bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards Effective CAIX-targeted Radionuclide and Checkpoint Inhibition Combination Therapy for Advanced Clear Cell Renal Cell Carcinoma
Authors: Kleinendorst Simone C. , Oosterwijk Egbert , Molkenboer-Kuenen Janneke , Frielink Cathelijne , Franssen Gerben M. , Boreel Daan F. , Tamborino Giulia , Gloudemans Manon , Hendrikx Merel , Kroon Dennis , Hillen Jopp , Bussink Johan , Muselaers Stijn , Mulders Peter , Konijnenberg Mark W. , Wheatcroft Michael P. , Twumasi-Boateng Kwame , Heskamp Sandra 
Published: February 2024

ABSTRACTBackgroundImmune checkpoint inhibitors (ICI) are routinely used in advanced clear cell renal cell carcinoma (ccRCC). However, a substantial group of patients does not respond to ICI therapy. Radiation is a promising approach to increase ICI response rates since it can generate anti-tumor immunity. Targeted radionuclide therapy (TRT) is a systemic radiation treatment, ideally suited for precision irradiation of metastasized cancer. Therefore, the aim of this study is to explore the potential of combined TRT, targeting carbonic anhydrase IX (CAIX) which is overexpressed in ccRCC, using [177Lu]Lu-DOTA-hG250, and ICI for the treatment of ccRCC.MethodsIn this study, we evaluated the therapeutic and immunological action of [177Lu]Lu-DOTA-hG250 combined with aPD-1/a-CTLA-4 ICI. First, the biodistribution of [177Lu]Lu-DOTA-hG250 was investigated in BALB/cAnNRj mice bearing Renca-CAIX or CT26-CAIX tumors. Renca-CAIX and CT26-CAIX tumors are characterized by poor versus extensive T-cell infiltration and homogeneous versus heterogeneous PD-L1 expression, respectively. Tumor-absorbed radiation doses were estimated through dosimetry. Subsequently, [177Lu]Lu-DOTA-hG250 TRT efficacy with and without ICI was evaluated by monitoring tumor growth and survival. Therapy-induced changes in the tumor microenvironment were studied by collection of tumor tissue before and 5 or 8 days after treatment and analyzed by immunohistochemistry, flow cytometry, and RNA profiling.ResultsBiodistribution studies showed high tumor uptake of [177Lu]Lu-DOTA-hG250 in both tumor models. Dose escalation therapy studies in Renca-CAIX tumor-bearing mice demonstrated dose-dependent anti-tumor efficacy of [177Lu]Lu-DOTA-hG250 and remarkable therapeutic synergy including complete remissions when a presumed subtherapeutic TRT dose (4 MBq, which had no significant efficacy as monotherapy) was combined with aPD-1+aCTLA-4. Similar results were obtained in the CT26-CAIX model for 4 MBq [177Lu]Lu-DOTA-hG250 + a-PD1.Ex vivoanalyses of treated tumors revealed DNA damage, T-cell infiltration, and modulated immune signaling pathways in the TME after combination treatment.ConclusionsSubtherapeutic [177Lu]Lu-DOTA-hG250 combined with ICI showed superior therapeutic outcome and significantly altered the TME. Our results underline the importance of investigating this combination treatment for patients with advanced ccRCC in a clinical setting. Further investigations should focus on how the combination therapy should be optimally applied in the future.Abstract Figure
Efficient targeting of heart lesions with cardiac myofibroblasts: Combined gene and cell therapy enhanced by magnetic steering
Authors: Schiffer M. , Wagner K. , Carls E. , Nicke J. , Hesse M. , Fratila R. , Hildebrand S. , Pfeifer A. , Eberbeck D. , Malek Mohammadi M. , De la Fuente J.M. , Fleischmann B.K. , Roell W. 
Published: February 2024

1AbstractThe cardiac scar is a collagen-rich area, which is populated by myofibroblasts and has proven little amenable for therapeutic interventions. Herein, we have established an efficient targeting strategy for cardiac lesions by genetically manipulating embryonic cardiac myofibroblasts (mFB)in vitro, load the cells with magnetic nanoparticles and inject these into infarcted mouse hearts using magnetic steering. This yields strongly increased numbers (∼4 fold compared to other cell types) of engrafted mFB. The injected mFB and endogenous myofibroblast (endoFB) population remain separate in the scar, but grafted mFB enhance the proliferation rate of endoFB by ∼4 fold. We also tested the functional impact of this approach by grafting lentiviral (LV)-transduced Connexin43 (Cx43) overexpressing mFB into the cardiac lesion. Prominent engraftment of Cx43+mFB provides strong protection against post-infarct ventricular tachycardia (VT)in vivo, as VT incidence is reduced by ∼50 % at two and eight weeks after cell injection. Thus,ex vivogene and subsequentin vivocell therapy combined with magnetic steering of cardiac mFB enable efficient functional targeting of the cardiac scar.
Cross-species modeling and enhancement of cognitive control with striatal brain stimulation
Authors: Reimer Adriano E , Dastin-van Rijn Evan M , Kim Jaejoong , Mensinger Megan E , Sachse Elizabeth M , Wald Aaron , Hoskins Eric , Singh Kartikeya , Alpers Abigail , Cooper Dawson , Lo Meng-Chen , Ribeiro de Oliveira Amanda , Simandl Gregory , Stephenson Nathaniel , Widge Alik S 
Published: February 2024

AbstractBrain disorders, particularly mental disorders, might be effectively treated by direct electrical brain stimulation, but clinical progress requires understanding of therapeutic mechanisms. Animal models have not helped, because there are no direct animal models of mental illness. We show a path past this roadblock, by leveraging a common ingredient of most mental disorders: impaired cognitive control. We previously showed that deep brain stimulation (DBS) improves cognitive control in humans. We now reverse translate that result, showing that DBS-like stimulation of the mid-striatum improves cognitive control in rats. Using this model, we identify a mechanism, improvement in domain-general cognitive control, and rule out competing hypotheses such as impulsivity. The rat findings explain prior human results and have immediate implications for clinical practice and future trial design.One Sentence Summary:Developing a reliable animal model of a human brain stimulation therapy reveals that this therapy works by enhancing the brain’s ability to process conflicting pieces of evidence.
First chromosome-level genome assembly of a ribbon worm from the Hoplonemertea clade,Emplectonema gracile, and its structural annotation
Authors: Valero-Gracia Alberto , Roberts Nickellaus G. , Yap-Chiongco Meghan , Capucho Ana Teresa , Kocot Kevin M. , Matschiner Michael , Struck Torsten H. 
Published: February 2024

AbstractGenome-wide information has so far been unavailable for ribbon worms of the clade Hoplonemertea, the most species-rich class within the phylum Nemertea. While species within Pilidiophora, the sister clade of Hoplonemertea, possess a pilidium larval stage and lack stylets on their proboscis, Hoplonemertea species have a planuliform larva and are armed with stylets employed for the injection of toxins into their prey. To further compare these developmental, physiological, and behavioral differences from a genomic perspective, the availability of a reference genome of a Hoplonemertea species is crucial. To this end, we herein present the annotated chromosome-level genome assembly forEmplectonema gracile(Nemertea; Hoplonemertea; Monostilifera; Emplectonematidae), an easily collected nemertean well-suited for laboratory experimentation. The genome is 157.9 Mbp in span. Hi-C scaffolding yielded 15 putative chromosomes with a scaffold N50 of 10.0 Mbp and a BUSCO completeness score of 95.3%. Structural annotation predicted 20,684 protein-coding genes. The high-quality reference genome reaches an Earth BioGenome standard level of 7.C.Q50. These data will be highly useful for future investigations towards a better understanding of the evolution, development, morphology, and toxicology of Nemertea.SignificanceThe genome ofEmplectonema gracileis highly contiguous, well annotated, and shorter than those of the other two ribbon worm species sequenced to date. This genome is a valuable resource for studies on molecular ecology, venom evolution, and regeneration in marine invertebrates.
Steatotic liver disease induced by TCPOBOP-activated hepatic constitutive androstane receptor: Primary and secondary gene responses with links to disease progression
Authors: Sonkar Ravi , Ma Hong , Waxman David J. 
Published: February 2024

AbstractConstitutive Androstane Receptor (CAR,Nr1i3), a liver nuclear receptor and xenobiotic sensor, induces drug, steroid and lipid metabolizing enzymes, stimulates liver hypertrophy and hyperplasia, and ultimately, hepatocellular carcinogenesis. The mechanisms linking early CAR responses to subsequent disease development are poorly understood. Here we show that exposure of CD-1 mice to TCPOBOP, a halogenated xenochemical and selective CAR agonist ligand, induces pericentral steatosis marked by hepatic accumulation of cholesterol and neutral lipid, and elevated circulating alanine aminotransferase levels, indicating hepatocyte damage. TCPOBOP-induced steatosis was weaker in the pericentral region but stronger in the periportal region in females compared to males. Early (1-day) TCPOBOP transcriptional responses were enriched for CAR-bound primary response genes, and for lipid and xenobiotic metabolism and oxidative stress protection pathways; late (2-wk) TCPOBOP responses included many CAR binding-independent secondary response genes, with enrichment for immune response, macrophage activation, and cytokine and reactive oxygen species production. Late upstream regulators specific to TCPOBOP-exposed male liver were linked to pro-inflammatory responses and hepatocellular carcinoma progression. TCPOBOP administered weekly to male mice using a high corn oil vehicle activated carbohydrate-responsive transcription factor (MLXIPL)-regulated target genes, dysregulated mitochondrial respiratory and translation regulatory pathways, and induced more advanced liver pathology. Thus, TCPOBOP exposure recapitulates histological and gene expression changes characteristic of emerging steatotic liver disease, including secondary expression changes in liver non-parenchymal cells indicative of transition to a more advanced disease state. Upstream regulators of both the early and late TCPOBOP gene responses include novel biomarkers for foreign chemical-induced metabolic dysfunction-associated steatotic liver disease.
A Multi-objective Simulation-Optimization Framework for the Design of a Compliant Gravity Balancing Orthosis
Authors: Chishty Haider A. , Sergi Fabrizio 
Published: February 2024

AbstractFlexion-synergy is a stereotypical movement pattern that inhibits independent joint control for those who have been affected by stroke; this abnormal co-activation of elbow flexors with shoulder abductors significantly reduces range of motion when reaching against gravity. While wearable orthoses based around compliant mechanisms have been shown to accurately compensate for the arm at the shoulder, it is unclear if accurate compensation can also be achieved while minimizing device bulk.In this work, we present a novel, multi-objective simulation-optimization framework towards the goal of designing practical gravity-balancing orthoses for the upper-limb. Our framework includes a custom built VB.NET application to run nonlinear finite element simulations in SolidWorks, and interfaces with a MATLAB-based particle swarm optimizer modified for multiple objectives. The framework is able to identify a set of Pareto-optimal compliant mechanism designs, confirming that compensation accuracy and protrusion minimization are indeed conflicting design objectives.The preliminary execution of the simulation-optimization framework demonstrates a capability of achieving designs that compensate for almost 90% of the arm’s gravity or that exhibit an average protrusion of less than 5% of the arm length, with different trade-offs between these two objectives.
Associations between regional blood-brain barrier disruption, aging, and Alzheimer’s disease biomarkers in cognitively normal older adults
Authors: Denkinger Marisa , Baker Suzanne , Inglis Ben , Kobayashi Sarah , Juarez Alexis , Mason Suzanne , Jagust William 
Published: February 2024

AbstractBackgroundBlood-brain barrier disruption (BBBd) has been hypothesized as a feature of aging that may lead to the development of Alzheimer’s disease (AD). We sought to identify the brain regions most vulnerable to BBBd during aging and examine their regional relationship with neuroimaging biomarkers of AD.MethodsWe studied 31 cognitively normal older adults (OA) and 10 young adults (YA) from the Berkeley Aging Cohort Study (BACS). Both OA and YA received dynamic contrast-enhanced MRI (DCE-MRI) to quantify Ktransvalues, as a measure of BBBd, in 37 brain regions across the cortex. The OA also received Pittsburgh compound B (PiB)-PET to create distribution volume ratios (DVR) images and flortaucipir (FTP)-PET to create partial volume corrected standardized uptake volume ratios (SUVR) images. Repeated measures ANOVA assessed the brain regions where OA showed greater BBBd than YA. In OA, Ktransvalues were compared based on sex, Aβ positivity status, and APOE4carrier status within a composite region across the areas susceptible to aging. We used linear models and sparse canonical correlation analysis (SCCA) to examine the relationship between Ktransand AD biomarkers.ResultsOA showed greater BBBd than YA predominately in the temporal lobe, with some involvement of parietal, occipital and frontal lobes. Within an averaged ROI of affected regions, there was no difference in Ktransvalues based on sex or Aβ positivity, but OA who were APOE4carriers had significantly higher Ktransvalues. There was no direct relationship between averaged Ktransand global Aβ pathology, but there was a trend for an Aβ status by tau interaction on Ktransin this region. SCCA showed increased Ktranswas associated with increased PiB DVR, mainly in temporal and parietal brain regions. There was not a significant relationship between Ktransand FTP SUVR.DiscussionOur findings indicate that the BBB shows regional vulnerability during normal aging that overlaps considerably with the pattern of AD pathology. Greater BBBd in brain regions affected in aging is related to APOE genotype and may also be related to the pathological accumulation of Aβ.
NeuroMDAVIS: Visualization of single-cell multi-omics data under deep learning framework
Authors: Maitra Chayan , Seal Dibyendu B. , Das Vivek , De Rajat K. 
Published: February 2024

AbstractSingle-cell technologies have favoured extensive advancements in cell-type discovery, cell state identi-fication, development of lineage tracing and disease understanding among others. Further, single-cell multi-omics data generated using modern technologies provide several views of omics contribution for the same set of cells. However, dimension reduction and visualization of biological datasets (single or multi-omics) remain a challenging task since obtaining a low-dimensional embedding that preserves information about local and global structures in data, is difficult. Further, combining different views obtained from each omics layer to interpret the underlying biology is even more challenging. Earlier, we have developed NeuroDAVIS which can perform the task of visualization of high-dimensional datasets of a single modality while preserving cluster-structures within the data. Nevertheless, there is no model so far that supports joint visualization of multi-omics datasets. Joint visualization refers to transforming the feature space of each individual modality and combining them to produce a latent embedding that supports visualization of the multi-modal dataset in the newly transformed feature space. In this work, we introduce NeuroMDAVIS which is a generalized version of NeuroDAVIS for visualization of biological datasets having multiple modalities. To the best of our knowledge, NeuroMDAVIS is the first of its kind multi-modal data visualization model. It is able to learn both local and global relationships in the data while generating a low-dimensional embedding useful for downstream tasks. NeuroMDAVIS competes against state-of-the-art visualization models like t-Distributed Stochastic Neighbor Embedding (t-SNE), Uniform Manifold Approximation and Projection (UMAP), Fast interpolation-based t-SNE (Fit-SNE), and the Siamese network-based visualization method (IVIS).
Cingulate cortex shapes early postnatal development of social vocalizations
Authors: Nagarajan Gurueswar , Matrov Denis , Pearson Anna C. , Yen Cecil , Bradley Sean P. , Chudasama Yogita 
Published: February 2024

AbstractThe social dynamics of vocal behavior has major implications for social development in humans. We asked whether early life damage to the anterior cingulate cortex (ACC), which is closely associated with socioemotional regulation more broadly, impacts the normal development of vocal expression. The common marmoset provides a unique opportunity to study the developmental trajectory of vocal behavior, and to track the consequences of early brain damage on aspects of social vocalizations. We created ACC lesions in neonatal marmosets and compared their pattern of vocalization to that of age-matched controls throughout the first 6 weeks of life. We found that while early life ACC lesions had little influence on the production of vocal calls, developmental changes to the quality of social contact calls and their associated sequential and acoustic characteristics were compromised. These animals made fewer social contact calls, and when they did, they were short, loud and monotonic. We further determined that damage to ACC in infancy results in a permanent alteration in downstream brain areas known to be involved in social vocalizations, such as the amygdala and periaqueductal gray. Namely, in the adult, these structures exhibited diminished GABA-immunoreactivity relative to control animals, likely reflecting disruption of the normal inhibitory balance following ACC deafferentation. Together, these data indicate that the normal development of social vocal behavior depends on the ACC and its interaction with other areas in the vocal network during early life.
Alternative Macrophage Activation Requires Granulocyte-Derived Lipids
Authors: Veremeyko Tatyana , Vik Anders , Hansen Trond Vidar , Ponomarev Eugene D. 
Published: February 2024

AbstractLipid metabolism is important for alternative (M2) macrophage activation, but it remains unclear whether it is essential for this process, and the underlying mechanisms have yet to be determined. It is also unclear how the M2 phenotype is induced during the resolution of inflammation and tissue repair. We used large-scale RNA-sequencing and high-throughput lipidomics approaches to identify that during blood coagulation, granulocytes release certain lipids that are loaded onto high-density lipoproteins (HDLs), which then act via scavenger receptors SR-B1 and SR-B3 - to mediate the expression of 26 of 32 M2-associated genes and oxidative phosphorylation (OXPHOS) in macrophages. We found that in the absence of these lipids, interleukin-4 (IL-4) induced only 6 of 32 M2 markers, and this cytokine alone failed to induce OXPHOS. We also found that the HDL-associated C18:0, C18:2, and C20:3 fatty acids (FAs) were the lipids that most potently induced the M1-to-M2 transition. Furthermore, we determined that during IL-4-mediated inflammation, the inhibition of blood coagulation, or platelet and granulocyte depletion, results in a substantial decrease in M2 marker expression. Thus, this study identified that granulocyte-derived FAs mediate the reprogramming of macrophages towards the M2 phenotype, thereby bridging the processes of blood coagulation, inflammation, and repair.HighlightsActivation of macrophages with IL-4 or IL-13 requires indispensable cofactorThe cofactor consists of high-density lipoproteins (HDLs) complexed with lipidsDuring blood coagulation, granulocytes produce lipids that are loaded on HDLsHDL-associated fatty acids were the most potent lipids to induce M2 phenotypeGraphic Abstract
An axonal brake on striatal dopamine output by cholinergic interneurons
Authors: Zhang Yan-Feng , Luan Pengwei , Qiao Qinbo , He Yiran , Zatka-Haas Peter , Zhang Guofeng , Lin Michael Z. , Lak Armin , Jing Miao , Mann Edward O. , Cragg Stephanie J. 
Published: February 2024

SummaryDepolarisation of distal axons is necessary for neurons to translate somatic action potentials into neurotransmitter release. Studies have shown that striatal cholinergic interneurons (ChIs) can directly drive ectopic action potentials in dopamine (DA) axons and trigger DA release. However, here we show that this action occurs within a broader context of axonal signal integration whereby activation of ChIs and depolarisation of DA axons by nicotinic receptors (nAChRs) limits the subsequent depolarisation and release of DA in response to ensuing activity. We demonstrate that activation of ChIs and nAChRs inex vivomouse striatum, even when it does not trigger DA release that is detectable by fast-scan cyclic voltammetry, limits DA release for ∼100 ms by depressing subsequent axonal depolarisation and calcium summation. This axonal brake on DA release is stronger in dorsal than ventral striatum, and is unrelated to DA depletion.In vivo, antagonism of nAChRs in dorsal striatum elevated extracellular DA levels and promoted conditioned place-preference, underscoring its physiological relevance. Our findings reveal that under physiological conditionsin vivo,ChIs acting via nAChRs dynamically attenuate DA output driven by DA neuron activity, leading to a predominantly inverse relationship between ACh and DA signalling that varies continuously with ChI activity.