bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole blood storage duration alters fibrinogen levels and thrombin formation
Authors: Chae Ryan , Nguyen Christopher , Archdeacon Chad , Wattley Lindsey , Sisak Stephanie , Price Adam , Perez Emma , Schuster Rebecca , Lentsch Alex , Caldwell Charles , Goodman Michael , Pritts Timothy
Published: March 2024

INTRODUCTION

Whole blood resuscitation for hemorrhagic shock in trauma represents an opportunity to correct coagulopathy in trauma while also supplying red blood cells. The production of microvesicles in stored whole blood and their effect on its hemostatic parameters have not been described in previous literature. We hypothesized that microvesicles in aged stored whole blood are procoagulant and increase thrombin production via phosphatidylserine.

METHODS

Whole blood was obtained from male C57BL/6 male mice and stored in anticoagulant solution for up to 10 days. At intervals, stored whole blood underwent examination with rotational thromboelastography, and platelet-poor plasma was prepared for analysis of thrombin generation. Microvesicles were prepared from 10-day-old whole blood aliquots and added to fresh whole blood or platelet-poor plasma to assess changes in coagulation and thrombin generation. Microvesicles were treated with recombinant mouse lactadherin prior to addition to plasma to inhibit phosphatidylserine's role in thrombin generation.

RESULTS

Aged murine whole blood had decreased fibrin clot formation compared with fresh samples with decreased plasma fibrinogen levels. Thrombin generation in plasma from aged blood increased over time of storage. The addition of microvesicles to fresh plasma resulted in increased thrombin generation compared with controls. When phosphatidylserine on microvesicles was blocked with lactadherin, there was no difference in the endogenous thrombin potential, but the generation of thrombin was blunted with lower peak thrombin levels.

CONCLUSION

Cold storage of murine whole blood results in decreased fibrinogen levels and fibrin clot formation. Aged whole blood demonstrates increased thrombin generation, and this is due in part to microvesicle production in stored whole blood. One mechanism by which microvesicles are procoagulant is by phosphatidylserine expression on their membranes.
Interest of rare autoantibodies in autoimmune encephalitis and paraneoplastic neurological syndromes: the utility (or futility) of rare antibody discovery
Authors: Segal Yahel , Zekeridou Anastasia
Published: March 2024

Purpose of review

The increasing recognition and diagnosis of autoimmune encephalitis (AE) and paraneoplastic neurological syndromes (PNS) is partly due to neural autoantibody testing and discovery. The past two decades witnessed an exponential growth in the number of identified neural antibodies. This review aims to summarize recent rare antibody discoveries in the context of central nervous system (CNS) autoimmunity and evaluate the ongoing debate about their utility.

Recent findings

In the last 5 years alone 15 novel neural autoantibody specificities were identified. These include rare neural antibody biomarkers of autoimmune encephalitis, cerebellar ataxia or other movement disorders, including multifocal presentations.

Although the clinical applications of these rare antibody discoveries may be limited by the low number of positive cases, they still provide important diagnostic, prognostic, and therapeutic insights.
Understanding multiple sclerosis as a disease spectrum: above and below the clinical threshold
Authors: Krieger Stephen , Cook Karin , Hersh Carrie M.
Published: March 2024

Purpose of review

Research in multiple sclerosis (MS) has long been predicated on clinical groupings that do not reflect the underlying biologic heterogeneity apparent within patient populations. This review explicates the various levels of explanation through which the spectrum of disease is described and investigated both above and below the clinical threshold of detection, as framed by the topographical model of MS, to help advance a cogent mechanistic framework.

Recent findings

Contemporary evidence has amended the view of MS as consisting of sequential disease phases in favor of a spectrum of disease with an admixture of interdependent and dynamic pathobiological axes driving tissue injury and progression. Recent studies have shown the presence of acute and compartmentalized inflammation and mechanisms of neurodegeneration beginning early and evolving throughout the disease continuum. Still, the gap between the understanding of immunopathologic processes in MS and the tools used to measure relevant molecular, laboratory, radiologic, and clinical metrics needs attention to enable better prognostication of disease and monitoring for changes along specific pathologic axes and variable treatment outcomes.

Aligning on a consistently-applied mechanistic framework at distinct levels of explanation will enable greater precision across bench and clinical research, and inform discourse on drivers of disability progression and delivery of care for individuals with MS.
Bruton tyrosine kinase inhibitors in multiple sclerosis: evidence and expectations
Authors: Krämer Julia , Wiendl Heinz
Published: March 2024

Purpose of review

Despite availability of high-efficacy therapies for multiple sclerosis (MS), many patients experience significant disability worsening due to limited effects of currently available drugs on central nervous system (CNS)-compartmentalized inflammation. Bruton tyrosine kinase (BTK) is an intracellular signaling molecule involved in regulation of maturation, survival, migration, and activation of B cells and microglia, which are central players in the immunopathogenesis of progressive MS. Therefore, CNS-penetrant BTK inhibitors may better prevent disease progression by targeting immune cells on both sides of the blood–brain barrier. This review gives an overview on the preliminary results of clinical trials.

Recent findings

Currently, the efficacy and safety of six BTK inhibitors are being evaluated in clinical trials in patients with relapsing and progressive MS. Evobrutinib, tolebrutinib and fenebrutinib have shown efficacy and safety in relapsing MS in phase 2 studies, and evobrutinib and tolebrutinib in their extension studies up to 3–5 years. However, evobrutinib failed to distinguish itself from the comparator drug teriflunomide in reduction of relapse rate (primary end point) in two phase 3 studies in relapsing MS.

Inhibition of BTK has emerged as a promising therapeutic approach to target the CNS-compartmentalized inflammation. Results from phase 3 clinical trials will shed light on differences in efficacy and safety of BTK inhibitors and its potential role in the future MS landscape.
Early social complexity influences social behaviour but not social trajectories in a cooperatively breeding cichlid fish
Authors: La Loggia Océane , Wilson Alastair J. , Taborsky Barbara
Published: March 2024

Social competence—defined as the ability to optimize social behaviour according to available social information—can be influenced by the social environment experienced in early life. In cooperatively breeding vertebrates, the current group size influences behavioural phenotypes, but it is not known whether the group size experienced in early life influences behavioural phenotypes generally or social competence specifically. We tested whether being reared in large versus small groups for the first two months of life affects social behaviours, and associated life-history traits, in the cooperatively breeding cichlid
Neolamprologus pulcher
between the ages of four and twelve months. As we predicted, fish raised in larger and more complex groups showed higher social competence later in life. This was shown in several ways: they exhibited more, and earlier, submissive behaviour in response to aggression from a dominant conspecific, and—in comparison to fish raised in small groups—they exhibited more flexibility in the expression of submissive behaviour. By contrast, there was no evidence that early social complexity, as captured by the group size, affects aggression or exploration behaviour nor did it influence the propensity to disperse or show helping behaviour. Our results emphasize the importance of early-life social complexity for the development of social competence.
Depth variation in benthic community response to repeated marine heatwaves on remote Central Indian Ocean reefs
Authors: Sannassy Pilly Sivajyodee , Roche Ronan C. , Richardson Laura E. , Turner John R.
Published: March 2024

Coral reefs are increasingly impacted by climate-induced warming events. However, there is limited empirical evidence on the variation in the response of shallow coral reef communities to thermal stress across depths. Here, we assess depth-dependent changes in coral reef benthic communities following successive marine heatwaves from 2015 to 2017 across a 5–25 m depth gradient in the remote Chagos Archipelago, Central Indian Ocean. Our analyses show an overall decline in hard and soft coral cover and an increase in crustose coralline algae, sponge and reef pavement following successive marine heatwaves on the remote reef system. Our findings indicate that the changes in benthic communities in response to elevated seawater temperatures varied across depths. We found greater changes in benthic group cover at shallow depths (5–15 m) compared with deeper zones (15–25 m). The loss of hard coral cover was better predicted by initial thermal stress, while the loss of soft coral was associated with repeated thermal stress following successive warming events. Our study shows that benthic communities extending to 25 m depth were impacted by successive marine heatwaves, supporting concerns about the resilience of shallow coral reef communities to increasingly severe climate-driven warming events.
Response of two temperate scleractinian corals to projected ocean warming and marine heatwaves
Authors: Carbonne Chloe , Comeau Steeve , Plichon Keyla , Schaub Sébastien , Gattuso Jean-Pierre , Teixidó Núria
Published: March 2024

The Mediterranean Sea is a hotspot of global change, particularly exposed to ocean warming and the increasing occurrence of marine heatwaves (MHWs). However, experiments based on long-term temperature data from the field are scarce. Here, we investigate the response of the zooxanthellate coral
Cladocora caespitosa
and the azooxanthellate coral
Astroides calycularis
to future warming and MHWs based on 8 years of
in situ
data. Corals were maintained in the laboratory for five months under four temperature conditions: Warming (3.2°C above the
in situ
mean from 2012 to 2020), Heatwave (temperatures of 2018 with two heatwaves), Ambient (
in situ
mean) and Cool (deeper water temperatures). Under the Warming treatment, some
C. caespitosa
colonies severely bleached and
A. calycularis
colonies presented necrosis.
Cladocora caespitosa
symbiosis was impaired by temperature with a decrease in the density of endosymbiotic algae and an increase in per cent whiteness in all the treatments except for the coolest. Recovery for both species was observed through different mechanisms such as regrowth of polyps of
A. calycularis
and recovery of pigmentation for
C. caespitosa
. These results suggest that
A. calycularis
and
C. caespitosa
may be resilient to heat stress and can recover from physiological stresses caused by heatwaves in the laboratory.
A mathematical model of thermoplastic elastomers for analysing the topology of microstructures and mechanical properties during elongation
Authors: Kodama Hiroki , Morita Hiroshi , Kotani Motoko
Published: March 2024

In this study, a mathematical model based on graph theory is developed to analyse the deformed structures and mechanical properties of thermoplastic elastomers (TPEs) using ABA-type triblock copolymers. TPEs exhibit a network structure formed by bridge chains; deformation of this network structure causes stress. During the deformation of TPEs, domain breakage and coalescence occur, accompanied by topological changes in the chains, such as conformational transitions between the bridge and loop chains. By employing the mathematical concepts of harmonic realization of graphs in the physical space and the tension tensor to quantify the stress in the bridge-chain network structure, an effective method for analysing topologicalchanges in microstructures caused by elongation is proposed. As an application of this method, optimal geometric structures of block copolymers with desired functionalities can be determined.
Variational implicit solvation with Legendre-transformed Poisson–Boltzmann electrostatics
Authors: Huang Zunding , Li Bo
Published: March 2024

The variational implicit-solvent model (VISM) is an efficient approach to biomolecular interactions, where electrostatic interactions are crucial. The total VISM free energy of a dielectric boundary (i.e. solute–solvent interface) consists of the interfacial energy, solute–solvent interaction energy and dielectric electrostatic energy. The last part is the maximum value of the classical and concave Poisson–Boltzmann (PB) energy functional of electrostatic potentials, with the maximizer being the equilibrium electrostatic potential governed by the PB equation. For the consistency of energy minimization and computational stability, here we propose alternatively to minimize the convex Legendre-transformed Poisson–Boltzmann (LTPB) electrostatic energy functional of all dielectric displacements constrained by Gauss’ Law in the solute region. Both integrable and discrete solute charge densities are treated, and the duality of the LTPB and PB functionals is established. A penalty method is designed for the constrained minimization of the LTPB functional. In application to biomolecular interactions, we minimize the total VISM free energy iteratively, while in each step of such iteration, minimize the LTPB energy. Convergence of such a min–min algorithm is shown. Our numerical results on the solvation of a single ion indicate that the LTPB performs better than the PB formulation, providing possibilities for efficient biomolecular simulations.
Structural identifiability analysis of linear reaction–advection–diffusion processes in mathematical biology
Authors: Browning Alexander P. , Taşcă Maria , Falcó Carles , Baker Ruth E.
Published: March 2024

Effective application of mathematical models to interpret biological data and make accurate predictions often requires that model parameters are identifiable. Approaches to assess the so-called structural identifiability of models are well established for ordinary differential equation models, yet there are no commonly adopted approaches that can be applied to assess the structural identifiability of the partial differential equation (PDE) models that are requisite to capture spatial features inherent to many phenomena. The differential algebra approach to structural identifiability has recently been demonstrated to be applicable to several specific PDE models. In this brief article, we present general methodology for performing structural identifiability analysis on partially observed reaction–advection–diffusion PDE models that are linear in the unobserved quantities. We show that the differential algebra approach can always, in theory, be applied to such models. Moreover, despite the perceived complexity introduced by the addition of advection and diffusion terms, consideration of spatial analogues of non-spatial models cannot exacerbate structural identifiability. We conclude by discussing future possibilities and the computational cost of performing structural identifiability analysis on more general PDE models.
The three-dimensionally articulated oral apparatus of a Devonian heterostracan sheds light on feeding in Palaeozoic jawless fishes
Authors: Dearden Richard P. , Jones Andy S. , Giles Sam , Lanzetti Agnese , Grohganz Madleen , Johanson Zerina , Lautenschlager Stephan , Randle Emma , Donoghue Philip C. J. , Sansom Ivan J.
Published: March 2024

Attempts to explain the origin and diversification of vertebrates have commonly invoked the evolution of feeding ecology, contrasting the passive suspension feeding of invertebrate chordates and larval lampreys with active predation in living jawed vertebrates. Of the extinct jawless vertebrates that phylogenetically intercalate these living groups, the feeding apparatus is well-preserved only in the early diverging stem-gnathostome heterostracans. However, its anatomy remains poorly understood. Here, we use X-ray microtomography to characterize the feeding apparatus of the pteraspid heterostracan
Rhinopteraspis dunensis
(Roemer, 1855). The apparatus is composed of 13 plates arranged approximately bilaterally, most of which articulate from the postoral plate. Our reconstruction shows that the oral plates were capable of rotating around the transverse axis, but likely with limited movement. It also suggests the nasohypophyseal organs opened internally, into the pharynx. The functional morphology of the apparatus in
Rhinopteraspis
precludes all proposed interpretations of feeding except for suspension/deposit feeding and we interpret the apparatus as having served primarily to moderate the oral gape. This is consistent with evidence that at least some early jawless gnathostomes were suspension feeders and runs contrary to macroecological scenarios that envisage early vertebrate evolution as characterized by a directional trend towards increasingly active food acquisition.
Synergistic response to climate stressors in coral is associated with genotypic variation in baseline expression
Authors: Dilworth Jenna , Million Wyatt C. , Ruggeri Maria , Hall Emily R. , Dungan Ashley M. , Muller Erinn M. , Kenkel Carly D.
Published: March 2024

As environments are rapidly reshaped due to climate change, phenotypic plasticity plays an important role in the ability of organisms to persist and is considered an especially important acclimatization mechanism for long-lived sessile organisms such as reef-building corals. Often, this ability of a single genotype to display multiple phenotypes depending on the environment is modulated by changes in gene expression, which can vary in response to environmental changes via two mechanisms: baseline expression and expression plasticity. We used transcriptome-wide expression profiling of eleven genotypes of common-gardened
Acropora cervicornis
to explore genotypic variation in the expression response to thermal and acidification stress, both individually and in combination. We show that the combination of these two stressors elicits a synergistic gene expression response, and that both baseline expression and expression plasticity in response to stress show genotypic variation. Additionally, we demonstrate that frontloading of a large module of coexpressed genes is associated with greater retention of algal symbionts under combined stress. These results illustrate that variation in the gene expression response of individuals to climate change stressors can persist even when individuals have shared environmental histories, affecting their performance under future climate change scenarios.
Synergistic negative effects between a fungicide and high temperatures on homing behaviours in honeybees
Authors: DesJardins Nicole S. , Chester Elise K. , Ozturk Cahit , Lynch Colin M. , Harrison Jon F. , Smith Brian H.
Published: March 2024

Interactions between environmental stressors may contribute to ongoing pollinator declines, but have not been extensively studied. Here, we examined the interaction between the agricultural fungicide Pristine (active ingredients: 25.2% boscalid, 12.8% pyraclostrobin) and high temperatures on critical honeybee behaviours. We have previously shown that consumption of field-realistic levels of this fungicide shortens worker lifespan in the field and impairs associative learning performance in a laboratory-based assay. We hypothesized that Pristine would also impair homing and foraging behaviours in the field, and that an interaction with hot weather would exacerbate this effect. Both field-relevant Pristine exposure and higher air temperatures reduced the probability of successful return on their own. Together, the two factors synergistically reduced the probability of return and increased the time required for bees to return to the hive. Pristine did not affect the masses of pollen or volumes of nectar or water brought back to the hive by foragers, and it did not affect the ratio of forager types in a colony. However, Pristine-fed bees brought more concentrated nectar back to the hive. As both agrochemical usage and heat waves increase, additive and synergistic negative effects may pose major threats to pollinators and sustainable agriculture.
An atypical case of esophageal actinobacillosis in a cow
Authors: KUMAR RAHUL , Kumar Gulshan , Pandey R. P.
Published: March 2024

Present case report describes a case of an atypical esophageal actinobacillosis in an adult cow presented to the university hospital with a history of inability to drink and swallow. Clinical examination revealed a five-inch swelling in the juglar groove. Skiagram revealed the presence of a small and slightly radio opaque round growth. Exploratory surgical excision of the growth was adapted as palliative treatment and the extirpated tissue was fixed in 10% buffered formalin. Histopathological examination revealed pyogranulomatous inflammation with radiating eosinophillic club shaped bodies surrounding small colonies of cocobacilli. Grams and Zeil neelson stains confirmed the presence of gram negative and non-acid fast cocobacilli. Histopathology confirmed the pathognomonic lesion and proved to be a modality of choice for pathologists to reach at a diagnosis of atypical esophageal actinobacillosis in a cow. After the exhaustive search of relevant literature on atypical actinobacillosis, the authors claim this to be the second report of esophageal actinobacillosis worldwide.
Pseudomonas hefeiensis sp. nov., isolated from the rhizosphere of multiple cash crops in China
Authors: Liao Kaiji , Li Qiang , Li Jun-Zhou , Wei Hai-Lei
Published: March 2024

Three bacterial strains, FP250T, FP821, and FP53, were isolated from the rhizosphere soil of oilseed rape, licorice, and habanero pepper in Anhui Province, Xinjiang Uygur Autonomous Region, and Jiangsu Province, PR China, respectively. All strains were shown to grow at 4–37 °C and pH 6.0–9.0, and in the presence of 0–4.0 % (w/v) NaCl. Phylogenetic analyses based on 16S rRNA gene sequences or housekeeping genes (16S rRNA, gyrB, rpoB, and rpoD) and phylogenomic analysis showed that strains FP250T, FP821, and FP53 belong to the genus Pseudomonas, and are closely related to Pseudomonas kilonensis DSM 13647T, Pseudomonas brassicacearum JCM 11938T, Pseudomonas viciae 11K1T, and Pseudomonas thivervalensis DSM 13194T. The DNA G+C content of strain FP205T was 59.8 mol%. The average nucleotide identity and digital DNA–DNA hybridization values of strain FP205T with the most closely related strain were 93.2 % and 51.4 %, respectively, which is well below the threshold for species differentiation. Strain FP205T contained summed feature 3 (C16 : 1
 ω6c and/or C16 : 1
 ω7c), summed feature 8 (C18 : 1
 ω7c and/or C18 : 1
 ω6c) as major fatty acids, and diphosphatidylglycerol along with phosphatidylethanolamine and aminophospholipid as major polar lipids. The predominant isoprenoid quinone was ubiquinone-9. Based on these phenotypic, phylogenetic, and chemotaxonomic results, strain FP205T represents a novel species of the genus Pseudomonas, for which the name Pseudomonas hefeiensis sp. nov. is proposed. The type strain is FP205T (=ACCC 62447T=JCM 35687T).
Alpha Traveling Waves during Working Memory: Disentangling Bottom-up Gating and Top-down Gain Control
Authors: Zeng Yifan , Sauseng Paul , Alamia Andrea
Published: March 2024

While previous works established the inhibitory role of alpha oscillations during working memory maintenance, it remains an open question whether such an inhibitory control is a top-down process. Here, we attempted to disentangle this issue by considering the spatio-temporal component of waves in the alpha band, i.e., alpha traveling waves. We reanalyzed two pre-existing and open-access EEG datasets where participants performed lateralized delayed match-to-sample working memory tasks. In the first dataset, the distractor load was manipulated (2, 4, or 6), whereas in the second dataset, the memory span varied between 1, 3, and 6 items. In both datasets, we focused on the propagation of alpha waves on the anterior-posterior axis during the retention period. Our results reveal an increase in alpha-band forward waves as the distractor load increased, but also an increase in forward waves and a decrease in backward waves as the memory set size increased. Notably, our results also showed a lateralization effect: alpha forward waves exhibited a more pronounced increase in the hemisphere contralateral to the distractors, whereas the reduction in backward waves was stronger in the hemisphere contralateral to the targets. In short, the forward waves were regulated by distractors, whereas targets inversely modulated backward waves. Such a dissociation of goal-related and goal-irrelevant physiological signals suggests the co-existence of bottom-up and top-down inhibitory processes: alpha forward waves might convey a gating effect driven by distractor load, while backward waves may represent direct top-down gain control of downstream visual areas.

Significance Statement

When exploring the functional role of alpha band neural oscillations during working memory, significant attention has been directed towards its amplitude modulation, with relatively limited exploration of spatial-temporal dynamics of this rather global brain oscillatory signature. The present study seeks to address this gap by examining the directionality of alpha wave propagation during working memory retention. Our findings offer novel insights into the well-established inhibitory role of alpha waves, demonstrating that this function is manifested differently according to their propagation directions: forward waves seem to facilitate bottom-up gating, while backward waves might mediate top-down gain control.
The technical-reasoning network is recruited when people observe others make or teach how to make tools: An fMRI study
Authors: Bluet Alexandre , Reynaud Emanuelle , Federico Giovanni , Bryche Chloé , Lesourd Mathieu , Fournel Arnaud , Lamberton Franck , Ibarrola Danielle , Rossetti Yves , Osiurak François
Published: March 2024

Cumulative technological culture is defined as the increase in efficiency and complexity of tools and techniques over generations. While the role of social cognitive skills in cultural transmission has been long acknowledged, recent accounts have emphasized that non-social cognitive skills such as technical reasoning, a form of causal reasoning aimed at understanding the physical world, are also at work during the social transmission of technical content. Here we contribute to this double process approach by reporting an fMRI study about the neurocognitive origins of social learning. Participants were shown videos depicting tool-making episodes in three social-learning conditions: Reverse engineering, Observation and Teaching. Our results showed that the technical-reasoning network, centred around the Area PF of the left inferior parietal cortex, was preferentially activated when watching tool-making episodes. Additionally, the teaching component was related to an activation of the right middle temporal gyrus. We propose that technical reasoning is at the heart of our technological culture and that the role of social cognition and teaching is to improve the learner’s technical reasoning by helping them concentrate on important parts of the technology. Thus, both technical reasoning and social-cognitive skills may play a key role in the cultural evolution of our technologies.
MelAnalyze: Fact-Checking Melatonin claims using Large Language Models and Natural Language Inference
Authors: Karkera Nikitha , Ghosh Samik , Escames Germaine , Palaniappan Sucheendra K
Published: March 2024

With the explosion of health related information in mainstream discourse, distinguishing accurate health-related claims from misinformation is important. Using computational tools and algorithms to help is key. Our focus in this paper is on the hormone Melatonin which is claimed to have broad health benefits and largely sold as a supplement. This paper introduces 'MelAnalyze,' a framework for using generative and transformer-based deep learning models adapted as a natural language inference (NLI) task, to semi-automate the fact-checking of general melatonin claims. MelAnalyze is built upon a comprehensive collection of melatonin-related scientific abstracts from PubMed for validation. The framework incorporates components for precise extraction of information from scientific literature, semantic similarity and NLI. At its core, MelAnalyze leverages pre trained NLI models that are fine-tuned on melatonin-specific claims along with semantic search based on vectorized representation of the articles. The best models, fine-tuned on LLaMA1 and RoBERTa, attain good precision, recall, and F1-scores of approximately 0.92. We also introduce a user-friendly web-based tool for fact-checking algorithm evaluation and use. In summary, we show MelAnalyze's role in empowering users and researchers to assess melatonin-related claims using evidence-based decision-making.
ChemPrint: An AI-Driven Framework for Enhanced Drug Discovery
Authors: Umansky Tyler J. , Woods Virgil A. , Russell Sean M. , Smith Davey M. , Haders Daniel J.
Published: March 2024

Traditional High-Throughput Screening (HTS) drug discovery is inefficient. Hit rates for compounds with clinical therapeutic potential are typically 0.5% and only up to 2% maximally. Deep learning models have enriched screening rates to 28%; however, these results include hits with non-therapeutic relevant concentrations, insufficient novelty to their training set, and traverse limited chemical space. This study introduces a novel artificial intelligence (AI)-driven platform, GALILEO, and the Molecular-Geometric Deep Learning (Mol-GDL) model, ChemPrint. This model deploys both t-distributed Stochastic Neighbor Embedding (t-SNE) data splitting to maximize chemical dissimilarity during training and adaptive molecular embeddings to enhance predictive capabilities and navigate uncharted molecular territories. When tested retrospectively, ChemPrint outperformed a panel of five models for the difficult-to-drug oncology targets, AXL and BRD4, achieving an average AUROC score of 0.897 for AXL and 0.876 for BRD4 using the t-SNE split, compared to benchmark model scores ranging from 0.826 to 0.885 for AXL and 0.801 to 0.852 for BRD4. In a zero-shot prospective study,in vitrotesting demonstrated that 19 of 41 compounds nominated by ChemPrint against AXL and BRD4 demonstrated inhibitory activity at concentrations ≤ 20 µM, a 46% hit rate. The 19 hits reported an average-maximum Tanimoto similarity score of 0.36 relative to their training set and scores of 0.13 (AXL) and 0.10 (BRD4) relative to clinical stage compounds for these targets. Our findings demonstrate that increasing test set difficulty through training and testing ChemPrint on datasets with maximal dissimilarity enhances the predictive capabilities of the model. This results in the discovery of compound libraries at high hit rates with low therapeutic concentrations and high chemical novelty. Taken together, the proposed platform sets a new performance standard.
Distinct roles of medial prefrontal cortex subregions in the consolidation and recall of remote spatial memories
Authors: Centofante Eleonora , Santoboni Mattia , Mombelli Elena LJ , Rinaldi Arianna , Mele Andrea
Published: March 2024

It is a common believe that memories with time become progressively independent of the hippocampus and are gradually stored in cortical areas. This view is mainly based on evidence demonstrating an impairing effect of prefrontal cortex (PFC) manipulations in the retrieval of remote memories paralleled by a lack of effect of hippocampal inhibition. What is more controversial is whether activity in the mPFC is required immediately after learning to initiate the consolidation process. Further question are possible functional differences among the subregions of the PFC in the formation and storage of remote memories. To address these issues, we directly contrasted the effects of loss-of-function manipulations of the the anterior cingulate cortex (aCC) and the ventro-medial prefrontal cortex (vmPFC), that includes the infralimbic and the prelimbic cortices, before testing, and immediately after training, on the ability of CD1 mice to recall the location of the hidden platform in the Morris water maze. To this aim we injected in the vmPFC or in the aCC an AAV carrying the hM4Di receptor. Interestingly, pre-test administrations of clozapine-N-oxide (CNO) revealed that the aCC, but not the vmPFC, is necessary to recall remote spatial information. Furthermore, systemic post-training administration of CNO (3mg/kg) impaired memory recall at remote time points but not recent time points in both experimental groups. Overall, these findings revealed a functional dissociation between the two prefrontal areas, demonstrating that they are both involved in the early consolidation of remote spatial memories, but that only the aCC is engaged in their recall.
Rapid Homolog Juxtaposition During Meiotic Chromosome Pairing
Authors: Nozaki Tadasu , Weiner Beth , Kleckner Nancy
Published: March 2024

A central basic feature of meiosis is pairing of homologous maternal and paternal chromosomes (“homologs”) intimately along their lengths. Recognition between homologs and their juxtaposition in space are mediated by axis-associated DNA recombination complexes. Additional effects ensure that pairing occurs without ultimately giving entanglements among unrelated chromosomes. Here we examine the process of homolog juxtaposition in real time by 4D fluorescence imaging of tagged chromosomal loci at high spatio-temporal resolution in budding yeast. We discover that corresponding loci start coming together from a quite large distance (∼1.8 µm) and progress to completion of pairing in a very short time, usually less than six minutes (thus, “rapid homolog juxtaposition” or “RHJ”). Juxtaposition initiates by motion-mediated extension of a nascent interhomolog DNA linkage, raising the possibility of a tension-mediated trigger. In a first transition, homolog loci move rapidly together (in ∼30 sec, at speeds of up to ∼60 nm/sec) into a discrete intermediate state corresponding to canonical ∼400 nm axis distance coalignment. Then, after a short pause, crossover/noncrossover differentiation (crossover interference) mediates a second short, rapid transition that brings homologs even closer together. If synaptonemal complex (SC) component Zip1 is present, this transition concomitantly gives final close pairing by axis juxtaposition at ∼100 nm, the “SC distance”. We also find that: (i) RHJ occurs after chromosomes acquire their prophase chromosome organization; (ii) is nearly synchronously over thirds (or more) of chromosome lengths; but (iii) is asynchronous throughout the genome. Furthermore, cytoskeleton-mediated movement is important for the timing and distance of RHJ onset and also for ensuring normal progression. Potential implications for local and global aspects of pairing are discussed.
Adaptive chunking improves effective working memory capacity in a prefrontal cortex and basal ganglia circuit
Authors: Soni Aneri V , Frank Michael J.
Published: March 2024

How and why is working memory (WM) capacity limited? Traditional cognitive accounts focus either on limitations on the number or items that can be stored (slots models), or loss of precision with increasing load (resource models). Here we show that a neural network model of prefrontal cortex and basal ganglia can learn to reuse the same prefrontal populations to store multiple items, leading to resource-like constraints within a slot-like system, and inducing a trade-off between quantity and precision of information. Such “chunking” strategies are adapted as a function of reinforcement learning and WM task demands, mimicking human performance and normative models. Moreover, adaptive performance requires a dynamic range of dopaminergic signals to adjust striatal gating policies, providing a new interpretation of WM difficulties in patient populations such as Parkinson’s disease, ADHD and schizophrenia. These simulations also suggest a computational rather than anatomical limit to WM capacity.
Noise schemas aid hearing in noise
Authors: Hicks Jarrod M. , McDermott Josh H.
Published: March 2024

Human hearing is robust to noise, but the basis of this robustness is poorly understood. Several lines of evidence are consistent with the idea that the auditory system adapts to sound components that are stable over time, potentially achieving noise robustness by suppressing noise-like signals. Yet background noise often provides behaviorally relevant information about the environment, and thus seems unlikely to be completely discarded by the auditory system. Motivated by this observation, we explored whether noise robustness might instead be mediated by internal models of noise structure that could facilitate the separation of background noise from other sounds. We found that detection, recognition, and localization in real-world background noise was better for foreground sounds positioned later in a noise excerpt, with performance improving over the initial second of exposure to a noise. These results are consistent with both adaptation-based and model-based accounts, since both explanations require online noise estimation that should benefit from acquiring more samples. However, performance was also robust to interruptions in the background noise and was enhanced for intermittently recurring backgrounds, neither of which would be expected from known forms of adaptation. Additionally, the performance benefit observed for foreground sounds occurring later within a noise excerpt was reduced for recurring noises, suggesting that a noise representation is built up during exposure to a new background noise and then maintained in memory. These findings suggest noise robustness is supported by internal models—“noise schemas”—that are rapidly estimated, stored over time, and used to estimate other concurrent sounds.
Analysis Pipeline to Quantify Uterine Gland Structural Variations
Authors: Khan Sameed , Alessio Adam , Arora Ripla
Published: March 2024

Technical advances in whole tissue imaging and clearing have allowed 3D reconstruction of exocrine uterine glands deep seated in the endometrium. However, there are limited gland structure analysis platforms to analyze these imaging data sets. Here we present a pipeline for segmenting and analyzing uterine gland shape. Using this segmentation methodology, we derive individual metrics to describe gland length, shape, and branching patterns. These metrics are applied to quantify gland behavior with respect to organization around the embryo and proximity of each individual unit to the uterine lumen. Using this image analysis pipeline we evaluate uterine glands at the peri-implantation time points of a mouse pregnancy. Our analysis reveals that upon embryo entry into the uterus glands show changes in length, tortuosity, and proximity to the uterine lumen while gland branch number stays the same. These shape changes aid in reorganization of the glands around the site of embryo implantation. We further apply our analysis pipeline to human and guinea pig uterine glands, extending feasibility to other mammalian species. This work serves as a resource for researchers to extract quantitative, reproducible morphological features from three-dimensional uterine gland images in order to reveal insights about functional and structural patterns.
A portable electrochemical DNA sensor for sensitive and tunable detection of piconewton-scale cellular forces
Authors: Tabrizi Mahmoud Amouzadeh , Ali Ahsan Ausaf , Singuru Murali Mohana Rao , Mi Lan , Bhattacharyya Priyanka , You Mingxu
Published: March 2024

Cell-generated forces are a key player in cell biology, especially during cellular shape formation, migration, cancer development, and immune response. A new type of label-free smartphone-based electrochemical DNA sensor is developed here for cellular force measurement. When cells apply tension forces to the DNA sensors, the rapid rupture of DNA duplexes allows multiple redox reporters to reach the electrode and generate highly sensitive electrochemical signals. The sensitivity of these portable sensors can be further enhanced by incorporating a CRISPR-Cas12a system. Meanwhile, the threshold force values of these DNA-based sensors can be rationally tuned based on the force application geometries and also DNA intercalating agents. Overall, these highly sensitive, portable, cost-efficient, and easy-to-use electrochemical sensors can be powerful tools for detecting different cell-generated molecular forces.

Graphical Abstract
Glucosylceramides impact cellulose deposition and cellulose synthase complex motility in Arabidopsis
Authors: Villalobos Jose A. , Cahoon Rebecca E. , Cahoon Edgar B. , Wallace Ian S.
Published: March 2024

Cellulose is an abundant component of plant cell wall matrices, and this para-crystalline polysaccharide is synthesized at the plasma membrane by motile Cellulose Synthase Complexes (CSCs). However, the factors that control CSC activity and motility are not fully resolved. In a targeted chemical screen, we identified the alkylated nojirimycin analogN-Dodecyl Deoxynojirimycin (ND-DNJ) as a small molecule that severely impacts Arabidopsis seedling growth. Previous work suggests that ND-DNJ-related compounds inhibit the biosynthesis of glucosylceramides (GlcCers), a class of glycosphingolipid associated with plant membranes. Our work uncovered major changes in the sphingolipidome of plants treated with ND-DNJ, including reductions in GlcCer abundance and altered acyl chain length distributions. Crystalline cellulose content was also reduced in ND-DNJ-treated plants as well as plants treated with the known GlcCer biosynthesis inhibitor N-[2-hydroxy-1-(4-morpholinylmethyl)-2-phenyl ethyl]-decanamide (PDMP) or plants containing a genetic disruption in GLUCOSYLCERAMIDE SYNTHASE (GCS), the enzyme responsible for sphingolipid glucosylation that results in GlcCer synthesis. Live-cell imaging revealed that CSC speed distributions were reduced upon treatment with ND-DNJ or PDMP, further suggesting an important relationship between glycosylated sphingolipid composition and CSC motility across the plasma membrane. These results indicated that multiple interventions compromising GlcCer biosynthesis disrupt cellulose deposition and CSC motility, suggesting that GlcCers impact cellulose biosynthesis in plants.
Megabase-Scale Transgene De-Duplication to Generate a Functional Single-Copy Full-Length Human DMD Transgenic Mouse Model
Authors: Chey Yu C. J. , Corbett Mark , Arudkumar Jayshen , Piltz Sandra , Thomas Paul Q. , Adikusuma Fatwa
Published: March 2024

The development of sequence-specific precision treatments like CRISPR gene-editing therapies for Duchenne Muscular Dystrophy (DMD) requires sequence humanised animal models to enable the direct clinical translation of tested strategies. The current available integrated transgenic mouse model containing the full-length humanDMDgene, Tg(DMD)72Thoen/J (hDMDTg), has been found to have two copies of the transgene per locus in a tail-to-tail orientation, which does not accurately simulate the true copy number of theDMDgene. This duplication also complicates the analysis when testing CRISPR therapy editing outcomes, as large genetic alterations and rearrangements can occur between the cut sites on the two transgenes. To address this, we performed long read nanopore sequencing on hDMDTg mice to better understand the structure of the duplicated transgenes. Following that, we performed a megabase-scale deletion of one of the transgenes by CRISPR zygotic microinjection to generate a single-copy, full-length, humanised DMD transgenic mouse model (hDMDTgSc). Functional, molecular, and histological characterisation show that the single remaining human transgene retains its function and rescues the dystrophic phenotype caused by endogenous murineDmdknockout. Our unique hDMDTgSc mouse model can potentially be used to further generation of DMD disease models, suited for the pre-clinical assessment of sequence-specific therapies.
Glutamine catabolism supports amino acid biosynthesis and suppresses the integrated stress response to promote photoreceptor survival
Authors: Goswami Moloy T. , Weh Eric , Subramanya Shubha , Weh Katherine M. , Durumutla Hima Bindu , Hager Heather , Miller Nicholas , Chaudhury Sraboni , Andren Anthony , Sajjakulnukit Peter , Zhang Li , Besirli Cagri G. , Lyssiotis Costas A. , Wubben Thomas J.
Published: March 2024

Photoreceptor loss results in vision loss in many blinding diseases, and metabolic dysfunction underlies photoreceptor degeneration. So, exploiting photoreceptor metabolism is an attractive strategy to prevent vision loss. Yet, the metabolic pathways that maintain photoreceptor health remain largely unknown. Here, we investigated the dependence of photoreceptors on glutamine (Gln) catabolism. Gln is converted to glutamate via glutaminase (GLS), so mice lacking GLS in rod photoreceptors were generated to inhibit Gln catabolism. Loss of GLS produced rapid rod photoreceptor degeneration. In vivo metabolomic methodologies and metabolic supplementation identified Gln catabolism as critical for glutamate and aspartate biosynthesis. Concordant with this amino acid deprivation, the integrated stress response (ISR) was activated with protein synthesis attenuation, and inhibiting the ISR delayed photoreceptor loss. Furthermore, supplementing asparagine, which is synthesized from aspartate, delayed photoreceptor degeneration. Hence, Gln catabolism is integral to photoreceptor health, and these data reveal a novel metabolic axis in these metabolically-demanding neurons.