bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuronal CBP-1 is required for enhanced body muscle proteostasis in response to reduced translation downstream of mTOR
Authors: Snow Santina , Mir Dilawar , Ma Zhengxin , Horrocks Jordan , Cox Matthew , Ruzga Marissa , Sayed Hussein , Rogers Aric N. 
Published: March 2024

AbstractBackgroundThe ability to maintain muscle function decreases with age and loss of proteostatic function. Diet, drugs, and genetic interventions that restrict nutrients or nutrient signaling help preserve long-term muscle function and slow age-related decline. Previously, it was shown that attenuating protein synthesis downstream of the mechanistic target of rapamycin (mTOR) gradually increases expression of heat shock response (HSR) genes in a manner that correlates with increased resilience to protein unfolding stress. Here, we investigate the role of specific tissues in mediating the cytoprotective effects of low translation.MethodsThis study uses genetic tools (transgenicC. elegans, RNA interference and gene expression analysis) as well as physiological assays (survival and paralysis assays) in order to better understand how specific tissues contribute to adaptive changes involving cellular cross-talk that enhance proteostasis under low translation conditions.ResultsWe use theC. eleganssystem to show that lowering translation in neurons or the germline increases heat shock gene expression and survival under conditions of heat stress. In addition, we find that low translation in these tissues protects motility in a body muscle-specific model of proteotoxicity that results in paralysis. Low translation in neurons or germline also results in increased expression of certain muscle regulatory and structural genes, reversing reduced expression normally observed with aging inC. elegans. Enhanced resilience to protein unfolding stress requires neuronal expression ofcbp-1.ConclusionLow translation in either neurons or the germline orchestrate protective adaptation in other tissues, including body muscle.
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

AbstractPoly 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 ContributionWe 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 PointsA 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

SummaryEndosperm 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.
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

AbstractMass-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

AbstractImmunomodulatory 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 SummaryEngineered 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

ABSTRACTThe 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

AbstractIntroductionRecent studies have shown that, following brain injury, sleep-like cortical dynamics intrude into wakefulness, potentially contributing to brain network disruption and behavioral deficits.AimWe employ TMS in combination with EEG to detect these dynamics and assess their impact on brain networks and clinical evolution in awake stroke patients.MethodsTwelve 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.ResultsResults 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).ConclusionThese 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

AbstractExtracellular 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

AbstractNatural 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.HighlightsBumblebees 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

AbstractPlant 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

AbstractVariants 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

AbstractStudies 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

AbstractTo 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.