bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thalamic contributions to psychosis susceptibility: Evidence from co-activation patterns accounting for intra-seed spatial variability (μCAPs)
Authors: Delavari Farnaz , Sandini Corrado , Kojovic Nada , Saccaro Luigi F. , Eliez Stephan , Van De Ville Dimitri , Bolton Thomas A. W. 
Published: May 2023

AbstractThe temporal variability of the thalamus in functional networks may provide valuable insights into the pathophysiology of schizophrenia. To address the complexity of the role of the thalamic nuclei in psychosis, we introduced micro-co-activation patterns (μCAPs) by employing this method on the human genetic model of schizophrenia 22q11.2 deletion syndrome (22q11.2DS). Participants underwent resting-state functional MRI and a data-driven iterative process resulting in the identification of six whole-brain μCAPs with specific activity patterns within the thalamus. Unlike conventional methods, μCAPs extract dynamic spatial patterns that reveal partially overlapping and non-mutually exclusive functional subparts. Thus, the μCAPs method detects finer foci of activity within the initial seed region, retaining valuable and clinically relevant temporal and spatial information. We found that a μCAP showing co-activation of the mediodorsal thalamus with brain-wide cortical regions was significantly less frequent in patients with 22q11.2DS, and its occurrence negatively correlated with the severity of positive psychotic symptoms. Additionally, the activity within the auditory-visual cortex and their respective geniculate nuclei were expressed in two different μCAPs. One of these auditory-visual μCAPs co-activated with salience areas, while the other co-activated with the default mode network (DMN). A significant shift of occurrence from the salience+visuo-auditory-thalamus to the DMN+visuo-auditory-thalamus μCAP was observed in patients with 22q11.2DS. Thus, our findings support existing research on the gatekeeping role of the thalamus for sensory information in the pathophysiology of psychosis and revisit the evidence of geniculate nuclei hyperconnectivity with the audio-visual cortex in 22q11.2DS in the context of dynamic functional connectivity as specific hyper-occurrence of these circuits with the task negative brain networks.
Setdb1-loss induces type-I interferons and immune clearance of melanoma
Authors: McGeary Meaghan K. , Damsky William , Daniels Andrew , Song Eric , Micevic Goran , Huet-Calderwood Clotilde , Lou Hua Jane , Paradkar Sateja , Kaech Susan , Calderwood David A. , Turk Benjamin E. , Iwasaki Akiko , Bosenberg Marcus W. 
Published: May 2023

SummaryDespite recent advances in the treatment of melanoma, many patients with metastatic disease still succumb to their disease. To identify tumor-intrinsic modulators of immunity to melanoma, we performed a whole-genome CRISPR screen in melanoma and identified multiple components of the HUSH complex, includingSetdb1, as hits. We found that loss ofSetdb1leads to increased immunogenicity and complete tumor clearance in a CD8+ T-cell dependent manner. Mechanistically, loss ofSetdb1causes de-repression of endogenous retroviruses (ERVs) in melanoma cells and triggers tumor-cell intrinsic type-I interferon signaling, upregulation of MHC-I expression, and increased CD8+ T-cell infiltration. Furthermore, spontaneous immune clearance observed inSetdb1-/-tumors results in subsequent protection from other ERV-expressing tumor lines, supporting the functional anti-tumor role of ERV-specific CD8+ T-cells found in theSetdb1-/-microenvironment. Blocking the type-I interferon receptor in mice grafted withSetdb1-/-tumors decreases immunogenicity by decreasing MHC-I expression, leading to decreased T-cell infiltration and increased melanoma growth comparable to Setdb1wttumors. Together, these results indicate a critical role forSetdb1and type-I interferons in generating an inflamed tumor microenvironment, and potentiating tumor-cell intrinsic immunogenicity in melanoma. This study further emphasizes regulators of ERV expression and type-I interferon expression as potential therapeutic targets for augmenting anti-cancer immune responses.
Foxp3 depends on Ikaros for control of regulatory T cell gene expression and function
Authors: Thomas Rajan M. , Pahl Matthew C. , Wang Liqing , Grant Struan F. A. , Hancock Wayne W. , Wells Andrew D. 
Published: May 2023

AbstractIkaros is a transcriptional factor required for conventional T cell development, differentiation, and anergy. While the related factors Helios and Eos have defined roles in regulatory T cells (Treg), a role for Ikaros has not been established. To determine the function of Ikaros in the Treg lineage, we generated mice with Treg-specific deletion of the Ikaros gene (Ikzf1). We find that Ikaros cooperates with Foxp3 to establish a major portion of the Treg epigenome and transcriptome. Ikaros-deficient Treg exhibit Th1-like gene expression with abnormal expression of IL-2, IFNg, TNFa, and factors involved in Wnt and Notch signaling. WhileIkzf1-Treg-cko mice do not develop spontaneous autoimmunity, Ikaros-deficient Treg are unable to control conventional T cell-mediated immune pathology in response to TCR and inflammatory stimuli in models of IBD and organ transplantation. These studies establish Ikaros as a core factor required in Treg for tolerance and the control of inflammatory immune responses.
Antigen spacing on protein nanoparticles influences antibody responses to vaccination
Authors: Ellis Daniel , Dosey Annie , Boyoglu-Barnum Seyhan , Park Young-Jun , Gillespie Rebecca , Syeda Hubza , Tsybovsky Yaroslav , Murphy Michael , Pettie Deleah , Matheson Nick , Chan Sidney , Ueda George , Fallas Jorge A. , Carter Lauren , Graham Barney S. , Veesler David , Kanekiyo Masaru , King Neil P. 
Published: May 2023

SUMMARYImmunogen design approaches aim to control the specificity and quality of antibody responses to enable the creation of next-generation vaccines with improved potency and breadth. However, our understanding of the relationship between immunogen structure and immunogenicity is limited. Here we use computational protein design to generate a self-assembling nanoparticle vaccine platform based on the head domain of influenza hemagglutinin (HA) that enables precise control of antigen conformation, flexibility, and spacing on the nanoparticle exterior. Domain-based HA head antigens were presented either as monomers or in a native-like closed trimeric conformation that prevents exposure of trimer interface epitopes. These antigens were connected to the underlying nanoparticle by a rigid linker that was modularly extended to precisely control antigen spacing. We found that nanoparticle immunogens with decreased spacing between closed trimeric head antigens elicited antibodies with improved hemagglutination inhibition (HAI) and neutralization potency as well as binding breadth across diverse HAs within a subtype. Our “trihead” nanoparticle immunogen platform thus enables new insights into anti-HA immunity, establishes antigen spacing as an important parameter in structure-based vaccine design, and embodies several design features that could be used to generate next-generation vaccines against influenza and other viruses.HIGHLIGHTSComputational design of a closed trimeric HA head (“trihead”) antigen platform.Design of a rigid, extendable linker between displayed antigen and underlying protein nanoparticle enables precise variation of antigen spacing.Decreased antigen spacing of triheads elicits antibodies with the highest HAI, neutralizing activity, and cross-reactivity.Changes to antigen spacing alter epitope specificities of vaccine-elicited antibodies.
Implementation of the PrAISED (Promoting Activity, Independence and Stability in Early Dementia) intervention in practice: a mixed methods study
Authors: Adams Emma J , Burgon Clare , Lock Juliette , Smith Helen , Vickers Robert , Tucker Rachael , Timmons Stephen , Orton Elizabeth , Goldberg Sarah E , Gladman John , Masud Tahir , Harwood Rowan H 
Published: May 2023

AbstractThere is a paucity of evidence relating to the implementation of dementia care. The Promoting Activity, Independence and Stability in Early Dementia (PrAISED) intervention is a newly developed 12-month, home-based, individually tailored rehabilitation programme, delivered by therapists and rehabilitation support workers, with a focus on strength, balance, physical activity and activities of daily living. The aim of this study was to identify what is required to implement PrAISED, or similar interventions, in routine clinical practice. PrAISED was delivered as a pilot service in one National Health Service organisation in England. Patient characteristics and the number and duration of visits were recorded by intervention delivery staff. Quantitative data were explored using descriptive statistics. Semi-structured interviews were conducted with seven members of staff delivering the PrAISED service (two managers, five delivery staff) and eight members of staff from other sites involved in the PrAISED Randomised Controlled Trial (RCT) (four managers, four delivery staff). The Consolidated Framework for Implementation Research was used to inform interview guides and conduct a codebook thematic analysis. Adaptations were needed to deliver PrAISED as a service and referrals were lower than expected. Five themes were identified from interviews relating to the pilot service: operational processes; workforce capacity; referral; intervention delivery and patient impact. A further six themes were identified regarding the wider implementation of dementia therapy programmes: the need for support post-dementia diagnosis; acceptability; effective delivery; reach/referral; intervention design and adaptability; and intervention materials and training. There is a need for interventions like PrAISED to fill a gap in support immediately post-dementia diagnosis. Future implementation will require attention to the identification of intervention funding; leadership and management; time to establish operational processes; therapists with appropriate skills and experience; providing training and resources to support intervention delivery; defining patient eligibility and referral processes; and maintaining fidelity of the intervention.
Hypoxia modulates P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) drug transporters in brain endothelial cells of the developing human blood-brain barrier
Authors: Mughis Hafsah , Lye Phetcharawan , Imperio Guinever E. , Bloise Enrrico , Matthews Stephen G. 
Published: May 2023

AbstractP-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are two multidrug resistance (MDR) transporters expressed at the blood-brain barrier (BBB). They confer protection against entry of harmful molecules into the fetal brain. The fetus develops under relatively low oxygen concentrations; however, pregnancy disorders (including pre-eclampsia) may lead to even lower intrauterine oxygen levels. We investigated the effects of hypoxia on transporter expression and activity in human fetal brain endothelial cells (hfBECs) isolated in early and mid-gestation. Results indicate decreased BCRP protein and activity under hypoxia in early-gestation hfBECs. Mid-gestation hfBECs exhibited an increase in P-gp and BCRP activity following hypoxia. Results suggest a hypoxia-induced reduction in fetal brain protection in early-pregnancy, but a potential increase in transporter-mediated protection at the BBB during mid-gestation. This would modify accumulation of various key P-gp and BCRP physiological and pharmacological substrates in the developing fetal brain and may play a role in the pathogenesis of neurodevelopmental disorders commonly associated within uterohypoxia.
Transcriptional reprogramming by IL-2 variant generates metabolically active stem-like T cells
Authors: Ortiz-Miranda Yaquelin , Masid Maria , Jiménez-Luna Cristina , Montalvo Bereau Galia Magela , Muller Tania , Rayroux Nicolas , Cribioli Elisabetta , Corría-Osorio Jesús , Carrasco Hope Helen , Vuillefroy de Silly Romain , Seijo Bili , Ginefra Pierpaolo , León Kalet , Vannini Nicola , Ho Ping-Chih , Crespo Isaac , Hatzimanikatis Vassily , Irving Melita , Coukos George 
Published: May 2023

SummaryInterleukin-2 receptor (IL-2R)-mediated intracellular signaling is a key regulator of T-cell fate decisions. While the potent signals generated by IL-2 engagement execute effector differentiation, elevated metabolic activities and rapid cellular expansion, IL-15 binding induces a stemness/memory phenotype and a quiescent metabolic state. Here, we demonstrate that weak but sustained signaling generated by a non-IL-2Rα-binding variant of IL-2 (IL-2v) drive proliferation/metabolic and stemness transcriptional programs, thereby reprogramming CD8+T cells into a hybrid ‘metabolically active stem-like state’. We further show that IL-2v-induced T cells are capable of superior engraftment, persistence, and tumor control when utilized in adoptive cell therapy. Taken together, our study highlights the ability to fine-tune cytokine engagement of cognate receptors in order to generate therapeutically relevant T-cell states and further reveals the metabolic plasticity of the T-cell memory program.
Molecular dynamics of the interaction between the ALS/FTD-associated (GGGGCC)n RNA G-quadruplex structure and the three RRM domains of hnRNP H
Authors: Cava Marvin Jericho , Billones Junie B , Galipon Josephine 
Published: May 2023

ABSTRACTHexanucleotide repeat expansions (HRE), located in the first intron of chromosome 9 open reading frame 72 (C9orf72) are the most common genetic abnormality associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Presence of the HRE may cause various effects to neuronal cells, leading to pathogenicity. One of these is the sequestration of RNA-binding proteins by three-quartet parallel RNA G-quadruplexes (RG4s) formed from repeated (GGGGCC)n sequences on the sense transcripts of the HRE. Multiple studies imply a major role of the sequestration of heterogeneous nuclear ribonucleoprotein H (hnRNP H) in the pathology of ALS/FTD. In this study, molecular docking and molecular dynamics (MD) were used to simulate the interaction of the three RNA recognition motifs (RRMs) of hnRNP H with the RG4. Molecular Mechanics with Generalised Born and Surface Area Solvation (MM-GBSA) and hydrogen bonding analyses of MD simulations were performed. The MM-GBSA analyses revealed that Arg29, Arg150, and Arg299 are important contributors to the binding, consistent with previous observations of arginine-mediated binding of protein to RNA. In addition, our results point to a previously unknown role of the stretch of residues from Lys72 to Tyr82 on hnRNP H for binding the (GGGGCC)n RG4, forming a hydrogen bonding hotspot. Interestingly, the identified residues are not located in the beta sheet, as would be expected of RRMs in general, suggesting that the binding of hnRNP H to this pathological RG4 may be specifically targeted. This has implications for futurein vitrostudies including but not limited to mutational analysis of these mentioned residues as well as drug development to prevent the sequestration of hnRNP H in ALS/FTD.
Macrophage-specific lipid nanoparticle therapy blocks the lung’s mechanosensitive immunity due to macrophage-epithelial interactions
Authors: Mthunzi Liberty , Islam Mohammad N , Gusarova Galina A , Bhattacharya Sunita , Karolewski Brian , Bhattacharya Jahar 
Published: May 2023

AbstractThe lung’s mechanosensitive immune response, which occurs when pulmonary alveoli are overstretched, is a major impediment to ventilation therapy for hypoxemic respiratory failure. The cause is not known. We tested the hypothesis that alveolar stretch causes stretch of alveolar macrophages (AMs), leading to the immune response. In lungs viewed by optical imaging, sessile AMs expressed gap junctional protein connexin-43 (Cx43), and they communicated with the alveolar epithelium through gap junctions. Alveolar hyperinflation increased Ca2+in the AMs but did not stretch the AMs. The Ca2+response, and concomitant TNFα secretion by AMs were blocked in mice with AM-specific deletion of Cx43. The AM responses, as also lung injury due to mechanical ventilation at high tidal volume, were inhibited by AM-specific delivery of lipid nanoparticles containing Xestospongin C, which blocked the induced Ca2+increases. We conclude, Cx43- and Ca2+-dependent AM-epithelial interactions determine the lung’s mechanosensitive immunity, providing a basis for therapy for ventilator- induced lung injury.
Estimating gross transcription rates from RNA level fluctuation data and the effects of sampling time intervals
Authors: Xu Zhongneng , Asakawa Shuichi 
Published: May 2023

ABSTRACTTranscription rates are key biological parameters, but the estimation of transcription rates from RNA level fluctuation data by current methods is still problematic, considering in particular the derived relationship between RNA fragments from different samples and the neglect of the effects of sampling time intervals. Based on defining the gross transcription rate as the amount of converted complete nascent RNA divided by time, the present study developed an algorithm that calculated the cumulative transcription amount and RNA abundance at each time point by simulating moving windows to estimate gross transcription rates from RNA level fluctuation data and explore the effects of sampling time intervals on the estimation. The results showed that the gross transcription rates could be calculated from RNA level fluctuation data with the models fitting the experimental data well. In the analysis of 384 yeast genes, the genes with the highest gross transcription rates mainly played roles in cell division regulation and DNA replication, and the gene utilizing the most cellular resources for gene expression during the experiment was YNR016c, whose main functions are fatty acid biosynthesis and transporting proteins into the nucleus. The shapes of the RNA level curves affected the estimation of gross transcription rates, and the crests and valleys of the RNA level curves responded to higher gross transcription rates. Different scenarios of sampling time intervals could change the shapes of the RNA level curves, resulting in different estimation values of gross transcription rates. Given the potential applications of the present method, further improvements are expected.
Noncanonical TRAIL Signaling Promotes Myeloid-Derived Suppressor Cell Abundance and Tumor Progression in Cholangiocarcinoma
Authors: Loeuillard Emilien , Li Binbin , Stumpf Hannah E. , Yang Jingchun , Willhite Jessica , Tomlinson Jennifer L. , Wang Juan , Rohakhtar Fred Rakhshan , Simon Vernadette A. , Graham Rondell P. , Smoot Rory L. , Dong Haidong , Ilyas Sumera I. 
Published: May 2023

ABSTRACTProapoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling as a cause of cancer cell death is a well-established mechanism. However, TRAIL-receptor (TRAIL-R) agonists have had very limited anticancer activity in humans, challenging the concept of TRAIL as a potent anticancer agent. Herein, we demonstrate that TRAIL+cancer cells can leverage noncanonical TRAIL signaling in myeloid-derived suppressor cells (MDSCs) promoting their abundance in murine cholangiocarcinoma (CCA). In multiple immunocompetent syngeneic, orthotopic murine models of CCA, implantation of TRAIL+murine cancer cells intoTrail-r-/-mice resulted in a significant reduction in tumor volumes compared to wild type mice. Tumor bearingTrail-r-/-mice had a significant decrease in the abundance of MDSCs due to attenuation of MDSC proliferation. Noncanonical TRAIL signaling with consequent NF-κB activation in MDSCs facilitated enhanced MDSC proliferation. Single cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) of CD45+cells in murine tumors from three distinct immunocompetent CCA models demonstrated a significant enrichment of an NF-κB activation signature in MDSCs. Moreover, MDSCs were resistant to TRAIL-mediated apoptosis due to enhanced expression of cellular FLICE inhibitory protein (cFLIP), an inhibitor of proapoptotic TRAIL signaling. Accordingly, cFLIP knockdown sensitized murine MDSCs to TRAIL-mediated apoptosis. Finally, cancer cell-restricted deletion ofTrailsignificantly reduced MDSC abundance and murine tumor burden. In summary, our findings define a noncanonical TRAIL signal in MDSCs and highlight the therapeutic potential of targeting TRAIL+cancer cells for the treatment of a poorly immunogenic cancer.
A bioinformatics tool for identifying intratumoral microbes from the ORIEN dataset
Authors: Wang Cankun , Ma Anjun , McNutt Megan E. , Hoyd Rebecca , Wheeler Caroline E. , Robinson Lary A. , Chan Carlos H.F. , Zakharia Yousef , Dodd Rebecca D. , Ulrich Cornelia M. , Hardikar Sheetal , Churchman Michelle L. , Tarhini Ahmad A. , Singer Eric A. , Ikeguchi Alexandra P. , McCarter Martin D. , Denko Nicholas , Tinoco Gabriel , Husain Marium , Jin Ning , Osman Afaf E.G. , Eljilany Islam , Tan Aik Choon , Coleman Samuel S. , Denko Louis , Riedlinger Gregory , Schneider Bryan P. , Spakowicz Daniel , Ma Qin 
Published: May 2023

ABSTRACTEvidence supports significant interactions among microbes, immune cells, and tumor cells in at least 10–20% of human cancers, emphasizing the importance of further investigating these complex relationships. However, the implications and significance of tumor-related microbes remain largely unknown. Studies have demonstrated the critical roles of host microbes in cancer prevention and treatment responses. Understanding interactions between host microbes and cancer can drive cancer diagnosis and microbial therapeutics (bugs as drugs). Computational identification of cancer-specific microbes and their associations is still challenging due to the high dimensionality and high sparsity of intratumoral microbiome data, which requires large datasets containing sufficient event observations to identify relationships, and the interactions within microbial communities, the heterogeneity in microbial composition, and other confounding effects that can lead to spurious associations. To solve these issues, we present a bioinformatics tool, MEGA, to identify the microbes most strongly associated with 12 cancer types. We demonstrate its utility on a dataset from a consortium of 9 cancer centers in the Oncology Research Information Exchange Network (ORIEN). This package has 3 unique features: species-sample relations are represented in a heterogeneous graph and learned by a graph attention network; it incorporates metabolic and phylogenetic information to reflect intricate relationships within microbial communities; and it provides multiple functionalities for association interpretations and visualizations. We analyzed 2704 tumor RNA-seq samples and MEGA interpreted the tissue-resident microbial signatures of each of 12 cancer types. MEGA can effectively identify cancer-associated microbial signatures and refine their interactions with tumors.SIGNIFICANCEStudying the tumor microbiome in high-throughput sequencing data is challenging because of the extremely sparse data matrices, heterogeneity, and high likelihood of contamination. We present a new deep-learning tool, microbial graph attention (MEGA), to refine the organisms that interact with tumors.