bluuebunny/crossref_metadata_2025_split huggingface dataset:
A bioactive soluble recombinant mouse LIGHT promotes effective tumor immune cell infiltration delaying tumor growth
Authors: del Rio Maria-Luisa , Roncador Giovanna , Cubria Juan Carlos , Schneider Pascal , Rodriguez-Barbosa Jose-Ignacio 
Published: July 2024

AbstractThe TNF family member LIGHT (TNFSF14) binds to two receptors, HVEM (TNFSFR14) and LTβR (TNFSFR3). HVEM functions as a costimulatory molecule, whereas LTβR is involved in the development of lymph nodes and ectopic tertiary lymphoid structures at chronic inflammation sites. The classical approach of fusing soluble recombinant proteins to the Fc fragment of IgG resulted in a functionally inactive Ig.mouse (m) LIGHT protein. However, in line with the fact that TNF family members cluster receptors as trimers, addition of a small homotrimeric domain (foldon) N-terminal of mLIGHT produced an active Ig.Foldon-mLIGHT protein able to bind and engage HVEM and LTβR in a reporter cell-based bioassay.In the tumor model of B16.F10 melanoma cells implanted into syngeneic recipients, cells transduced with membrane-bound mLIGHT grew as aggressively as mock-transduced cells, but growth of tumors of B16.F10 cells expressing Ig.Foldon-mLIGHT was delayed and characterized by significant immune cell infiltration.This work unveils the potential of active soluble LIGHT, as a single agent, to recruit cytotoxic cells and dendritic cells at the tumor site to inhibit tumor growth. This effect may be further enhanced with immune checkpoint blockade therapies.
Distinct adaptation and epidemiological success of different genotypes withinSalmonella entericaserovar Dublin
Authors: Sia Cheryll M , Ambrose Rebecca L , Valcanis Mary , Andersson Patiyan , Ballard Susan A , Howden Benjamin P , Williamson Deborah A , Pearson Jaclyn S , Ingle Danielle J 
Published: July 2024

ABSTRACTSalmonellaDublin is a host-adapted, invasive non-typhoidalSalmonella(iNTS) serovar that causes bloodstream infections in humans and demonstrates increasing prevalence of antimicrobial resistance (AMR). Using a global dataset of 1,303 genomes, coupled within vitroassays, we examined the evolutionary, resistance, and virulence characteristics ofS. Dublin. Our analysis revealed strong geographic associations between AMR profiles and plasmid types, with highly resistant isolates confined predominantly to North America, linked to IncC plasmids co-encoding AMR and heavy metal resistance. By contrast, Australian isolates were largely antimicrobial-susceptible, reflecting differing AMR pressures. We identified two phylogenetically distinct Australian lineages, ST10 and ST74, with a small number of ST10 isolates harbouring a novel hybrid plasmid encoding both AMR and mercuric resistance. Whereas the ST10 lineage remains globally dominant, the ST74 lineage was less prevalent. ST74 exhibited unique genomic features including a larger pan genome compared to ST10 and the absence of key virulence loci including SPI-19 which encodes a type VI secretion system (T6SS). Despite these genomic differences, the ST74 lineage displayed enhanced intracellular replication in human macrophages and induced less pro-inflammatory responses compared with ST10, suggesting alternative virulence strategies that may support systemic dissemination of ST74. The Vi antigen was absent in all ST10 and ST74 genomes, highlighting challenges for serotyping and vaccine development, and has implications for current diagnostic and control strategies forS.Dublin infections. Collectively, this study represents the most comprehensive investigation ofS. Dublin to date and importantly, has revealed distinct adaptations of two genotypes within the same serovar, leading to different epidemiological success. The regional emergence and evolution of distinctS.Dublin lineages highlights the need to understand the divergence of intra-serovar virulence mechanisms which may impact the development of effective control measures against this important global pathogen.
Wild-type bone marrow cells repopulate tissue resident macrophages and reverse the impacts of homozygous CSF1R mutation
Authors: Carter-Cusack Dylan , Huang Stephen , Keshvari Sahar , Patkar Omkar , Sehgal Anuj , Allavena Rachel , Byrne Robert , Morgan Paul , Bush Stephen J. , Summers Kim M. , Irvine Katharine M. , Hume David A. 
Published: July 2024

AbstractAdaptation to existence outside the womb is a key event in the life of a mammal. The absence of macrophages in rats with a homozygous mutation in theCsf1rgene (Csf1rko) severely compromises pre-weaning somatic growth and maturation of organ function. Transfer of wild-type bone marrow cells (BMT) at weaning rescues tissue macrophage populations permitting normal development and long-term survival. To dissect the phenotype and function of macrophages in postnatal development, we generated transcriptomic profiles of all major organs of wild-type andCsf1rkorats at weaning and selected organs following rescue by BMT. The transcriptomic profiles revealed subtle effects of macrophage deficiency on development of all major organs. Network analysis revealed a common signature of CSF1R-dependent resident tissue macrophages that includes the components of complement C1Q (C1qa/b/cgenes). Circulating C1Q was almost undetectable inCsf1rkorats and rapidly restored to normal levels following BMT. Tissue-specific macrophage signatures were also identified, notably including sinus macrophage populations in the lymph nodes. Their loss inCsf1rkorats was confirmed by immunohistochemical localisation of CD209B (SIGNR1). By 6-12 weeks,Csf1rkorats succumb to emphysema-like pathology associated with the selective loss of interstitial macrophages and granulocytosis. This pathology was reversed by BMT. Along with physiological rescue, BMT precisely regenerated the abundance and expression profiles of resident macrophages. The exception was the brain, where BM-derived microglia-like cells had a distinct expression profile compared to resident microglia. In addition, the transferred BM failed to restore blood monocyte or CSF1R-positive bone marrow progenitors. These studies provide a model for the pathology and treatment of CSF1R mutations in humans and the innate immune deficiency associated with prematurity.
Unraveling cysteine deficiency-associated rapid weight loss
Authors: Varghese Alan , Gusarov Ivan , Gamallo-Lana Begña , Dolgonos Daria , Mankan Yatin , Shamovsky Ilya , Phan Mydia , Jones Rebecca , Gomez-Jenkins Maria , White Eileen , Wang Rui , Jones Drew , Papagiannakopoulos Thales , Pacold Michael E. , Mar Adam C , Littman Dan R , Nudler Evgeny 
Published: July 2024

AbstractForty percent of the US population and 1 in 6 individuals worldwide are obese, and the incidence of this disease is surging globally1,2. Various dietary interventions, including carbohydrate and fat restriction, and more recently amino acid restriction, have been explored to combat this epidemic3–6. We sought to investigate the impact of removing individual amino acids on the weight profiles of mice. Compared to essential amino acid restriction, induction of conditional cysteine restriction resulted in the most dramatic weight loss, amounting to 20% within 3 days and 30% within one week, which was readily reversed. This weight loss occurred despite the presence of substantial cysteine reserves stored in glutathione (GSH) across various tissues7. Further analysis demonstrated that the weight reduction primarily stemmed from an increase in the utilization of fat mass, while locomotion, circadian rhythm and histological appearance of multiple other tissues remained largely unaffected. Cysteine deficiency activated the integrated stress response (ISR) and NRF2-mediated oxidative stress response (OSR), which amplify each other, leading to the induction of GDF15 and FGF21, hormones associated with increased lipolysis, energy homeostasis and food aversion8–10. We additionally observed rapid tissue coenzyme A (CoA) depletion, resulting in energetically inefficient anaerobic glycolysis and TCA cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen rich compounds and amino acids. In summary, our investigation highlights that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism, and stress signaling compared to other amino acid restrictions. These findings may pave the way for innovative strategies for addressing a range of metabolic diseases and the growing obesity crisis.
Intraperitoneal programming of tailored CAR macrophages via mRNA-LNP to boost cancer immunotherapy
Authors: Gu Kedan , Liang Ting , Hu Luting , Zhao Yifan , Ying Weiyang , Zhang Mengke , Chen Yashuang , Liang Benmeng , Lin Xinrui , Zhang Yanqi , Wu Hongyu , Wang Meng , Zhu Yuping , Wang Wenxi , Zhang Yu , Zuo Chao , Du Zhen , Zhang Penghui , Song Jia , Liu Xiangsheng , Xie Sitao , Tan Weihong 
Published: July 2024

ABSTRACTTherapeutic strategies for peritoneal metastasis in solid tumors are urgently needed in the clinic. Programming chimeric antigen receptor macrophages (CAR-Ms)in situoffers opportunities for an unmet demand. However, potential intracellular domains (ICDs) for CAR design and their antitumor mechanisms for macrophage empowerment remain to be explored systematically. By developing a targeted mRNA-LNP delivery system for macrophages, we have investigated 36 CAR combinations to determine the impact of CAR-Ms on immune regulationin vitroandin vivo. In two solid tumor mouse models, intraperitoneal programming of CAR-Ms was shown to elicit robust adaptive immune activation and significantly synergize with PD-1/L1 therapy. Single-cell RNA sequencing (scRNA-seq) analysis revealed that CAR-Ms could reshape the immunosuppressive tumor microenvironment (TME) and boost the TCF1+PD-1+progenitor- exhausted CD8+T cells (Tpex) population. Meanwhile, we found that tailored CAR-M with CD3ζ/TLR4 ICDs could favorably maintain proinflammatory phenotype and simultaneously upregulate MHC I and PD-L1 expression by perturbing NF-κB pathways. Moreover, the synergism between macrophage PD-L1 knockdown and CAR-M therapy highlighted the need to block the PD-1/L1 axis in antigen cross-presentation. In short, we developed an mRNA-LNP delivery system for intraperitoneal programming of tailored CAR-Msin vivoand broadened understanding of both regulatory and feedback mechanisms for CAR-M therapies against solid tumors.
Extending the capabilities of deconvolution to provide cell type specific pathway analysis of bulk RNA-seq data for idiopathic pulmonary fibrosis
Authors: Calvero Mifflin-Rae , Meghadri Sri Harsha , Carleo Alfonso , Prasse Antje , DeLuca David S. 
Published: July 2024

AbstractMotivationTranscriptome data are confounded by differences in cell type proportions. Differentiating between regulated changes in gene expression and changes due to differing cell type proportions remains a challenge. Therefore, we apply a deconvolution method to correct for changes in cell type proportions and provide a novel cell-type specific pathway analysis.ResultsWe demonstrate the technique in the context of idiopathic pulmonary fibrosis. Inferred cell type proportions indicated a significant increase in fibroblasts, myofibroblasts, and a decrease in vascular endothelial capillary cells. Pathway analysis after adjustment for proportions indicated IPF-related changes in extracellular matrix organization and TGF-β regulation. Cell-type specific pathway analysis suggested the role of interferon signaling in ATII cells. These results demonstrate that deconvolution is not only useful for assessing cell type proportions, but also can provide cell type-specific pathway analysis, allowing for a much more nuanced interpretation of bulk RNA-seq data.
Regulatory T-cells in multiple sclerosis are activated by Epstein-Barr Virus and produce IL-10 in the central nervous system
Authors: Pulvirenti N. , Righetti C. , Clemente F. , Serafini B. , Pietroboni A. , Galeota E. , Rosicarelli B. , Cordiglieri C. , Iannone C. , de Riz M. , Vasco C. , Espadas de Arias A. , De Feo T. , Valenti L. , Prati D. , Abrignani S. , Gerosa M. , Caporali R. , Galimberti D. , Scarpini E. , Geginat J. 
Published: July 2024

AbstractRegulatory T-cells (Tregs) maintain immune homeostasis, but antigens activating adaptive Tregs in human pathologies are ill-defined. EOMES+type-1 regulatory (EOMES+Tr1-like) T-cells had a dysregulated homeostasis in multiple sclerosis (MS), which was related to their activation in the central nervous system (CNS). EOMES+Tr1-like cells were strongly enriched in patient’s cerebrospinal fluid (CSF) and were the main IL-10-producing T-cells in the CSF. IL-10+EOMES+Tr1-like were present in MS brain lesions, and some were found close to Epstein-Barr Virus (EBV)-infected B-cells. EOMES+Tr1-like cells and FOXP3+Tregs produced IL-10 with EBV-derived antigens, but not with major myelin antigens. EOMES+Tr1-like cells responded selectively to the latency-associated antigen EBNA1, whereas FOXP3+Tregs responded also to lytic antigens. EBNA1-specific EOMES+Tr1-like cells were associated with anti-EBNA1 IgG, disappeared upon therapeutic B-cell depletion and were relatively abundant in patients with the HLA-DRB1*15 risk haplotype. The aberrant anti-viral specificities of Tregs in MS could undermine their protective functions and anti-EBV immune surveillance.
Structural Basis of βKNL2 Centromeric Targeting Mechanism and Its Role in Plant-Specific Kinetochore Assembly
Authors: Yadala Ramakrishna , Camara Amanda S , Yalagapati Surya P , Jaroschinsky Pascal , Meitzel Tobias , Ariyoshi Mariko , Fukagawa Tatsuo , Rutten Twan , Bui Thu-Giang T , Lermontova Inna 
Published: July 2024

AbstractThe kinetochore is an essential protein complex that ensures proper chromosome segregation during cell division. Kinetochore assembly is initiated by the incorporation of CENP-A/CENH3. This process depends on KNL2/M18BP1 and CENP-C proteins. In plants, two variants of KNL2, αKNL2 and βKNL2, are present. Both possess the conserved SANTA domain, while αKNL2 additionally has the centromere-targeting CENPC-k motif. Despite lacking the CENPC-like motif, the plant-specific βKNL2 localizes to centromeres and aids in CENP-A/CENH3 loading. We found that efficient centromeric targeting of βKNL2 requires the SANTA domain and the C-terminal part, while nuclear targeting depends on a conserved C-terminal motif-III. Structural predictions and experimental validations reveal that βKNL2 forms homodimers and interacts with centromeric DNA and αKNL2. We confirm that centromeric targeting of βKNL2 depends on αKNL2 in a tissue-dependent manner. Our findings provide crucial insights into the unique mechanisms of plant-specific kinetochore assembly, highlighting βKNL2’s essential role in this process.Graphical abstract
The representational nature of spatio-temporal recurrent processing in visual object recognition
Authors: Xie Siying , Singer Johannes , Yilmaz Bati , Kaiser Daniel , Cichy Radoslaw M. 
Published: July 2024

SummaryThe human brain orchestrates object vision through an interplay of feedforward processing in concert with recurrent processing. However, where, when and how recurrent processing contributes to visual processing is incompletely understood due to the difficulties in teasing apart feedforward and recurrent processing. We combined a backward masking paradigm with multivariate analysis on EEG and fMRI data to isolate and characterize the nature of recurrent processing. We find that recurrent processing substantially shapes visual representations across the ventral visual stream, starting early on at around 100ms in early visual cortex (EVC) and in two later phases of around 175 and 300ms in lateral occipital cortex (LOC), adding persistent rather than transient neural dynamics to visual processing. Using deep neural network models for comparison with the brain, we show that recurrence changes the feature format in LOC from predominantly mid-level to more high-level features. Finally, we show that recurrence is mediated by four distinct spectro-temporal neural components in EVC and LOC, which span the theta to beta frequency range. Together, our results reveal the nature and mechanisms of the effects of recurrent processing on the visual representations in the human brain.
Second impact of an acute total body irradiation on thymic epithelial cells
Authors: Namiki Kano , Muramatsu Wataru , Miyao Takahisa , Ishii Hiroto , Endo Rin , Hagiwara Naho , Miyauchi Maki , Yoshida Masaki , Akiyama Nobuko , Akiyama Taishin 
Published: July 2024

AbstractThe thymus, a crucial organ for T cell development, undergoes transient involution following exposure to sublethal total body irradiation. The impact of sublethal irradiation on the thymus is reportedly bimodal: thymic involution recurs after the recovery of the thymus from the initial impact of acute sublethal irradiation. While the second impact of acute irradiation has been acknowledged for thymocytes, its influence on thymic epithelial cells (TECs), which are crucial for thymic T cell differentiation and selection, remains to be elucidated. In this study, we aim to elucidate this influence. Mice were subjected to acute sublethal total body irradiation, and TECs were evaluated at three distinct time points: during the initial impact, during the recovery phase post-initial impact, and during the second impact phase. Flow cytometry analysis revealed that during the second impact phase, mTECs were reduced, whereas cTECs remained unaffected. Among mTECs, the subset expressing high levels of the co-stimulatory molecule CD80 (mTEChi) experienced the most pronounced reduction. RNA sequencing analysis of mTEChicells at early differentiation stages revealed significant alterations in gene expression profiles during the second impact phase. Notably, gene signatures of tuft-like TECs and Aire-expressing TECs were preferentially influenced in these mTEChisubpopulations. These findings suggest that acute total body irradiation disrupts mTEC frequencies and gene expression in a bimodal manner, possibly compromising thymic functions over extended periods.
Derivation of aerial insect concentration with a 94GHz FMCW cloud radar
Authors: Lochmann Moritz , Kalesse-Los Heike , Haest Birgen , Vogl Teresa , van Klink Roel , Addison Freya , Maahn Maximilian , Schimmel Willi , Wirth Christian , Quaas Johannes 
Published: July 2024

AbstractAerial insects are vital for nature and society. Though methods to observe flying insects have consistently improved in the last decades, insects remain difficult to monitor systematically and consistently over large spatial and temporal scales. Remote sensing with radars has proved to be one of the more effective tools for observation. However, as radars are most sensitive to targets similar in size to the radar wavelength, the detectable sub-group of aerial insects of a certain size range depends on the employed radar. Here, we present a novel method based on data of a zenith-pointing W-band (94 GHz,λ= 0.32 cm) Doppler cloud radar to estimate insect concentration in a vertical profile. Multiple meteorological state-of-the-art algorithms are combined to extract insect signals from the radar data and quantify their abundance from 50 m to 1000 m above the ground. For evaluation, this method is applied to Doppler cloud radar data from a summertime 30 day observation period in central Germany. Results are compared to data from an X-band (9.4 GHz,λ= 3.2 cm) radar in the same region. Aerial insect concentration derived from the W-band radar, which is sensitive to insects in the mm size range, is substantially higher than from the X-band radar, detecting insects in the cm size range. In addition, diel flight timings vary between the different sub-groups of aerial insects observed by the two radar instruments. With its superior sensitivity to smaller insects like aphids, the proposed methodology complements existing entomological radar techniques and contributes to achieving a more complete description of aerial insect activity.
Aging and Germination of Long-term Stored Seeds: Can MicroRNAs Unlock the Secrets?
Authors: Puchta-Jasińska Marta , Bolc Paulina , Groszyk Jolanta , Boczkowska Maja 
Published: July 2024

AbstractBackgroundSmall non-coding RNAs appear to be one of the key components of the germination process. To investigate how small non-coding RNAs correlate with germination of seeds with different levels of viability, miRNA-Seq analyses were performed.ResultsOur analysis sequencing identified 62 known miRNAs from 11 families and 234 new miRNAs after imbibition process. Among the miRNAs with the highest expression levels, we can mention: miR159, miR168 and miR166. The study placed particular emphasis on miRNAs with significant differences in expression levels at different stages of imbibition and among seeds with different viability. DEG analysis identified 28 miRNAs with significant differences in expression levels, their function was assessed byin silicoanalyses and confirmed by degradome-seq analysis. The expression of miRNAs was verified by qRT-PCR.ConclusionOur data provides a useful source of information on miRNA during germination long term storage seeds with different viability. The studies suggest that miRNAs are involved in the germination process by their regulation DNA and RNA binding, regulation of developmental process and ribosome.
Sequence and structural analysis of adaptors of Toll-like receptor 4 sheds light on the evolutionary trajectory and functional emergence
Authors: Verma Shailya , Sowdhamini Ramanathan 
Published: July 2024

1.AbstractType 4 Toll-like receptors 4 (TLR4) recognise lipopolysaccharides (LPS) from bacteria as their conventional ligands and undergo downstream signalling to produce cytokines. They mediate the signalling either by the TIRAP-MyD88 complex or by the TRAM-TRIF complex. The MyD88 pathway is common to all other TLRs, whereas the TRAM-TRIF complex is largely exclusive to TLR4. We studied the TIR domain of TRAM and TRIF homologue proteins, that are crucial for downstream signalling. From our previous work on pan-genome-wide survey, we findCallorhincus millito be the ancestral organism with both TRAM and TRIF proteins. To gain a deeper insight about the functioning of these proteins and comparison with the adaptor proteins inHomo sapiens, we performed TRAM and TRIF dimer docking to model the TRAM-TRIF complex of representative organisms across various taxa. These provide us insights to ascertain a possible interaction surface, calculate the energetics, electrostatic potential, and then employ Normal Mode Analysis (NMA) to examine fluctuating, interacting and specific residue clusters which can be important for the protein functioning in both organisms. We also performed molecular dynamics simulations of these complexes and cross validated the functionally important residues using network parameters. While the critical residues of TIRAP, TRIF, and MyD88 were preserved, we found that the important residues of TRAM signalling were not conserved inCallorhincus milli. This suggests the presence of functional TIRAP-MyD88 mediated TLR4 signalling and TRIF mediated TLR3 signalling in the ancestral species. The overall biological function of this signalling domain appears to be gradually acquired through the orchestration of several motifs through evolutionary scale.