bluuebunny/crossref_metadata_2025_split huggingface dataset:
The genome sequence of the Montseny horsehair worm,Gordionus montsenyensissp. nov., a key resource to investigate Ecdysozoa evolution
Authors: Eleftheriadi Klara , Guiglielmoni Nadège , Salces-Ortiz Judit , Vargas-Chavez Carlos , Martínez-Redondo Gemma I. , Gut Marta , Flot Jean-François , Schmidt-Rhaesa Andreas , Fernández Rosa 
Published: June 2023

AbstractNematomorpha, also known as Gordiacea or Gordian worms, are a phylum of parasitic organisms that belong to the Ecdysozoa, a clade of invertebrate animals characterized by molting. They are one of the less scientifically studied animal phyla, and many aspects of their biology and evolution are still unknown, partially due to the lack of genomic resources for this phylum. As part of the European Reference Genome Atlas pilot effort to generate reference genomes for European biodiversity, we present the taxonomic description and chromosome-level genome assembly of a newly described species of Nematomorpha (Gordionus montsenyensisSchmidt-Rhaesa & Fernández sp. nov.). The final assembly has a total length of 288 Mb in 396 scaffolds with an N50 of 64.4 Mb, 97% of which is scaffolded into 5 pseudochromosomes. The circular mitochondrial genome was also assembled into a 15-kilobases sequence. Gene annotation predicted 10,320 protein-coding genes in the nuclear genome. In this study, we contribute a key genomic resource to not only explore the evolution of Ecdysozoa, but also to further our understanding on the genomic basis of parasitic lifestyles. In addition, we describe a species new to science from this enigmatic animal phyla.
Transfemoral limb loss modestly increases the metabolic cost of optimal control simulations of walking
Authors: Miller Ross H. , Bell Elizabeth M. , Esposito Elizabeth Russell 
Published: June 2023

ABSTRACTUnlike the case of transtibial limb loss, high-functioning military service members with transfemoral limb loss have a high metabolic cost of walking compared to able-bodied peers. In transtibial limb loss, computer simulations suggest that the maintenance of muscle strength between pre- and post-limb loss can maintain the pre-limb loss metabolic cost. Here we performed optimal control simulations of walking with and without transfemoral limb loss to determine if transfemoral limb lossper seincreases the metabolic cost of walking. OpenSim Moco was used to generate optimal control simulations of walking in 15 virtual subjects that minimized the weighted sum of (i) deviations from average able-bodied gait mechanics and (ii) the gross metabolic cost of walking, pre-limb loss in models with two intact biological limbs, and post-limb loss with one of the limbs replaced by a transfemoral prosthesis. No other changes were made to the model. Metabolic cost post-limb loss increased by 0.7-9.3% (p< 0.01) depending on whether cost was scaled by total body mass or biological body mass and on whether the prosthetic knee was passive or non-passive. The post-limb loss model had numerous features that predisposed it to low metabolic cost. These results suggest that transfemoral limb lossper seincreases the metabolic cost of walking, but that the large differences above able-bodied peers of ∼20% or more in most gait analysis experiments may be avoidable, even when minimizing deviations from able-bodied gait mechanics.
Intraspecific variation in the placement of campaniform sensilla on the wings of the hawkmothManduca sexta
Authors: Stanchak Kathryn E. , Deora Tanvi , Weber Alison I. , Hickner Michelle K. , Moalin Abna , Abdalla Laila , Daniel Thomas L. , Brunton Bingni W. 
Published: June 2023

AbstractFlight control requires active sensory feedback, and insects have many sensors that help them estimate their current locomotor state, including campaniform sensilla, which are mechanoreceptors that sense strain resulting from deformation of the cuticle. Campaniform sensilla on the wing detect bending and torsional forces encountered during flight, providing input to the flight feedback control system. During flight, wings experience complex spatio-temporal strain patterns. Because campaniform sensilla detect only local strain, their placement on the wing is presumably critical for determining the overall representation of wing deformation; however, how these sensilla are distributed across wings is largely unknown. Here, we test the hypothesis that campaniform sensilla are found in stereotyped locations across individuals ofManduca sexta, a hawkmoth. We found that although campaniform sensilla are consistently found on the same veins or in the same regions of the wings, their total number and distribution can vary extensively. This suggests that there is some robustness to variation in sensory feedback in the insect flight control system. The regions where campaniform sensilla are consistently found provide clues to their functional roles, although some patterns might be reflective of developmental processes. Collectively, our results on intraspecific variation in campaniform sensilla placement on insect wings will help reshape our thinking on the utility of mechanosensory feedback for insect flight control and guide further experimental and comparative studies.
Chemically-induced epileptic seizures in zebrafish: a systematic review
Authors: Chitolina Rafael , Gallas-Lopes Matheus , Reis Carlos G. , Benvenutti Radharani , Stahlhofer-Buss Thailana , Calcagnotto Maria Elisa , Herrmann Ana P. , Piato Angelo 
Published: June 2023

ABSTRACTThe use of zebrafish as a model organism is gaining evidence in the field of epilepsy as it may help to understand the mechanisms underlying epileptic seizures. As zebrafish assays became popular, the heterogeneity between protocols increased, making it hard to choose a standard protocol to conduct research while also impairing the comparison of results between studies. We conducted a systematic review to comprehensively profile the chemically-induced seizure models in zebrafish. Literature searches were performed in PubMed, Scopus and Web of Science, followed by a two-step screening process based on inclusion/exclusion criteria. Qualitative data were extracted and a sample of 100 studies was randomly selected for risk of bias assessment. Out of the 1058 studies identified after removing duplicates, 201 met the inclusion criteria. We found that the most common chemoconvulsants used in the reviewed studies were pentylenetetrazole (n = 180), kainic acid (n = 11), and pilocarpine (n = 10), which increase seizure severity in a dose-dependent manner. The main outcomes assessed were seizure scores and locomotion. Significant variability between the protocols was observed for administration route, duration of exposure, and dose/concentration. Of the studies subjected to risk of bias assessment, most were rated as low risk of bias for selective reporting (94%), baseline characteristics of the animals (67%), and blinded outcome assessment (54%). Randomization procedures and incomplete data were rated as unclear in 81% and 68% of the studies, respectively. None of the studies reported the sample size calculation. Overall, these findings underscore the need for improved methodological and reporting practices to enhance reproducibility and reliability of zebrafish models for studying epilepsy. Our study offers a comprehensive overview of the current state of chemically-induced seizure models in zebrafish, highlighting the common chemoconvulsants used and the variability in protocol parameters. This may be particularly valuable to researchers interested in understanding the underlying mechanisms of epileptic seizures and screening potential drug candidates in zebrafish models.HIGHLIGHTS- We systematically reviewed the effects of chemically-induced seizures in zebrafish;- PTZ is the most used epileptic seizure inducer in zebrafish;- More than 50% of the studies fail to report data such as outlier exclusion criteria and sample size estimation;- The results showed a need for better standardization of protocols.
Single-cell transcriptomes identify patient-tailored therapies for selective co-inhibition of cancer clones
Authors: Ianevski Aleksandr , Nader Kristen , Bulanova Daria , Giri Anil K , Ruokoranta Tanja , Kuusanmäki Heikki , Ikonen Nemo , Sergeev Philipp , Vähä-Koskela Markus , Vähärautio Anna , Kontro Mika , Porkka Kimmo , Heckman Caroline A. , Wennerberg Krister , Aittokallio Tero 
Published: June 2023

AbstractIntratumoral cellular heterogeneity necessitates multi-targeting therapies for improved clinical benefits in patients with advanced malignancies. However, systematic identification of patient-specific treatments that selectively co-inhibit cancerous cell populations poses a combinatorial challenge, since the number of possible drug-dose combinations vastly exceeds what could be tested in scarce patient cells. Here, we developed scTherapy, a machine learning model that leverages single-cell transcriptomic profiles to prioritize multi-targeting treatment options for individual patients with hematological cancers or solid tumors.
Molecular signature and functional properties of human pluripotent stem cell-derived brain pericytes
Authors: Bosworth Allison , Griffin Casey , Chakhoyan Ararat , Sagare Abhay P. , Nelson Amy R. , Wang Yaoming , Kisler Kassandra , Montagne Axel , Clementel Veronica , TCW Julia , Rust Ruslan , Coba Marcelo , Zlokovic Berislav V. 
Published: June 2023

AbstractBrain pericytes maintain blood-brain barrier (BBB), secrete neurotrophic factors and clear toxic proteins. Their loss in neurological disorders leads to BBB breakdown, neuronal dysfunction, and cognitive decline. Therefore, cell therapy to replace lost pericytes holds potential to restore impaired cerebrovascular and brain functions. Here, we show by a quantitative analysis of 8,344 proteins and 20,572 phosphopeptides that human iPSC-derived brain pericytes (iPSC-PC) share 96% of total proteins and 98% of protein phosphorylation sites with primary human brain pericytes. This includes cell adhesion and tight junction proteins, transcription factors, and different protein kinase families of the human kinome. In pericyte-deficient mice, iPSC-PC home to host brain capillaries to form hybrid human-mouse microvessels. They repair BBB leaks and protect against neuron loss, which we show requires PDGRFB and pleiotrophin. They also clear Alzheimer’s amyloid-β and tau neurotoxins via lipoprotein receptor. Thus, iPSC-PC may offer a valuable replacement therapy for pericyte-deficient neurological disorders.
The evolution and mutational robustness of chromatin accessibility inDrosophila
Authors: Khodursky Samuel , Zheng Eric B , Svetec Nicolas , Durkin Sylvia M , Benjamin Sigi , Gadau Alice , Wu Xia , Zhao Li 
Published: June 2023

AbstractThe evolution of regulatory regions in the genome plays a critical role in shaping the diversity of life. While this process is primarily sequence-dependent, the enormous complexity of biological systems has made it difficult to understand the factors underlying regulation and its evolution. Here, we apply deep neural networks as a tool to investigate the sequence determinants underlying chromatin accessibility in different tissues ofDrosophila. We train hybrid convolution-attention neural networks to accurately predict ATAC-seq peaks using only local DNA sequences as input. We show that a model trained in one species has nearly identical performance when tested in another species, implying that the sequence determinants of accessibility are highly conserved. Indeed, model performance remains excellent even in distantly-related species. By using our model to examine species-specific gains in chromatin accessibility, we find that their orthologous inaccessible regions in other species have surprisingly similar model outputs, suggesting that these regions may be ancestrally poised for evolution. We then usein silicosaturation mutagenesis to reveal evidence of selective constraint acting specifically on inaccessible chromatin regions. We further show that chromatin accessibility can be accurately predicted from short subsequences in each example. However,in silicoknock-out of these sequences does not qualitatively impair classification, implying that chromatin accessibility is mutationally robust. Subsequently, we demonstrate that chromatin accessibility is predicted to be robust to large-scale random mutation even in the absence of selection. We also performin silicoevolution experiments under the regime of strong selection and weak mutation (SSWM) and show that chromatin accessibility can be extremely malleable despite its mutational robustness. However, selection acting in different directions in a tissue-specific manner can substantially slow adaptation. Finally, we identify motifs predictive of chromatin accessibility and recover motifs corresponding to known chromatin accessibility activators and repressors. These results demonstrate the conservation of the sequence determinants of accessibility and the general robustness of chromatin accessibility, as well as the power of deep neural networks as tools to answer fundamental questions in regulatory genomics and evolution.
De NovoDesign of Peptide Binders to Conformationally Diverse Targets with Contrastive Language Modeling
Authors: Bhat Suhaas , Palepu Kalyan , Hong Lauren , Mao Joey , Ye Tianzheng , Iyer Rema , Zhao Lin , Chen Tianlai , Vincoff Sophia , Watson Rio , Wang Tian , Srijay Divya , Kavirayuni Venkata Srikar , Kholina Kseniia , Goel Shrey , Vure Pranay , Desphande Aniruddha J. , Soderling Scott H. , DeLisa Matthew P. , Chatterjee Pranam 
Published: June 2023

AbstractDesigning binders to target undruggable proteins presents a formidable challenge in drug discovery, requiring innovative approaches to overcome the lack of putative binding sites. Recently, generative models have been trained to design binding proteins via three-dimensional structures of target proteins, but as a result, struggle to design binders to disordered or conformationally unstable targets. In this work, we provide a generalizable algorithmic framework to design short, target-binding linear peptides, requiring only the amino acid sequence of the target protein. To do this, we propose a process to generate naturalistic peptide candidates through Gaussian perturbation of the peptidic latent space of the ESM-2 protein language model, and subsequently screen these novel linear sequences for target-selective interaction activity via a CLIP-based contrastive learning architecture. By integrating these generative and discriminative steps, we create aPeptidePrioritization viaCLIP(PepPrCLIP) pipeline and validate highly-ranked, target-specific peptides experimentally, both as inhibitory peptides and as fusions to E3 ubiquitin ligase domains, demonstrating functionally potent binding and degradation of conformationally diverse protein targetsin vitro. Overall, our design strategy provides a modular toolkit for designing short binding linear peptides to any target protein without the reliance on stable and ordered tertiary structure, enabling generation of programmable modulators to undruggable and disordered proteins such as transcription factors and fusion oncoproteins.
Bacillus subtilisYisK possesses oxaloacetate decarboxylase activity and exhibits Mbl-dependent localization
Authors: Guo Tingfeng , Sperber Anthony M. , Krieger Inna V. , Duan Yi , Chemelewski Veronica , Sacchettini James C. , Herman Jennifer K. 
Published: June 2023

ABSTRACTYisK is an uncharacterized protein inBacillus subtilispreviously shown to interact genetically with the elongasome protein Mbl. YisK overexpression leads to cell widening and lysis, phenotypes that are dependent onmbland suppressed bymblmutations. In the present work we characterize YisK’s localization, structure, and enzymatic activity. We show that YisK localizes in a punctate and/or punctate-helical pattern that depends on Mbl, and that YisK interacts directly with another elongasome protein, FtsE. YisK belongs to the fumarylacetoacetate hydrolase (FAH) superfamily and crystal structures revealed close structural similarity to two oxaloacetate (OAA) decarboxylases: human mitochondrial FAHD1 andCorynebacterium glutamicumCg1458. We demonstrate that YisK can also catalyze the decarboxylation of OAA (Km= 134 µM, Kcat= 31 min-1). A catalytic dead variant (YisK E148A, E150A) retains wild-type localization and still widens cells following overexpression, indicating these activities are not dependent on YisK catalysis. Conversely, a non-localizing variant (YisK E30A) retains wild-type enzymatic activity in vitro, but no longer widens cells following overexpression. Together these results suggest YisK may be subject to spatial regulation that depends on the cell envelope synthesis machinery.IMPORTANCEThe elongasome is a protein complex that guides lengthwise growth in some bacteria. We previously showed that inB. subtilis, overexpression of an uncharacterized enzyme (YisK), perturbed function of the actin-like elongasome protein Mbl. Here we show that YisK exhibits Mbl-dependent localization and interacts directly with another component of the elongasome, FtsE. Through biochemical and structural characterization, we demonstrate that like it’s mitochondrial homolog FAHD1, YisK can catalyze the decarboxylation of the oxaloacetate to pyruvate and CO2. YisK is the first example of an enzyme implicated in central carbon metabolism with subcellular localization that depends on Mbl.
Make like a tree and leave: How will tree species loss and climate change alter future temperate broadleaved forests?
Authors: West Bede , Jones Davey L. , Robinson Emma L. , Keith Aidan M. , Kallow Simon , Marrs Robert H. , Smart Simon M. 
Published: June 2023

AbstractForest creation has the potential to reduce biodiversity loss and mitigate climate change but, tree disease emergence may counteract this. Further, given decadal timescales required for forest establishment, climate change is increasingly likely to act as a filter on plant community assembly. In the temperate lowlands succession takes 30 to 50 years for non-forest land to establish woodland plant assemblages, while the timescales required for new forest to sequester carbon suggest unassisted succession will be too slow for net zero 2050 targets. However, if plantations can establish faster than succession it would be beneficial to recommend planting native species as soon as possible. We explore scenarios of broadleaved woodland development across Wales, UK, as a case study area. We use a suite of empirical species niche models for British plants to estimate the potential species composition of forests with, and without, projected climate change. Additionally, we examine how tree canopy composition alters ifFraxinus excelsioris widely impacted by ash-dieback (Hymenoscyphus fraxineus). The results suggest soil total carbon and nitrogen could achieve baseline broadleaved forest values in less than 30 years. However only timber and woody flora species groups showed diversity surpassing baseline broadleaved forest diversity, with nectar plants and ancient woodland indicator species failing to reach baseline equivalents within 30 years; although complete congruence is unlikely given baseline forests could be hundreds of years old. WhereFraxinus excelsiorwas removed from the species pool we predicted that a scrub phase will persist or, if present,Acer pseudoplatanuswill become the canopy dominant. The heavier shade cast this species is likely to result in differences in species composition of the understory and ground flora diversity is likely to decrease. Reliance on unassisted succession will also depend critically on (a) dispersal from local source populations and (b) on establishment filters that could be severe in landscapes with high management intensity history. These findings indicate that leaving the UK’s fragmented habitats to relying on already degraded successional processes could lead to poor afforestation outcomes.HighlightsAfforestation can mitigate global change but tree disease makes outcomes uncertainAfforestation methods establishment timescales and time for benefits to occurWe model afforestation and predict how soils and plants change with climateAsh loss from die-back is replaced by low low-canopy woodland / scrub over 30 yearsAfforestation achieves baseline forest values for some variables within 30 years
Antiviral Type III CRISPR signalling via conjugation of ATP and AdoMet
Authors: Chi Haotian , Hoikkala Ville , Grüschow Sabine , Graham Shirley , Shirran Sally , White Malcolm F 
Published: June 2023

ABSTRACTCRISPR systems are widespread in the prokaryotic world, providing adaptive immunity against mobile genetic elements (MGE)1, 2. Type III CRISPR systems, with the signature genecas10, use CRISPR RNA (crRNA) to detect non-self RNA, activating the enzymatic Cas10 subunit to defend the cell against MGE either directly, via the integral HD nuclease domain3–5or indirectly, via synthesis of cyclic oligonucleotide (cOA) second messengers to activate diverse ancillary effectors6–9. A subset of type III CRISPR systems encode an uncharacterised CorA-family membrane protein and an associated NrN family phosphodiesterase predicted to function in antiviral defence. Here, we demonstrate that the CorA associated type III-B (Cmr) CRISPR system fromBacteroides fragilisprovides immunity against MGE when expressed inE. coli. However,B. fragilisCmr does not synthesise cOA species on activation, instead generating a previously undescribed sigalling molecule, SAM-AMP (3’-adenylyl-AdoMet) by conjugating ATP to S-adenosyl methionine via a phosphodiester bond. Once synthesised, SAM-AMP binds to the CorA effector, presumably leading to cell death by disruption of the membrane integrity. SAM-AMP is degraded by CRISPR associated phosphodiesterases or a SAM-AMP lyase, providing an “off switch” analogous to cOA specific ring nucleases10. SAM-AMP thus represents a new class of second messenger for antiviral signalling, which may function in different roles in diverse cellular contexts.