10.40, 22.72, and 16.67% under high, low, and no nitrogen treatments, respectively. Under low-nitrogen conditions, the symbiosis between AMF and roots increased root surface area, tip number, branch number, mean diameter, and biomass; and increased soil extracellular enzyme activity (protease, NAG, PER, and PPO), the microbial biomass carbon-to-nitrogen ratio, active carbon content, and the soil nitrogen mineralization rate. Soil NO3--N, NH4+-N, and organic nitrogen content decreased, whereas the absorption of NO3--N by AMF hyphae was higher than that of NH4+-N.

Under low-nitrogen conditions, AMF promoted the decomposition of soil organic matter and the transformation of soil nitrogen through the action of hyphal microorganisms.
Knowledge and perceptions of uterine fibroids: A descriptive cross-sectional survey among women of childbearing age in KwaZulu-Natal, South Africa
Authors: Dlamini Amanda , Nxumalo Celenkosini Thembelenkosini , Mpofana Nomakhosi , Paulse Michael , Makgobole Mokgadi , Pillay Pavitra
Published: March 2024

Background

Uterine fibroids are the leading cause of hysterectomies among women of childbearing age. This study aims to elicit the knowledge, attitude and perceptions of childbearing women towards uterine fibroids in order to provide empirical evidence informing relevant interventions oriented toward health promotion in this regard.

Methods

A quantitative, cross-sectional descriptive design was used and data were collected from a sample of 362 women of reproductive age residing in a selected township in KwaZulu-Natal, South Africa. Ethical approval to conduct the study was obtained from the Durban University of Technology’s Institutional Research Ethics’ Committee (IREC – Ref No. BIREC 014/21). A pre-tested survey was conducted to gather data on knowledge, attitudes, and perceptions concerning uterine fibroids. The collected data were analyzed using SPSS version 27, employing descriptive statistics. Inferential statistics were also conducted to examine associations between key variables and respondents who self-reported being diagnosed with uterine fibroids.

Results

Most participants, 73.8% (n=267), had no awareness of uterine fibroids. Participants also demonstrated poor knowledge regarding the aetiology and symptoms of the condition. However, most participants, 49.2% (n=178), perceived uterine fibroids to be of spiritual origin, citing evil spirits and witchcraft as the cause. Participants subsequently reported that treatment would require herbal approaches and consultation with spiritualists such as traditional healers and seers. In summary, the study highlights various factors influencing self-reporting behaviours, including age, education level, employment status, marital status, number of children, awareness of the condition, perception of requiring treatment, family history, and symptom severity.

Discussion and conclusion

The study findings seem to suggest that women in the selected township lack accurate knowledge about uterine fibroids. These insights are valuable for shaping targeted health interventions and policies. Recognizing the complexities of self-reporting is crucial for improving health outcomes through early detection and tailored interventions.
Prevalence and factors associated with short birth interval in Kaya Municipality, North Central Burkina Faso: a multilevel Poisson regression modeling with a robust variance of a community survey
Authors: Coulibaly Abou , Baguiya Adama , Meda Bertrand Ivlabèhiré , Millogo Tiéba , Koumbem Aristide Marie Arsène , Garanet Franck , Kouanda Seni
Published: March 2024

A short birth interval adversely affects the health of mothers and children. This study aimed to measure the prevalence of short birth intervals and identify their associated factors in a semi-urban setting in Burkina Faso. We conducted a cross-sectional study in which data were collected in households between May and October 2022. The dependent variable was the short birth interval (SBI), defined by the World Health Organization as the time between two live births. We performed a multilevel mixed-effects Poisson regression with robust variance to determine the factors associated with the SBI by reporting adjusted prevalence ratios (aPR) with a 95% confidence interval (CI). A total of 5544 birth intervals were recorded from 4067 women. A short birth interval was found in 1503 cases out of 5544, i.e., a frequency of 27.1%. The prevalence of short birth interval (time between two live births less than 33 months) was higher in never users of modern contraceptive users (aPR=1.24; 95% CI [1.14-1.34] vs. previous users), in younger ages with aPR of 4.21 (95% CI [3.30-5.37]), 2.47 (95% CI [1.96-3.11]), and 1.45 (95% CI [1.16-1.81]), respectively for under 18, 18-24 years old, and 25-34 years old, compared to 35 and over. Childbirths occurring before the implementation of the maternal and infant free health care policy (aPR=2.13; 95% CI [1.98-2.30]) and also before the free FP policy (aPR=1.53; 95% CI [1.28-1.81]) were found also protective against SBI. Women with low socio-economic positions were more likely to have SBI. This study found a high SBI in Burkina Faso (more than one woman out of four). Our results have programmatic implications, as some factors, such as contraceptive practice and socioeconomic status, are modifiable. These factors need particular attention to lengthen birth intervals and, in turn, improve mother-child couple health by reducing short birth interval consequences.
Examination of a novel limb symmetry index to discriminate movement strategies during bilateral jump landing in individuals with ACLR and with and without a history of ankle sprains
Authors: Sugimoto Yuki A. , Garrison Craig J. , Acosta Ana Maria , Dewald Julius P.A.
Published: March 2024

INTRODUCTION

The Limb Symmetry Index (LSI), computed from kinetic parameters, tracks knee functionality post Anterior Cruciate Ligament Reconstruction (ACLR). However, LSI may lack accuracy in individuals with ACLR and ankle sprains, as it overlooks kinetic chain coordination across lower limb joints. Previous ankle sprains (AS) contribute to altered neuromuscular control in ACLR, emphasizing the need to evaluate within-limb coordination during bilateral tasks to prevent secondary ACL injuries. The effect of Energy Absorption Contribution (EAC) on joint work provides insight into the coordination between joints during observed movements. Thus, the purpose of this study was to validate a novel LSI based on EAC for discriminating movement strategies in bilateral drop vertical jump landing (DVJL) among individuals with ACLR and ACLR-AS

METHODS

39 healthy athletes, including 13 healthy controls, 13 ACLR, and 13 ACLR-AS were matched by age, height, weight, sex, sports involvement, and limb dominance. Participants performed five DVJLs with kinematics and ground reaction forces recorded. Individual joint work (M) and EAC were calculated and averaged across the middle three trials to compute the LSI on individual joint work (LSIM) and EAC (LSIEAC). Negative LSI indicates asymmetry toward the nonsurgical limb, while positive LSI indicates asymmetry toward the surgical limb. A 3x2x3 repeated measures analysis of variance was utilized to analyze interactions between groups, the LSI method, and joint. Tukey’s LSD post-hoc analyses were used to examine within and between groups (alpha=0.05).

RESULTS

There was a significant interaction between the group, LSI method, and joint (F4,72=3.216,P=.017). LSIEACidentified significant loading asymmetry at the hip (P=.046) and knee (P=.015) when compared to healthy controls.

CONCLUSIONS

LSIEACproved to be the method capable of distinguishing group differences in loading asymmetry at the hip and knee for the ACLR-AS group compared to healthy controls during bilateral DVJL. Overall, LSIEACprovided a more comprehensive insight into the movement strategies employed during DVJL, particularly for individuals with ACLR and ACLR-AS. This emphasizes its suitability for effectively monitoring the rehabilitation progression post ACLR towards RTS. Our findings suggest that clinicians should prioritize computing the LSI based on EAC and assessing the history of ankle sprains for precise RTS decision-making. This approach not only aids in identifying loading asymmetry at the knee and hip but also underscores the critical importance of restoring modified movement strategies in adolescents with ACLR-AS, ultimately reducing the risk of secondary ACL injury following RTS.
Comparative venom analysis between melanistic and normally-colored phenotypes of the common adder (Vipera berus)
Authors: Schulte Lennart , Uhrig Lilien , Eichberg Johanna , Schwartze Michael , Auth Ingve , Schulz Miriam , Lindner Thomas , Hien Paul , Hardes Kornelia , Vilcinskas Andreas , Lüddecke Tim
Published: March 2024

1

Snake venom is an ecologically-relevant functional trait directly linked with a snake’s fitness and survival, facilitating predation and defense. Snake venom variation occurs at all taxonomic levels, but the study of variation at intraspecific level is still in its early stages. The common adder (Vipera berus) exhibits considerable variation in color phenotypes across its distribution range. Melanistic (fully black) individuals are the subject of myths and fairytales, and in German folklore such “hell adders” are considered more toxic than their normally-colored conspecifics. However, these claims have never been formally tested. Here, we provide the first comparative analysis of venoms from melanistic and normally-colored common adders. Specifically, we compared the venom profiles by SDS-PAGE and RP-HPLC, and tested the protease, phospholipase A2and cytotoxic activities of the venoms of both phenotypes. Phospholipase A2activity was similar in both phenotypes, whereas general protease activity was higher in the melanistic venom, which was also more cytotoxic at two concentrations (6.25 and 12.5 µg/ml). These minor differences between the venoms of melanistic and normally-colored adders are unlikely to be of clinical relevance in the context of human envenomation. In light of our results, the claim that melanistic adders produce more toxic venom than their normally-colored conspecifics appears rooted entirely in folklore.
GLP-1 receptor agonist exenatide uncouples food intake from hedonic and anticipatory regulation in non-human primates: Insights from an operant meal schedule paradigm
Authors: Knakker Balázs , Inkeller Judit , Kovács Péter , Lendvai Balázs , Hernádi István
Published: March 2024

Glucagon-like peptide 1 (GLP-1), a neuroendocrine signal of energy balance and satiety, has a major role in regulating food intake behaviour. Here we investigated the effects of the GLP-1 agonist exenatide on palatability-driven feeding regulation in adult male rhesus macaques (n=5) using a novel operant food intake paradigm with four meal schedule conditions where two types of pellets with different palatability values were offered as meal in all combinations in two consecutive daily feeding sessions (S1 and S2). In control conditions, a strong, palatability-driven anticipatory effect was found in S1, followed by a complementary positive contrast effect in S2. After acute subcutaneous treatment with 1 µg/kg dose of exenatide 1 h before S1, food intake decreased to the same very low level in all meal schedule conditions in S1, completely erasing the previously observed anticipatory effect. Conversely, exenatide induced hypoglycaemia in an anticipatory meal schedule dependent pattern. Interestingly, the previously observed positive contrast effect was spared in S2, with a weaker residual effect specifically on the consumption of the more palatable pellet type. To conclude, the food intake reducing effects of exenatide may temporally evolve from strong anorectic to weak anhedonic modulations, where hedonic experience and anticipation during the early anorectic phase is conserved but uncoupled from food intake behaviour.
Mycobacteriumdormancy and antibiotic tolerance within the retinal pigment epithelium of ocular tuberculosis
Authors: Liu Rachel , Dang Joshua N. , Lee Rhoeun , Lee Jae Jin , Kesavamoorthy Niranjana , Ameri Hossein , Rao Narsing , Eoh Hyungjin
Published: March 2024

Tuberculosis (TB) is a leading cause of death among infectious diseases worldwide due to latent TB infection, which is the critical step for the successful pathogenic cycle. In this stage,Mycobacterium tuberculosisresides inside the host in a dormant and antibiotic-tolerant state. Latent TB infection can lead to a multisystemic diseases becauseM. tuberculosisinvades virtually all organs, including ocular tissues. Ocular tuberculosis (OTB) occurs when the dormant bacilli within ocular tissues reactivate, originally seeded by hematogenous spread from pulmonary TB. Timely and accurate diagnosis as well as efficient chemotherapies are crucial in preventing poor visual outcomes of OTB patients. Histological evidence suggests that retinal pigment epithelium (RPE) cells play a central role in immune privilege and in the protection from the antibiotic effects, making them an anatomical niche for invadingM. tuberculosis. RPE cells exhibit high tolerance to environmental redox stresses, allowing phagocytosedM. tuberculosisbacilli to maintain viability in a dormant state. However, the microbiological and metabolic mechanisms determining the interaction between the RPE intracellular environment and phagocytosedM. tuberculosisare largely unknown. Here, liquid chromatography mass spectrometry (LC-MS) metabolomics was used to illuminate the metabolic state within RPE cells reprogrammed to harbor dormantM. tuberculosisbacilli and enhance the antibiotic tolerance. The results have led to propose a novel therapeutic option to synthetically kill the dormantM. tuberculosisinside the RPE cells by modulating the phenotypic state ofM. tuberculosis, thus laying the foundation for a new, innovative regimen for treating OTB.

Importance

Understanding the metabolic environment within the retinal pigment epithelium (RPE) cells altered by infection withM. tuberculosisand mycobacterial dormancy is crucial to identify new therapeutic methods to cure OTB. The present study showed that RPE cellular metabolism is altered to foster intracellular M. tuberculosis to enter into the dormant and drug tolerant state, thereby blunting the efficacy of anti-TB chemotherapy. RPE cells serve as an anatomical niche as the cells protect invading bacilli from antibiotic treatment. LC-MS metabolomics of RPE cells after co-treatment with H2O2 and M. tuberculosis infection showed that intracellular environment within RPE cells is enriched with greater level of oxidative stress. The antibiotic tolerance of intracellularM. tuberculosiswithin RPE cells can be restored by a metabolic manipulation strategy such as co-treatment of antibiotic with the most downstream glycolysis metabolite, phosphoenolpyruvate.