bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein Retrieval via Integrative Molecular Ensembles (PRIME) through extended similarity indices
Authors: Chen Lexin , Mondal Arup , Perez Alberto , Miranda-Quintana Ramón Alain 
Published: March 2024

AbstractMolecular dynamics (MD) simulations are ideally suited to describe conformational ensembles of biomolecules such as proteins and nucleic acids. Microsecond-long simulations are now routine, facilitated by the emergence of graphical processing units. Processing such ensembles on the basis of statistical mechanics can bring insights about different biologically relevant states, their representative structures, states, and even dynamics between states. Clustering, which groups objects based on structural similarity, is typically used to process ensembles, leading to different states, their populations, and the identification of representative structures. For some purposes, such as in protein structure prediction, we are interested in identifying the representative structure that is more similar to the native state of the protein. The traditional pipeline combines hierarchical clustering for clustering and selecting the cluster centroid as representative of the cluster. However, even when the first cluster represents the native basin, the centroid can be several angstroms away in RMSD from the native state – and many other structures inside this cluster could be better choices of representative structures, reducing the need for protein structure refinement. In this study, we developed a module—Protein Retrieval via Integrative Molecular Ensemble (PRIME), that consists of tools to determine the most prevalent states in an ensemble using extended continuous similarity. PRIME is integrated with our Molecular Dynamics Analysis withN-ary Clustering Ensembles (MDANCE) package and can be used as a post-processing tool for arbitrary clustering algorithms, compatible with several MD suites. PRIME was validated with ensembles of different protein and protein complex systems for their ability to reliably identify the most native-like state, which we compare to their experimental structure, and to the traditional approach. Systems were chosen to represent different degrees of difficulty such as folding processes and binding which require large conformational changes. PRIME predictions produced structures that when aligned to the experimental structure were better superposed (lower RMSD). A further benefit of PRIME is its linear scaling – rather than the traditional O(N2) traditionally associated to comparisons of elements in a set.
Targeting Diffuse Midline Glioma with a novel anti-CD99 Antibody
Authors: Balakrishnan Ilango , Madhavan Krishna , Pierce Angela M , Michlin Joshua , Brunt Breauna , Chetty Senthilnath Lakshmana , Wang Dong , DeSisto John , Nuss Zachary , Davidson Nathan , Donson Andrew , Jones Kenneth , Mitra Siddhartha , Green Adam , Dahl Nathan , Vibhakar Rajeev , Venkataraman Sujatha 
Published: March 2024

AbstractDiffuse midline gliomas (DMGs) are devastating brain tumors that occur primarily in children. The salient feature of these tumors is the presence of a H3K27M mutation (K27M), associated with the worst prognosis. We identified the cell surface antigen CD99 as notably expressed in DMGs, particularly in K27M+DMGs. We found that the increased expression of CD99 in K27M+DMGs was a result of the onco-histone K27M mutation. In K27M+DMG cells, CD99 inactivation impaired tumor growth by inducing cell differentiation, indicating an oncogenic role of CD99 enabled by blocking differentiation. We then developed a novel therapeutic anti-CD99 chimeric antibody, 10D1, with a membrane-proximal binding epitope, and evaluated its antitumor efficacy in preclinical models of K27M+DMG. 10D1 suppressed DMG growthin vitroandin vivoby inducing apoptosis. When combined with radiation treatment, 10D1 exhibited improved antitumor efficiency and xenograft survival, providing a strong justification for its clinical development as a therapy for DMGs.Statement of SignificanceThis study emphasizes that CD99 overexpression occurs due to the H3K27M mutation in Diffuse Midline Gliomas (DMGs). This heightened expression suppresses apoptosis, inhibits differentiation, and induces radio-resistance in DMGs. This research justifies using a novel CD99 antibody alone or combined with radiation therapy in human pediatric clinical trials.
Brief Physical Activity Selectively Modulates the Performance of Serial Subtract 7 in Young Adults – A Wearable Sensor-based, Randomized, Control Study
Authors: Chu Xin Ran , Newaz Tanmoy , Tom Elbert , Yang Allison , Chomiak Taylor , Hu Bin 
Published: March 2024

AbstractOBJECTIVEThis study explores the effects of physical activities on cognitive performance in healthy subjects, specifically evaluating Serial Subtract 7 Test (SST) performance during a cognitive-stepping dual task influenced by the 6-Minute Walking Test (6MWT) with and without music.METHODSA controlled experiment was conducted using the Ambulosono device to standardize walking exercises. 54 high school students participated, undergoing the 6MWT in different scenarios: Verbal 6-Minute Walking Test (6MWT) or Music-Guided Walking (MU). Final data from 43 students was used in the analysis. The SST measured cognitive changes in both single-task and dual-task conditions.RESULTSThe 6MWT significantly enhanced cognitive performance in both single and dual-task conditions. However, the addition of music did not show a substantial improvement in cognitive performance. The findings indicated the positive impact of 6MWT on cognitive abilities, irrespective of musical accompaniment.CONCLUSIONSThis research contributes to the understanding of how physical exercises can modulate cognitive functions in healthy individuals. It highlights the potential of 6MWT in enhancing cognitive performance, suggesting further exploration into the role of physical activity in cognitive health.
A multicenter evaluation of a novel microfluidic rapid AST assay for Gram-negative bloodstream infections
Authors: Berinson Benjamin , Davies Emma , Torpner Jessie , Flinkfeldt Linnea , Fernberg Jenny , Åman Amanda , Bergqvist Johan , Öhrn Håkan , Ångström Jonas , Johansson Cecilia , Jäder Klara , Andersson Helena , Ghaderi Ehsan , Rolf Maria , Sundqvist Martin , Rohde Holger , Fernandez-Zafra Teresa , Malmberg Christer 
Published: March 2024

AbstractObjectivesCommon phenotypic methods for antibiotic susceptibility testing (AST) of bacteria are slow, labour intensive and display considerable technical variability. The QuickMIC system provides rapid AST using a microfluidic linear gradient. Here we evaluate the performance of QuickMIC at four different laboratories with regards to speed, precision, accuracy, and reproducibility in comparison to broth microdilution (BMD).MethodsSpiked blood cultures (n=411) and clinical blood cultures (n=148) were tested with the QuickMIC Gram negative (GN) panel and compared with BMD for the 12 on-panel antibiotics, and 10 defined strains were run at each site to measure reproducibility. Logistic and linear regression analysis was applied to explore factors affecting assay performance.ResultsThe overall essential agreement (EA) and categorical agreement (CA) between QuickMIC and BMD were 95.6% and 96.0%, respectively. Very major error (VME), Major error (ME) and minor error (mE) rates were 1.0, 0.6 and 2.4%, respectively. Inter-laboratory reproducibility between the sites was high at 98.9% using the acceptable standard of ±1 log2 unit. The mean in-instrument analysis time overall was 3h 13 min (SD: 29 min). Regression analysis indicated that QuickMIC is robust with regards to initial inoculate and delay time after blood culture positivity.ConclusionsWe conclude that QuickMIC can be used to rapidly measure MIC directly from blood cultures in clinical settings, with high reproducibility, precision, and accuracy. The microfluidics-generated linear gradient ensures high repeatability and reproducibility between laboratories, thus allowing a high level of trust in MIC values from single testing, at the cost of reduced measurement range compared to BMD.
Identifying associations ofde novononcoding variants with autism through integration of gene expression, sequence and sex information
Authors: Li Runjia , Ernst Jason 
Published: March 2024

AbstractWhole-genome sequencing (WGS) data is facilitating genome-wide identification of rare noncoding variants, while elucidating their roles in disease remains challenging. Towards this end, we first revisit a reported significant brain-related association signal of autism spectrum disorder (ASD) detected fromde novononcoding variants attributed to deep-learning and show that local GC content can capture similar association signals. We further show that the association signal appears driven by variants from male proband-female sibling pairs that are upstream of assigned genes. We then develop Expression Neighborhood Sequence Association Study (ENSAS), which utilizes gene expression correlations and sequence information, to more systematically identify phenotype-associated variant sets. Applying ENSAS to the same set ofde novovariants, we identify gene expression-based neighborhoods showing significant ASD association signal, enriched for synapse-related gene ontology terms. For these top neighborhoods, we also identify chromatin states annotations of variants that are predictive of the proband-sibling local GC content differences. Our work provides new insights into associations of non-codingde novomutations in ASD and presents an analytical framework applicable to other phenotypes.
Exploring Inflammatory Dysregulation in Alveolar Macrophages: Implications for Novel Therapeutic Targets in Chronic Obstructive Pulmonary Disease
Authors: Adeyanju Saheed 
Published: March 2024

AbstractChronic obstructive pulmonary disease is a severe lung disease characterized by tissue destruction and limited airflow mainly caused by exposure to harmful environmental substances. Primary symptoms of this lung disorder include dyspnea, sputum production, and cough, which leads to respiratory failure. Prevalence increases with age, making it the most common cause of death worldwide. The primary objective of this study was to identify novel therapeutic targets via gene expression meta-analysis and to utilize them for drug reprofiling of FDA-approved drugs in treating chronic obstructive pulmonary disease. Multiple microarray and RNA-seq datasets from alveolar macrophages comprising healthy and diseased patients were processed to pinpoint significant dysregulated genes involved in this disease. Next, a meta-analysis was performed to identify the consistently differentially expressed genes in all datasets. Functional enrichment and protein-protein interaction analyses were conducted to single out the hub genes. Moreover, 3D structure prediction, virtual screening, and molecular dynamics simulations were utilized to explore the selected hub gene for drug repurposing. The number of significantly dysregulated genes identified via RNA-seq and microarray meta-analysis was found to be 104 and 57, respectively. Interestingly, VGLL3, ITIH5, ELOVL7, ACOD1, LAMB1, CXCL9, and GBP5 were common between the two sets revealing their significant association with the disease. CXCL9 and CCL3L3 were identified as the common hub genes between both sets. However, CXCL9, a chemokine, was prioritized for drug repurposing endeavors as it exhibits remarkable involvement in immune response and inflammation. Virtual screening of CXCL9 against selected drugs disclosed that CXCL9 has the highest binding affinity of −7.3 kcal/mol for Nintedanib, and binding affinities ranged from −2.4 kcal/mol to −7.3 kcal/mol. Moreover, Tepotinib and Crizotinib were found to be the second and third top-scoring drugs of −6.8 kcal/mol and −6.2 kcal/mol, respectively. Furthermore, the molecular dynamics simulation revealed that Crizotinib showed the most prominent results; however, its binding affinity is lower than Nintedanib. Therefore, Nintedanib is suggested as the better therapeutic agent to inhibit CXCL9 for treating chronic obstructive pulmonary disease.HighlightsMeta-analysis of microarray and RNA-Seq datasets of alveolar macrophages from healthy and diseased patients disclosed novel therapeutic targets.Common significantly dysregulated hub gene CXCL9 is a novel drug target for COPD.CXCL9 is a chemokine responsible for inflammatory and immune responses utilized for drug reprofiling.Nintedanib, Tepotinib, and Crizotinib exhibited strong binding affinities against CXCL9.Virtual screening and simulation results revealed that inhibition of CXCL9 may be a potential treatment for COPD.
Co-translational sorting enables a single mRNA to generate distinct polysomes with different localizations and protein fates
Authors: Salloum Soha , Séveno Martial , El Koulali Khadija , Rialle Stephanie , George Simon , Lemmers Benedicte , Zibara Kazem , Eliscovich Carolina , Hahne Michael , Bertrand Edouard 
Published: March 2024

Abstractβ-catenin is a multi-functional protein playing essential roles in tissue homeostasis and cancer. It bridges E-cadherin to the cytoskeleton and also activates transcription in response to Wnt. Plasma membrane β-catenin is stable whereas without Wnt, cytoplasmic β-catenin is degraded by the destruction complex, composed of APC and Axin. Here, we show that APC and Axin associate with many mRNAs and that this occurs via the nascent protein chains. Notably, APC and Axin bind β-catenin mRNAs present as either single polysome or polysome condensates, and co-translational interactions constitute the major fraction of their binding to the β-catenin protein. Remarkably, E-cadherin also binds β-catenin co-translationally, and β-catenin mRNAs localize either with APC in the cytosol or E-cadherin at the plasma membrane. Thus, co-translational interactions sort β-catenin mRNAs into distinct polysome populations that spatially segregate in cells and synthesize proteins with different functions. Co-translational polysome sorting provides a mechanism to regulate the fate of multi-functional proteins.
Ultrasound as a reliable guide for lumbar intrathecal injection in rats: A pilot study
Authors: Pryambodho  , Dilogo Ismail Hadisoebroto , Tantri Aida R. , Aman Renindra Ananda , Tjokorda Gde A. S. , Purba Jan S. , Siregar Nuryati C. 
Published: March 2024

AbstractLumbar intrathecal administration provides an ideal route for drug delivery into the central nervous system, especially when dorsal root ganglions are the main target for the therapy in rat model of chronic pain. Two main methods of lumbar intrathecal administrations are chronic catheter implantation and the acute needle puncture. Chronic catheter implantation involves surgical manipulation to insert micro indwelling catheter into the intrathecal space. However, this method is invasive, produces inflammatory reactions, and generates more surgical stress. Acute needle puncture is less invasive and cheaper but is technically challenging to perform. We performed an ultrasound-guided lumbar intrathecal injection in six male Sprague Dawley rat cadavers, on average weighing 250–300 grams. Fresh rat cadavers were positioned in a sternal recumbent position, vertebrae were palpated and scanned using a linear probe ultrasound. A 25G needle insertion was advanced with real-timeultrasound guidance, and placement was confirmed prior to dye injection (Methylene blue, Sigma Aldrich). Cadavers were then dissected, and the vertebrae were visually inspected for dye staining. All three cadavers that underwent intrathecal injection with sagittal and axial plane ultrasound guidance showed positive dye staining within the intrathecal space, confirming successful acute intrathecal administration. There was one successful intrathecal injection under sagittal plane-only ultrasound guidance. Ultrasound is a useful, operator-dependent tool to guide acute needle puncture intrathecal administration.
Baraitser–Winter Syndrome Hotspot Mutation R196H in Cytoskeletal β–actin Reduces F–actin Stability and Perturbs Interaction with the Arp2/3 Complex
Authors: Greve Johannes N. , Manstein Dietmar J. 
Published: March 2024

AbstractBaraitser–Winter cerebrofrontofacial syndrome (BWCFF) is the most common and best–defined clinical entity associated with heterozygous single–point missense mutations in cytoskeletal β–actin. Patients present with distinct craniofacial anomalies and neurodevelopmental disabilities of variable severity. To date, the most frequently observed variants affect residue R196 of cytoskeletal β–actin, with the variant p.R196H being the most common. Patients carrying the p.R196H variant are likely to suffer from pachygyria, probably due to neuronal migration defects contributing to the development of abnormally thick convolutions of the cerebral cortex. Here, we describe the recombinant production, purification and biochemical characterization of the BWCFF hotspot variant p.R196H. The stability and nucleotide interaction of monomeric p.R196H are unaffected, indicating a disease mechanism involving incorporation of p.R196H protomers into actin filaments. Incorporation of the variant strongly affects F–actin stability and polymerization dynamics, consistent with the position of residue R196 close to the helical axis of the actin filament and an important interstrand contact. The changes observed include an increased critical concentration of polymerization, a reduced elongation rate and an increase in the rate of filament depolymerization. In the Arp2/3–generated branch junction complex, which is essential for cell migration and endocytosis, R196 is located at the interface between the first protomer of the nucleated daughter filament and the Arp2 subunit of the Arp2/3 complex. Assays probing the interaction of p.R196H filaments with the Arp2/3 complex show a reduced efficiency of branch generation. Branch stability is impaired, as evidenced by a reduction in the number of branches and spontaneous debranching events. Furthermore, in their interaction with different types of cytoskeletal myosin motors, p.R196H filaments show isoform–specific differences. While p.R196H filaments move WT–like on lawns of surface–immobilized non–muscle myosin–2A, motility on myosin–5A is 30 % faster.
Template Learning: Deep Learning with Domain Randomization for Particle Picking in Cryo-Electron Tomography
Authors: Harastani Mohamad , Patra Gurudatt , Kervrann Charles , Eltsov Mikhail 
Published: March 2024

AbstractCryo-electron tomography (cryo-ET) enables the three-dimensional visualization of biomolecules and cellular components in their near-native state. Particle picking, a crucial step in cryo-ET data analysis, is traditionally performed by template matching—a method utilizing cross-correlations with available biomolecular templates. Despite the effectiveness of recent deep learning-based particle picking approaches, their dependence on initial data annotation datasets for supervised training remains a significant limitation. Here, we propose a technique that combines the accuracy of deep learning particle identification with the convenience of the model training on biomolecular templates enabled through a tailored domain randomization approach. Our technique, named Template Learning, automates the simulation of training datasets, incorporating considerations for molecular crowding, structural variabilities, and data acquisition variations. This reduces or even eliminates the dependence of supervised deep learning on annotated experimental datasets. We demonstrate that models trained on simulated datasets, optionally fine-tuned on experimental datasets, outperform those exclusively trained on experimental datasets. Also, we illustrate that Template Learning used as an alternative to template matching, can offer higher precision and better orientational isotropy, especially for picking small non-spherical particles. Template Learning software is open-source, Python-based, and GPU and CPU parallelized.
Comparing the effect of multi gradient echo and multi band fMRI during a semantic task
Authors: Halai Ajay D. , Henson Richard N. , Finoia Paola , Correia Marta M. 
Published: March 2024

AbstractThe Blood Oxygenation Level Dependent (BOLD) signal, as measured using functional magnetic resonance imaging (fMRI), is known to vary in sensitivity across the brain due to magnetic susceptibility artefacts. In particular, the ventral anterior temporal lobes (vATL) have been implicated with semantic cognition using convergent methods (i.e., neuropsychology, PET, MEG, brain stimulation) but less so with fMRI using conventional gradient-echo protocols. There are methods to alleviate signal loss but multi-echo fMRI has gained popularity. Here, additional volumes are collected that span across a range of T2* values, however, this results sub-optimum parameters (i.e., repetition times, resolution, acceleration). “Multi-band” imaging has been used with multi-echo to speed up data acquisition; however, it is unclear how these modifications contribute to fMRI sensitivity across the brain and for univariate/multivariate analyses. In the current study, we used a factorial design where we manipulated the echo and/or band to assess how well the semantic network can be detected. When comparing the precision with which activations were detected (i.e, average T-statistics), we found that multi-band protocols were beneficial, with no evidence of signal leakage artefacts. When comparing the magnitude of activations, multi-echo protocols increased activations in regions prone to susceptibility artefacts (specifically the anterior temporal lobes, ATLs). Both multi-banding and independent component analysis (ICA)-denoising of multi-echo data tended to improve multi-voxel decoding of conditions. However, multi-echo protocols reduced activation magnitude in more central regions, such as the medial temporal lobes, possibly due to higher in-plane acceleration required to collect multiple-echoes. Nonetheless, the multi-echo multi-band protocol is a promising default option for fMRI on most regions, particularly those that suffer from susceptibility artefacts, as well as offering the potential to apply advanced post-processing methods to take advantage of the increased temporal (or spatial) resolution of multi-band protocols and more principled ICA-denoising based on TE-dependence of BOLD signals.
Frequent intertrophic transmission ofWolbachiaby parasitism but not predation
Authors: Yan Zhi-Chao , Qi Lan-Da , Ji Han-Le , Wang Xiao-Xiang , Hong Xiao-Yue , Li Yuan-Xi 
Published: March 2024

AbstractWolbachiais one of the most pervasive symbionts, estimated to infect ∼50% of arthropod species. It is primarily transmitted vertically, inducing a variety of fascinating reproductive manipulations to promote its spread within host populations. However, incongruences between host andWolbachiaphylogenies indicate substantial horizontal transmissions, the mechanisms of which are largely unexplored. By systematically analyzingWolbachiasurface protein (wsp) sequences on NCBI, we found that parasitism, not predation, is the primary route of intertrophicWolbachiatransmission. This conclusion held after accounting sampling bias. One example of frequentWolbachiatransfers is between egg parasitoid wasps,Trichogramma, and their lepidopteran hosts. Moreover, both bioinformatics and experimental results showed thatWolbachiafrom the parasitoid waspEncarsia formosacan be transmitted to its whitefly hostBemisia tabaci, through unsuccessful parasitism. OnceEn. formosa Wolbachiais transferred to whiteflies, it can be vertically transmitted within whiteflies and induce fitness costs. To our knowledge, this is the first compelling evidence thatWolbachiacan be transmitted from parasitoid wasps to their hosts, revealing the bidirectional nature ofWolbachiatransfers between parasitoids and their hosts. Overall, our findings enrich the current understanding of the horizontal transmission ofWolbachiaand shed new light on its ecology and evolution.