bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cooperative Armoring of CAR and TCR T Cells by T Cell–Restricted IL15 and IL21 Universally Enhances Solid Tumor Efficacy
Authors: Nguyen Rosa , Doubrovina Ekaterina , Mousset Charlotte M. , Jin Benjamin Y. , Okada Reona , Zhang Xiyuan , Clavel Arina , Reyes-Gonzalez Jeyshka M. , Dyomin Vadim , Diaz Louis , Zhang Ling , Abbas Shahroze , Sun Ming , Hsieh Chao-Ming , Ho Mitchell , Shern Jack F. , Gulley James L. , Hinrichs Christian S. 
Published: November 2023

Abstract

Purpose:
Chimeric antigen receptor (CAR) and T-cell receptor (TCR) T-cell therapies are effective in a subset of patients with solid tumors, but new approaches are needed to universally improve patient outcomes. Here, we developed a technology to leverage the cooperative effects of IL15 and IL21, two common cytokine-receptor gamma chain family members with distinct, pleiotropic effects on T cells and other lymphocytes, to enhance the efficacy of adoptive T cells.

Experimental Design:
We designed vectors that induce the constitutive expression of either membrane-tethered IL15, IL21, or IL15/IL21. We used clinically relevant preclinical models of transgenic CARs and TCRs against pediatric and adult solid tumors to determine the effect of the membrane-tethered cytokines on engineered T cells for human administration.

Results:
We found that self-delivery of these cytokines by CAR or TCR T cells prevents functional exhaustion by repeated stimulation and limits the emergence of dysfunctional natural killer (NK)-like T cells. Across different preclinical murine solid tumor models, we observed enhanced regression with each individual cytokine but the greatest antitumor efficacy when T cells were armored with both.

Conclusions:
The coexpression of membrane-tethered IL15 and IL21 represents a technology to enhance the resilience and function of engineered T cells against solid tumors and could be applicable to multiple therapy platforms and diseases.
See related commentary by Ruffin et al., p. 1431
Ultra-Deep Sequencing Reveals the Mutational Landscape of Classical Hodgkin Lymphoma
Authors: Gomez Felicia , Fisk Bryan , McMichael Joshua F. , Mosior Matthew , Foltz Jennifer A. , Skidmore Zachary L. , Duncavage Eric J. , Miller Christopher A. , Abel Haley , Lee Yi-Shan , Russler-Germain David A. , Krysiak Kilannin , Watkins Marcus P. , Ramirez Cody A. , Schmidt Alina , Martins Rodrigues Fernanda , Trani Lee , Khanna Ajay , Wagner Julia A. , Fulton Robert S. , Fronick Catrina C. , O'Laughlin Michelle D. , Schappe Timothy , Cashen Amanda F. , Mehta-Shah Neha , Kahl Brad S. , Walker Jason , Bartlett Nancy L. , Griffith Malachi , Fehniger Todd A. , Griffith Obi L. 
Published: November 2023

Abstract

The malignant Hodgkin and Reed Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) are scarce in affected lymph nodes, creating a challenge to detect driver somatic mutations. As an alternative to cell purification techniques, we hypothesized that ultra-deep exome sequencing would allow genomic study of HRS cells, thereby streamlining analysis and avoiding technical pitfalls. To test this, 31 cHL tumor/normal pairs were exome sequenced to approximately 1,000× median depth of coverage. An orthogonal error-corrected sequencing approach verified &gt;95% of the discovered mutations. We identified mutations in genes novel to cHL including: CDH5 and PCDH7, novel stop gain mutations in IL4R, and a novel pattern of recurrent mutations in pathways regulating Hippo signaling. As a further application of our exome sequencing, we attempted to identify expressed somatic single-nucleotide variants (SNV) in single-nuclei RNA sequencing (snRNA-seq) data generated from a patient in our cohort. Our snRNA analysis identified a clear cluster of cells containing a somatic SNV identified in our deep exome data. This cluster has differentially expressed genes that are consistent with genes known to be dysregulated in HRS cells (e.g., PIM1 and PIM3). The cluster also contains cells with an expanded B-cell clonotype further supporting a malignant phenotype. This study provides proof-of-principle that ultra-deep exome sequencing can be utilized to identify recurrent mutations in HRS cells and demonstrates the feasibility of snRNA-seq in the context of cHL. These studies provide the foundation for the further analysis of genomic variants in large cohorts of patients with cHL.

Significance:
Our data demonstrate the utility of ultra-deep exome sequencing in uncovering somatic variants in Hodgkin lymphoma, creating new opportunities to define the genes that are recurrently mutated in this disease. We also show for the first time the successful application of snRNA-seq in Hodgkin lymphoma and describe the expression profile of a putative cluster of HRS cells in a single patient.
Circuits in the motor cortex explain oscillatory responses to transcranial magnetic stimulation
Authors: Haggie Lysea , Besier Thor , McMorland Angus 
Published: November 2023

Abstract
Transcranial magnetic stimulation (TMS) is a popular method used to investigate brain function. Stimulation over the motor cortex evokes muscle contractions known as motor evoked potentials (MEPs) and also high-frequency volleys of electrical activity measured in the cervical spinal cord. The physiological mechanisms of these experimentally derived responses remain unclear, but it is thought that the connections between circuits of excitatory and inhibitory neurons play a vital role. Using a spiking neural network model of the motor cortex, we explained the generation of waves of activity, so called ‘I-waves’, following cortical stimulation. The model reproduces a number of experimentally known responses including direction of TMS, increased inhibition, and changes in strength. Using populations of thousands of neurons in a model of cortical circuitry we showed that the cortex generated transient oscillatory responses without any tuning, and that neuron parameters such as refractory period and delays influenced the pattern and timing of those oscillations. By comparing our network with simpler, previously proposed circuits, we explored the contributions of specific connections and found that recurrent inhibitory connections are vital in producing later waves that significantly impact the production of motor evoked potentials in downstream muscles (Thickbroom, 2011). This model builds on previous work to increase our understanding of how complex circuitry of the cortex is involved in the generation of I-waves.
Weighting the structural connectome: Exploring its impact on network properties and predicting cognitive performance in the human brain
Authors: Gast Hila , Assaf Yaniv 
Published: November 2023

Abstract
Brain function does not emerge from isolated activity, but rather from the interactions and exchanges between neural elements that form a network known as the connectome. The human connectome consists of structural and functional aspects. The structural connectome (SC) represents the anatomical connections, and the functional connectome represents the resulting dynamics that emerge from this arrangement of structures. As there are different ways of weighting these connections, it is important to consider how such different approaches impact study conclusions. Here, we propose that different weighted connectomes result in varied network properties, and while neither superior the other, selection might affect interpretation and conclusions in different study cases. We present three different weighting models, namely, number of streamlines (NOS), fractional anisotropy (FA), and axon diameter distribution (ADD), to demonstrate these differences. The later, is extracted using recently published AxSI method and is first compared to commonly used weighting methods. Moreover, we explore the functional relevance of each weighted SC, using the Human Connectome Project (HCP) database. By analyzing intelligence-related data, we develop a predictive model for cognitive performance based on graph properties and the National Institutes of Health (NIH) toolbox. Results demonstrate that the ADD SC, combined with a functional subnetwork model, outperforms other models in estimating cognitive performance.
Linking fast and slow: The case for generative models
Authors: Medrano Johan , Friston Karl , Zeidman Peter 
Published: November 2023

Abstract
A pervasive challenge in neuroscience is testing whether neuronal connectivity changes over time due to specific causes, such as stimuli, events, or clinical interventions. Recent hardware innovations and falling data storage costs enable longer, more naturalistic neuronal recordings. The implicit opportunity for understanding the self-organised brain calls for new analysis methods that link temporal scales: from the order of milliseconds over which neuronal dynamics evolve, to the order of minutes, days, or even years over which experimental observations unfold. This review article demonstrates how hierarchical generative models and Bayesian inference help to characterise neuronal activity across different time scales. Crucially, these methods go beyond describing statistical associations among observations and enable inference about underlying mechanisms. We offer an overview of fundamental concepts in state-space modeling and suggest a taxonomy for these methods. Additionally, we introduce key mathematical principles that underscore a separation of temporal scales, such as the slaving principle, and review Bayesian methods that are being used to test hypotheses about the brain with multiscale data. We hope that this review will serve as a useful primer for experimental and computational neuroscientists on the state of the art and current directions of travel in the complex systems modelling literature.
NBS-SNI, an extension of the network-based statistic: Abnormal functional connections between important structural actors
Authors: Normand Francis , Gajwani Mehul , Côté Daniel C. , Allard Antoine 
Published: November 2023

Abstract
Elucidating the coupling between the structure and the function of the brain and its development across maturation has attracted a lot of interest in the field of network neuroscience in the last 15 years. Mounting evidence supports the hypothesis that the onset of certain brain disorders is linked with the interplay between the structural architecture of the brain and its functional processes, often accompanied with unusual connectivity features. This paper introduces a method called the network-based statistic–simultaneous node investigation (NBS-SNI) that integrates both representations into a single framework, and identifies connectivity abnormalities in case-control studies. With this method, significance is given to the properties of the nodes, as well as to their connections. This approach builds on the well-established network-based statistic (NBS) proposed in 2010. We uncover and identify the regimes in which NBS-SNI offers a gain in statistical resolution to identify a contrast of interest using synthetic data. We also apply our method on two real case-control studies, one consisting of individuals diagnosed with autism and the other consisting of individuals diagnosed with early psychosis. Using NBS-SNI and node properties such as the closeness centrality and local information dimension, we found hypo- and hyperconnected subnetworks and show that our method can offer a 9 percentage points gain in prediction power over the standard NBS.
Predictability of cortico-cortical connections in the mammalian brain
Authors: Molnár Ferenc , Horvát Szabolcs , Ribeiro Gomes Ana R. , Martinez Armas Jorge , Molnár Botond , Ercsey-Ravasz Mária , Knoblauch Kenneth , Kennedy Henry , Toroczkai Zoltan 
Published: November 2023

Abstract
Despite a five order of magnitude range in size, the brains of mammals share many anatomical and functional characteristics that translate into cortical network commonalities. Here we develop a machine learning framework to quantify the degree of predictability of the weighted interareal cortical matrix. Partial network connectivity data were obtained with retrograde tract-tracing experiments generated with a consistent methodology, supplemented by projection length measurements in a nonhuman primate (macaque) and a rodent (mouse). We show that there is a significant level of predictability embedded in the interareal cortical networks of both species. At the binary level, links are predictable with an area under the ROC curve of at least 0.8 for the macaque. Weighted medium and strong links are predictable with an 85%–90% accuracy (mouse) and 70%–80% (macaque), whereas weak links are not predictable in either species. These observations reinforce earlier observations that the formation and evolution of the cortical network at the mesoscale is, to a large extent, rule based. Using the methodology presented here, we performed imputations on all area pairs, generating samples for the complete interareal network in both species. These are necessary for comparative studies of the connectome with minimal bias, both within and across species.
The evolution of whole-brain turbulent dynamics during recovery from traumatic brain injury
Authors: Martínez-Molina Noelia , Escrichs Anira , Sanz-Perl Yonatan , Sihvonen Aleksi J. , Särkämö Teppo , Kringelbach Morten L. , Deco Gustavo 
Published: November 2023

Abstract
It has been previously shown that traumatic brain injury (TBI) is associated with reductions in metastability in large-scale networks in resting-state fMRI (rsfMRI). However, little is known about how TBI affects the local level of synchronization and how this evolves during the recovery trajectory. Here, we applied a novel turbulent dynamics framework to investigate whole-brain dynamics using an rsfMRI dataset from a cohort of moderate to severe TBI patients and healthy controls (HCs). We first examined how several measures related to turbulent dynamics differ between HCs and TBI patients at 3, 6, and 12 months post-injury. We found a significant reduction in these empirical measures after TBI, with the largest change at 6 months post-injury. Next, we built a Hopf whole-brain model with coupled oscillators and conducted in silico perturbations to investigate the mechanistic principles underlying the reduced turbulent dynamics found in the empirical data. A simulated attack was used to account for the effect of focal lesions. This revealed a shift to lower coupling parameters in the TBI dataset and, critically, decreased susceptibility and information-encoding capability. These findings confirm the potential of the turbulent framework to characterize longitudinal changes in whole-brain dynamics and in the reactivity to external perturbations after TBI.
Phosphoproteomics and morphology of stored human red blood cells treated by protein tyrosine phosphatases inhibitor
Authors: Bardyn Manon , Crettaz David , Rappaz Benjamin , Hamelin Romain , Armand Florence , Tissot Jean-Daniel , Turcatti Gerardo , Prudent Michel 
Published: November 2023

Abstract
The process of protein phosphorylation is involved in numerous cell functions. In particular, phosphotyrosine (pY) has been reported to play a role in red blood cell (RBC) functions, including the cytoskeleton organization. During their storage before transfusion, RBCs suffer from storage lesions that affect their energy metabolism and morphology. This study investigated the relationship between pY and the storage lesions. To do so, RBCs were treated (in the absence of calcium) with a protein tyrosine phosphatase inhibitor (orthovanadate [OV]) to stimulate phosphorylation and with 3 selective kinase inhibitors (KIs). Erythrocyte membrane proteins were studied by western blot analyses and phosphoproteomics (data are available via ProteomeXchange with identifier PXD039914) and cell morphology by digital holographic microscopy. The increase of pY triggered by OV treatment (inducing a global downregulation of pS and pT) disappeared during the storage. Phosphoproteomic analysis identified 609 phosphoproteins containing 1752 phosphosites, of which 41 pY were upregulated and 2 downregulated by OV. After these phosphorylation processes, the shape of RBCs shifted from discocytes to spherocytes, and the addition of KIs partially inhibited this transition. The KIs modulated either pY or pS and pT via diverse mechanisms related to cell shape, thereby affecting RBC morphology. The capacity of RBCs to maintain their function is central in transfusion medicine, and the presented results contribute to a better understanding of RBC biology.
What is the impact of integrated care on the job satisfaction of primary healthcare providers: a systematic review
Authors: Liu Mei , Wang Jian , Lou Jiaxu , Zhao Ruonan , Deng Jiahui , Liu Ziyu 
Published: November 2023

Abstract
Background and objectives
The integration of care influenced the job satisfaction of healthcare professionals, especially affecting primary healthcare providers (PCPs). This study aimed to perform a systematic review to explore the impact of integrated care on the job satisfaction of PCPs on the basis of Herzberg’s two-factor theory.

Methods
This review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched 6 electronic databases, including CNKI, WANFANG, PubMed, Web of Science, Cochrane Library, and Embase. Data were retrieved from inception to 19 March 2023. The Mixed Methods Appraisal Tool (MMAT) version 2018 was used to assess the methodological quality of studies for inclusion in the review.

Results
A total of 805 articles were retrieved from databases, of which 29 were included in this review. 2 categories, 9 themes, and 14 sub-themes were derived from the data. 2 categories were identified as intrinsic and extrinsic factors. Intrinsic factors included 4 themes: responsibilities, promotion opportunities, recognition, and a sense of personal achievements and growth. Extrinsic factors included 5 themes: salaries and benefits, organizational policy and administration, interpersonal relationships, working conditions, and work status. To specify some key information under certain themes, we also identify sub-themes, such as the sub-theme “workload”, “work stress”, and “burnout” under the theme “work status”.

Conclusions
Findings suggested that the integration of care had both negative and positive effects on the job satisfaction of PCPs and the effects were different depending on the types of integration. Since PCPs played a vital role in the successful integration of care, their job satisfaction was an important issue that should be carefully considered when implementing the integration of care.
Carbamazepine regulates USP10 through miR-20a-5p to affect the deubiquitination of SKP2 and inhibit osteogenic differentiation
Authors: Wang Huan , Liu Ziye , Niu Dawei , Li Haobo , Han Yaguang , Peng Jinhui , Qian Qirong 
Published: November 2023

Abstract
Background
Antiepileptic drugs (AEDs) harm bone health and are significantly associated with osteoporosis development. In this study, we aimed to explore the mechanisms involved in carbamazepine (CBZ) and microRNA (miR)-20a-5p/ubiquitin-specific peptidase 10 (USP10)/S-phase kinase-associated protein 2 (SKP2) axis in osteoporosis.

Methods
Human bone marrow mesenchymal stem cells (BMSCs) were treated with different concentrations of CBZ. Knocking down or overexpressing miR-20a-5p, USP10, and SKP2 cell lines were constructed. The expressions of miR-20a-5p, USP10, SKP2, runt-related transcription factor 2 (Runx2), Alkaline phosphatase (ALP), Osterix (Osx), osteocalcin (OCN) and Collagen I were detected with western blot (WB) and reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR). Alizarin Red S (ARS) staining was performed to measure calcium deposition. Dual-luciferase assay and RNA immunoprecipitation (RIP) were applied to verify the binding relationship between miR-20a-5p and USP10. USP10 and SKP2 combination was verified by Co-Immunopurification (Co-IP). The stability of the SKP2 protein was verified by Cycloheximide chase assay.

Results
CBZ could reduce cell activity. ALP activity and ARS staining were enhanced in the osteogenic induction (OM) group. The expressions of Runx2, ALP, Osx, OCN and Collagen I were increased. CBZ reduced miR-20a-5p expressions. Verification experiments showed miR-20a-5p could target USP10. USP10 increased SKP2 stability and promoted SKP2 expression. CBZ regulated miR-20a-5p/USP10/SPK2 and inhibited BMSCs osteogenic differentiation.

Conclusions
CBZ regulated USP10 through miR-20a-5p to affect the deubiquitination of SKP2 and inhibit osteogenic differentiation, which provided a new idea for osteoporosis treatment.
Epidemiology and survival outcomes of HIV-associated cervical cancer in Nigeria
Authors: Musa Jonah , Kocherginsky Masha , Magaji Francis A. , Maryam Ali J. , Asufi Joyce , Nenrot Danjuma , Burdett Kirsten , Katam Neelima , Christian Elizabeth N. , Palanisamy Nisha , Odukoya Olukemi , Silas Olugbenga A. , Abdulkareem Fatimah , Akpa Philip , Badmos Kabir , Imade Godwin E. , Akanmu Alani S. , Gursel Demirkan B. , Zheng Yinan , Joyce Brian T. , Achenbach Chad J. , Sagay Atiene S. , Anorlu Rose , Wei Jian-Jun , Ogunsola Folasade , Murphy Robert L. , Hou Lifang , Simon Melissa A. 
Published: November 2023

Abstract
Introduction
Invasive cervical cancer (ICC) is an HIV-associated cancer that is preventable and precancerous stages including early ICC stages could be detected through screening offering opportunities for treatment and cure. The high incidence in women living with HIV and late presentation often at advanced stages of ICC with limited treatment facilities often result in early mortality. We sought to compare the epidemiologic characteristics and survival differences in HIV status of ICC patients in Nigeria.

Methods
We conducted a cohort study at two federal academic hospital-based research sites in Jos University Teaching Hospital, and Lagos University Teaching Hospital Nigeria, between March 2018 and September 2022. We enrolled women with histologically confirmed ICC with known HIV status, and FIGO staging as part of the United States of America’s National Institutes of Health/National Cancer Institute funded project titled ‘Epigenomic Biomarkers of HIV-Associated Cancers in Nigeria’. The primary outcome was all-cause mortality with assessment of overall survival (OS) and time to death after ICC diagnosis. OS distribution was estimated using the method of Kaplan–Meier and compared between groups using the log-rank test.

Results
A total of 239 women with confirmed ICC were enrolled and included in this analysis, of whom 192 (80.3%) were HIV-negative (HIV−/ICC +), and 47 (19.7%) were HIV-positive (HIV +/ICC +). The HIV +/ICC + patients were younger with median age 46 (IQR: 40–51) years compared to 57 (IQR: 45–66) among HIV−/ICC + (P < 0.001). Squamous cell carcinoma was the commonest histopathologic variant in 80.4% of ICC diagnosis, moderately differentiated tumor grade in 68.1% in both groups. HIV +/ICC + diagnosis was at FIGO advanced stages in 64.9% compared to 47.9% in HIV−/ICC +. The HIV−/ICC + women had better OS compared to HIV +/ICC + participants (p = 0.018), with 12-month OS 84.1% (95%CI 75–90%) and 67.6% (95%CI 42–84%) respectively.

Conclusion
ICC is diagnosed at a relatively young age in women living with HIV, with a significantly lower overall survival probability compared to women without HIV. The trend of presentation and diagnosis at advanced stages in women living with HIV could partly explain the differences in overall survival.