bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interpretable Spatial Gradient Analysis for Spatial Transcriptomics Data
Authors: Liang Qingnan , Solis Soto Luisa , Haymaker Cara , Chen Ken 
Published: March 2024

AbstractCellular anatomy and signaling vary across niches, which can induce gradated gene expressions in subpopulations of cells. Such spatial transcriptomic gradient (STG) makes a significant source of intra-tumor heterogeneity and can influence tumor invasion, progression, and response to treatment. Here we reportLocal Spatial Gradient Inference(LSGI), a computational framework that systematically identifies spatial locations with prominent, interpretable STGs from spatial transcriptomic (ST) data. To achieve so, LSGI scrutinizes each sliding window employing non-negative matrix factorization (NMF) combined with linear regression. With LSGI, we demonstrated the identification of spatially proximal yet opposite directed pathway gradients in a glioblastoma dataset. We further applied LSGI to 87 tumor ST datasets reported from nine published studies and identified both pan-cancer and tumor-type specific pathways with gradated expression patterns, such as epithelial mesenchymal transition, MHC complex, and hypoxia. The local gradients were further categorized according to their association to tumor-TME (tumor microenvironment) interface, highlighting the pathways related to spatial transcriptional intratumoral heterogeneity. We conclude that LSGI enables highly interpretable STG analysis which can reveal novel insights in tumor biology from the increasingly reported tumor ST datasets.
Neuropeptide Modulation Enables Biphasic Inter-network Coordination via a Dual-Network Neuron
Authors: Gnanabharathi Barathan , Fahoum Savanna-Rae H , Blitz Dawn M 
Published: March 2024

AbstractLinked rhythmic behaviors, such as respiration/locomotion or swallowing/chewing often require coordination for proper function. Despite its prevalence, the cellular mechanisms controlling coordination of the underlying neural networks remain undetermined in most systems. We use the stomatogastric nervous system of the crabCancer borealisto investigate mechanisms of inter-network coordination, due to its small, well characterized feeding-related networks (gastric mill [chewing, ∼0.1 Hz]; pyloric [filtering food, ∼1 Hz]). Here, we investigate coordination between these networks during the Gly1-SIFamide neuropeptide modulatory state. Gly1-SIFamide activates a unique triphasic gastric mill rhythm in which the typically pyloric-only LPG neuron generates dual pyloric- plus gastric mill-timed oscillations. Additionally, the pyloric rhythm exhibits shorter cycles during gastric mill rhythm-timed LPG bursts, and longer cycles during IC, or IC plus LG gastric mill neuron bursts. Photoinactivation revealed that LPG is necessary to shorten pyloric cycle period, likely through its rectified electrical coupling to pyloric pacemaker neurons. Hyperpolarizing current injections demonstrated that although LG bursting enables IC bursts, only gastric mill rhythm bursts in IC are necessary to prolong the pyloric cycle period. Surprisingly, LPG photoinactivation also eliminated prolonged pyloric cycles, without changing IC firing frequency or gastric mill burst duration, suggesting that pyloric cycles are prolonged via IC synaptic inhibition of LPG, which indirectly slows the pyloric pacemakers via electrical coupling. Thus, the same dual-network neuron directly conveys excitation from its endogenous bursting and indirectly funnels synaptic inhibition to enable one network to alternately decrease and increase the cycle period of a related network.Significance StatementRelated rhythmic behaviors frequently exhibit coordination, yet the cellular mechanisms coordinating the underlying neural networks are not determined in most systems. We investigated coordination between two small, well-characterized crustacean feeding-associated networks during a neuropeptide-elicited modulatory state. We find that a dual fast/slow network neuron directly shortens fast network cycles during its slow, intrinsically generated bursts, likely via electrical coupling to fast network pacemakers, despite rectification favoring the opposite direction. Additionally, the fast network is indirectly prolonged during another slow-network phase, via chemical synaptic inhibition that is likely funneled through the same electrical synapse. Thus, a dual-network neuron alternately reinforces and diminishes neuropeptide actions, enabling distinct frequencies of a faster network across different phases of a related slower rhythm.
Prioritizing disease-related rare variants by integrating gene expression data
Authors: Guo Hanmin , Urban Alexander Eckehart , Wong Wing Hung 
Published: March 2024

AbstractRare variants, comprising a vast majority of human genetic variations, are likely to have more deleterious impact on human diseases compared to common variants. Here we present carrier statistic, a statistical framework to prioritize disease-related rare variants by integrating gene expression data. By quantifying the impact of rare variants on gene expression, carrier statistic can prioritize those rare variants that have large functional consequence in the diseased patients. Through simulation studies and analyzing real multi-omics dataset, we demonstrated that carrier statistic is applicable in studies with limited sample size (a few hundreds) and achieves substantially higher sensitivity than existing rare variants association methods. Application to Alzheimer’s disease reveals 16 rare variants within 15 genes with extreme carrier statistics. The carrier statistic method can be applied to various rare variant types and is adaptable to other omics data modalities, offering a powerful tool for investigating the molecular mechanisms underlying complex diseases.
“Comparison between topical Platelet Rich Plasma and Normal Saline dressing, in conjunction with Total Contact Casting in Treatment of Diabetic Foot Ulcer– a Randomized Control Trial”
Authors: Das Subha , Kumar Sanyal , Pandey Sanjay Kumar , Kumar Anjani , Kumar Niraj , Kumar Ranjeet 
Published: March 2024

AbstractIntroductionWound care, which includes cleaning and fostering a moist wound healing environment, play a crucial role in the management of diabetic foot ulcers.. Total-contact casts are widely used as the most effective external technique for off-loading plantar ulcers. This study compared the effectiveness of PRP and normal saline dressings in conjunction with TCC.Methods36 patients with diabetic foot ulcers were divided into two groups using computer generated randomization into PRP and NS groups with 18 patients in each group. The PRP group was given autologous PRP, and the NS group was given wet dressing with NS, following which TCC was applied in each case for off-loading. Follow-up was performed every 15 days for 90 days. In each follow-up measurement and TCC application, the time to heal and PUSH score was used to measure the condition of the wound.ResultsIn the PRP group, the mean wound size 8.28±1.18 and the mean Push tool total 13.44±0.98 at base line which gradually decreased, and finally, on day 90, it was reduced to 0.61±1.20 and 1.89±3.68, respectively. In NS group the mean wound size 8.45±1.13 and mean Push tool total 13.50±0.92 at baseline which was gradually decreased and finally at day 90 it was reduced to 1.58±1.55 and 4.61±4.37 respectively. A significant difference was observed in both groups during the final evaluation. Compared with the NS group, the PRP group showed greater improvement.ConclusionBoth autologous PRP and NS are effective in treating DFU, when used along with TCC. However, PRP therapy is better at reducing the healing time and hospital visits.
Hand-Crafted Quantitative Radiomic Analysis of Computed Tomography Scans Using Machine and Deep Learning Techniques Accurately Predicts Histological Subtypes of Non-Small Cell Lung Cancer
Authors: Panchawagh Suhrud 
Published: March 2024

AbstractBackgroundNon-small cell lung cancer (NSCLC) histological subtypes impact treatment decisions. While pre-surgical histopathological examination is ideal, it’s not always possible. CT radiomic analysis shows promise to predict NSCLC histological subtypes.ObjectiveTo use CT scan radiomic analysis from NSCLC-Radiomics data to predict NSCLC histological subtypes using machine learning and deep learning models.Methods422 CT scans from The Cancer Imaging Archive (TCIA) were analyzed. Primary neoplasms were segmented by expert radiologists. Using PyRadiomics, 2446 radiomic features were extracted; post-selection, 179 features remained. Machine learning models like logistic regression, SVM, random forest, XGBoost, LightGBM, and CatBoost were employed, alongside a deep neural network (DNN) model.ResultsRandom forest demonstrated the highest accuracy at 78% (95% CI: 70%-84%) and AUC-ROC at 94% (95% CI: 90%-96%). LightGBM, XGBoost, and CatBoost had AUC-ROC values of 95%, 93%, and 93% respectively. The DNN’s AUC was 94.4% (95% CI: 94.1% to 94.6%). Logistic regression had the least efficacy. For histological subtype prediction, random forest, boosting models, and DNN were superior.ConclusionsQuantitative radiomic analysis with machine learning can accurately determine NSCLC histological subtypes. Random forest, ensemble models, and DNNs show significant promise for pre-operative NSCLC classification, which can streamline therapy decisions.
Reprogramming genetic circuits using space
Authors: Alejaldre Lorea , Miró-Bueno Jesús , Hueso-Gil Angeles , Grozinger Lewis , Tas Huseyin , Geißler Sina , Goñi-Moreno Ángel 
Published: March 2024

AbstractGenetic circuits confer computing abilities to living cells, performing novel transformations of input stimuli into output responses. Circuit editing often focuses on substituting DNA components, such as RBSs, regulators, or promoters, from part libraries to achieve desired performance. However, this approach is inherently limited by the availability of DNA components. Here, we show that circuit performance can be reprogrammed without altering its DNA sequence by using a library of positions: a set of physical locations within the cell’s volume. Using bacteria as the living chassis, we engineer 219 spatially unique genetic circuits of four different types—three regulatory cascades and a toggle switch—by either inserting the entire circuit in a specific chromosomal position or separating and distributing circuit modules. Their analysis, together with a mathematical model, reveals that spatial positioning can be used not only to optimize circuits but also to switch circuits between modes of operation, giving rise to new functions as circuit complexity increases. We provide foundational insights into leveraging intracellular space for circuit design.
Towards sequential conjugation-assisted laboratory evolution (SCALE) of Cas nucleases
Authors: Swartjes Thomas , Doets Kristel , Staals Raymond HJ , van der Oost John 
Published: March 2024

AbstractDNA endonucleases such as the CRISPR-associated enzymes Cas9 and Cas12a constitute powerful molecular tools with a wide range of applications. To facilitate optimization of these enzymes, we investigated a fullyin vivoselection system for laboratory evolution based on plasmid conjugation. In the proposed method, DNA cleavage promotes plasmid transfer to other cells, allowing cleaving variants to spread through the bacterial culture via consecutive conjugations. We have investigated whether the conjugation system of the F plasmid ofE. coliis suitable for laboratory evolution of Cas nucleases. Through a series of conjugation experiments, we found (i) that the F plasmid can spread through bacterial cultures, (ii) that the FinOP conjugation inhibition system is a potential nuclease target as it can prevent transfer of non-cleaving variants (counterselection), and (iii) that a trimmed version of the F plasmid allows for consecutive conjugations. Overall, we were able to show that in many regards, conjugation can indeed be used as means ofin vivolaboratory evolution. We discuss the potential of the here presented concept for a yet to be developed laboratory evolution platform.
High-throughput Kinetics using Capillary Electrophoresis and Robotics (HiKER) platform used to Study T7, T3, and Sp6 RNA Polymerase Misincorporation
Authors: Carter Zachariah I. , O’Brien William B. , Lund Sean , Gardner Andrew F. 
Published: March 2024

AbstractT7 RNA Polymerase (RNAP) is a well-studied and widely used enzyme with recent applications in the production of RNA vaccines. For over 50 years denaturing sequencing gels have been used as a key analysis tool for probing the kinetic mechanism of T7 RNAP nucleotide addition. However, sequencing gels are both slow and low throughput limiting their utility for comprehensive enzyme analysis. Here, we report the development of HiKER; (High-throughputKinetics using CapillaryElectrophoresis andRobotics) a high-throughput pipeline to quantitatively measure enzyme kinetics. We adapted a traditional polymerase misincorporation assay for fluorescent detection at scale allowing rapid estimates of RNAP misincorporation in different experimental conditions. In addition, high-throughput kinetics reactions were automated using an open-source OT-2 liquid handling robot. The platform allows multiple weeks’ worth of data to be collected in mere days. Using this platform, ∼1500 time points were collected in a single workday. T7 RNAP exhibited dramatic differences in both observed rate constant and amplitude depending on the mismatch examined. An average misincorporation frequency of ∼45 misincorporations per million bases was estimated using HiKER and is consistent with previous observations from next generation sequencing studies. Misincorporation time courses for T3 RNAP and Sp6 RNAP were similar to T7 RNAP suggesting conserved kinetic mechanisms. Interestingly, dramatic changes in the extent of misincorporation were observed in the three RNAPs depending on the mismatch. Extension from base mismatch experiments showed differences between T7, T3, and Sp6 RNAP. Sp6 RNAP was the slowest to extend from a mismatch followed by T7 RNAP and then T3 RNAP. Taken together the results presented here demonstrate the capabilities of HiKER to carry out high-throughput enzymology studies. Importantly, this pipeline and the corresponding analysis strategies are affordable, open-source, and broadly applicable to many enzymes.
Loss of an extensive ciliary connectome induces proteostasis and cell fate switching in a severe motile ciliopathy
Authors: Brody Steven L. , Pan Jiehong , Huang Tao , Xu Jian , Xu Huihui , Koenitizer Jeffrey , Brennan Steven K. , Nanjundappa Rashmi , Saba Thomas G. , Berical Andrew , Hawkins Finn J. , Wang Xiangli , Zhang Rui , Mahjoub Moe R. , Horani Amjad , Dutcher Susan K. 
Published: March 2024

SummaryMotile cilia have essential cellular functions in development, reproduction, and homeostasis. Genetic causes for motile ciliopathies have been identified, but the consequences on cellular functions beyond impaired motility remain unknown. Variants inCCDC39andCCDC40cause severe disease not explained by loss of motility. Using human cells with pathological variants in these genes,Chlamydomonasgenetics, cryo-electron microscopy, single cell RNA transcriptomics, and proteomics, we identified perturbations in multiple cilia-independent pathways. Absence of the axonemal CCDC39/CCDC40 heterodimer results in loss of a connectome of over 90 proteins. The undocked connectome activates cell quality control pathways, switches multiciliated cell fate, impairs microtubule architecture, and creates a defective periciliary barrier. Both cilia-dependent and independent defects are likely responsible for the disease severity. Our findings provide a foundation for reconsidering the broad cellular impact of pathologic variants in ciliopathies and suggest new directions for therapies.
Chemoproteomics reveals immunogenic and tumor-associated cell surface substrates of ectokinase CK2α
Authors: Delaveris Corleone S. , Kong Sophie , Glasgow Jeff , Loudermilk Rita P. , Kirkemo Lisa L. , Zhao Fangzhu , Salangsang Fernando , Phojanakong Paul , Camara Serrano Juan Antonio , Steri Veronica , Wells James A. 
Published: March 2024

SummaryNew epitopes for immune recognition provide the basis of anticancer immunity. Due to the high concentration of extracellular adenosine triphosphate in the tumor microenvironment, we hypothesized that extracellular kinases (ectokinases) could have dysregulated activity and introduce aberrant phosphorylation sites on cell surface proteins. We engineered a cell-tethered version of the extracellular kinase CK2α, demonstrated it was active on cells under tumor-relevant conditions, and profiled its substrate scope using a chemoproteomic workflow. We then demonstrated that mice developed polyreactive antisera in response to syngeneic tumor cells that had been subjected to surface hyperphosphorylation with CK2α. Interestingly, these mice developed B cell and CD4+ T cell responses in response to these antigens but failed to develop a CD8+ T cell response. This work provides a workflow for probing the extracellular phosphoproteome and demonstrates that extracellular phosphoproteins are immunogenic even in a syngeneic system.
CDK12Loss Promotes Prostate Cancer Development While Exposing Vulnerabilities to Paralog-Based Synthetic Lethality
Authors: Tien Jean Ching-Yi , Chang Yu , Zhang Yuping , Chou Jonathan , Cheng Yunhui , Wang Xiaoju , Yang Jianzhang , Mannan Rahul , Shah Palak , Wang Xiao-Ming , Todd Abigail J. , Eyunni Sanjana , Cheng Caleb , Rebernick Ryan J. , Xiao Lanbo , Bao Yi , Neiswender James , Brough Rachel , Pettitt Stephen J. , Cao Xuhong , Miner Stephanie J. , Zhou Licheng , Wu Yi-Mi , Labanca Estefania , Wang Yuzhuo , Parolia Abhijit , Cieslik Marcin , Robinson Dan R. , Wang Zhen , Feng Felix Y. , Lord Christopher J. , Ding Ke , Chinnaiyan Arul M. 
Published: March 2024

SUMMARYBiallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration-resistant prostate cancer (mCRPC). It remains unclear, however, whetherCDK12lossper seis sufficient to drive prostate cancer development—either alone, or in the context of other genetic alterations—and whetherCDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specificCdk12ablation is sufficient to induce preneoplastic lesions and robust T cell infiltration in the mouse prostate. Allograft-based CRISPR screening demonstrated thatCdk12loss is positively associated withTrp53inactivation but negatively associated withPteninactivation—akin to what is observed in human mCRPC. Consistent with this, ablation ofCdk12in prostate organoids with concurrentTrp53loss promotes their proliferation and ability to form tumors in mice, whileCdk12knockout in thePten-null prostate cancer mouse model abrogates tumor growth. BigenicCdk12andTrp53loss allografts represent a new syngeneic model for the study of androgen receptor (AR)-positive, luminal prostate cancer. Notably,Cdk12/Trp53loss prostate tumors are sensitive to immune checkpoint blockade.Cdk12-null organoids (either with or withoutTrp53co-ablation) and patient-derived xenografts from tumors withCDK12inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identifyCDK12as abona fidetumor suppressor gene with impact on tumor progression and lends support to paralog-based synthetic lethality as a promising strategy for treatingCDK12-mutant mCRPC.
Toward UV models of kinetic mixing and portal matter. V. Indirect probes of the new physics scale
Authors: Rizzo Thomas G. 
Published: March 2024

Kinetic mixing of the dark photon, the gauge boson of a hidden U(1)D, with the Standard Model (SM) gauge fields to induce an interaction between ordinary matter and dark matter (DM) at 1-loop requires the existence of portal matter (PM) fields having both dark and SM charges. As discussed in earlier work, these same PM fields can also lead to other loop-level mechanisms besides kinetic mixing that can generate significant interactions between SM fermions and the dark photon in a manner analogous to those that can be generated between a Dirac neutrino and a SM photon, i.e., dark moments. In either case, there are reasons to believe, e.g., due to the renormalization group equation running of the U(1)D gauge coupling, that PM fields may have ∼TeV-scale masses that lie at or above those directly accessible to the HL-LHC. If they lie above the reach of the HL-LHC, then the only way to possibly explore the physics at this high scale in the short term is via indirect measurements made at lower energies, e.g., at lepton colliders operating in the mZ to 1 TeV range. In particular, processes such as e+e−→γ+DM or e+e−→f¯f, where f is a SM fermion, may be most useful in this regard. Here we explore these possibilities within the framework of a simple toy PM model, introduced in earlier work, based on a non-Abelian dark gauge group completion operating at the PM scale. In the kinetic mixing setup, we show these efforts fail due to the inherently tiny cross sections in the face of substantial SM backgrounds. However, in the case of interactions via induced dark moments, since they necessarily take the form of higher dimensional operators whose influence grows with energy, we show that access to PM-scale information may become possible for certain ranges of the toy model parameters for both of these e+e− processes at a 1 TeV collider.

Published by the American Physical Society
2024
The impact of digital financial literacy on financial behavior: customers’ perspective
Authors: Abdallah Wael , Tfaily Fatima , Harraf Arrezou 
Published: March 2024

Purpose
This study aims to examine the nexus between digital financial literacy and customers’ perceived financial behavior within the Kuwaiti context. Moreover, it will further explore how digital financial literacy relates to financial behavior dimensions.

Design/methodology/approach
Data collection was facilitated by creating a questionnaire derived from multiple literature sources. This study used a cross-sectional, time-based dimension. Data was analyzed using the partial least square (PLS) structural equation modeling approach, using the Smart-PLS 4 software for computation.

Findings
Findings demonstrated a significant relationship between digital financial literacy and financial behavior, with a path coefficient of 0.542, a p-value of 0.000 and an R2 value of 0.581. The explorative model revealed substantial relationships between many dimensions of digital financial literacy and various dimensions of financial behavior. More precisely, financial knowledge, awareness and decision-making were the factors that had the most significant impact on financial behavior.

Practical implications
Kuwaiti policymakers should consider including digital financial literacy programs in comprehensive financial education programs to improve public understanding of digital financial instruments and their consequences.

Originality/value
As the authors know, this is the initial endeavor to evaluate the relationship between digital financial literacy, financial behavior and their respective dimensions.