bluuebunny/crossref_metadata_2025_split huggingface dataset:
Capitella teletagets left out: Possible evolutionary shift causes loss of left tissues rather than increased neural tissue from dominant-negative BMPR1
Authors: Webster Nicole B. , Meyer Néva P. 
Published: October 2023

AbstractBackgroundThe evolution of centralized nervous systems (CNSs) a fascinating and complex topic; further work is needed to understand the genetic and developmental homology between organisms with a CNS. Research into a limited number of species suggests that CNSs may be homologous across Bilateria. This hypothesis is based in part on similar functions of BMP signaling in establishing fates along the dorsal-ventral (D-V) axis including limiting neural specification to one region of ectoderm. From an evolutionary-developmental perspective, the best way to understand a system is to explore it in a wide range of organisms to create a full picture.MethodsHere we expand our understanding of BMP signaling in Spiralia, the third major clade of bilaterians, by examining phenotypes after expression of a dominant-negative BMP Receptor 1 and after knock-out of the putative BMP antagonist Chordin-like using CRISPR/Cas9 gene editing in the annelidCapitella teleta(Pleistoannelida).ResultsEctopic expression of the dominant-negative Cte-BMPR1 did not increase CNS tissue or alter overall D-V axis formation in the trunk. Instead, we observed a unique asymmetric phenotype: a distinct loss of left tissues including the left eye, brain, foregut, and trunk mesoderm. Adding ectopic BMP4 early during cleavage stages reversed the dominant-negative Cte-BMPR1 phenotype, leading to a similar loss or reduction of right tissues instead. Surprisingly, a similar asymmetric loss of left tissues was evident from CRISPR knock-out ofCte-Chordin-likebut concentrated in the trunk rather than the episphere.ConclusionsWe further solidify the hypothesis that the function of BMP signaling during establishment of the D-V axis and CNS is fundamentally different in at least Pleistoannelida, possibly in Spiralia, and is not required for nervous system delimitation in this group. Our results support hypotheses of either multiple evolutionary origins of CNSs across Bilateria or divergence in the molecular mechanisms of CNS specification and D-V axis formation in annelids.
mRNA vaccines encoding membrane-anchored receptor-binding domains of SARS-CoV-2 mutants induce strong humoral responses and can overcome immune imprinting
Authors: Al-Wassiti Hareth A. , Fabb Stewart A. , Grimley Samantha L. , Kochappan Ruby , Ho Joan K. , Wong Chinn Yi , Tan Chee Wah , Payne Thomas J. , Takanashi Asuka , Sicilia Horatio , Teo Serena L.Y. , McAuley Julie , Ellenberg Paula , Cooney James P , Davidson Kathryn C. , Bowen Richard , Pellegrini Marc , Rockman Steven , Godfrey Dale I. , Nolan Terry M. , Wang Lin-fa , Deliyannis Georgia , Purcell Damian F.J. , Pouton Colin W. 
Published: October 2023

AbstractTo address the limitations of whole-spike COVID vaccines, we explored mRNA vaccines encoding membrane-anchored receptor-binding domain (RBD-TMs), each a fusion of a variant RBD, the transmembrane (TM) and cytoplasmic tail (CT) fragments of the SARS-CoV-2 spike protein. In naive mice, RBD-TM mRNA vaccines against ancestral SARS-CoV-2, Beta, Delta, Delta-plus, Kappa, Omicron BA.1 or BA.5, all induced strong humoral responses against the target RBD. Multiplex surrogate viral neutralization (sVNT) assays indicated broad neutralizing activity against a range of variant RBDs. In the setting of a heterologous boost, against the background of exposure to ancestral whole spike vaccines, sVNT studies suggested that RBD-TM vaccines were able to overcome the detrimental effects of immune imprinting. Omicron BA.1 and BA.5 RBD-TM booster vaccines induced serum antibodies with 12 and 22-fold higher neutralizing activity against the target RBD than their equivalent whole spike variants. Boosting with BA.1 or BA.5 RBD-TM provided good protection against more recent variants including XBB and XBB.1.5. Each RBD-TM mRNA is 28% of the length of its whole-spike equivalent. This advantage will enable tetravalent mRNA vaccines to be developed at well-tolerated doses of formulated mRNA.One Sentence SummarymRNA vaccines encoding membrane-anchored RBDs of SARS-CoV-2 mutants are effective vaccines that can overcome immune imprinting in mice
Innate immune memory after brain injury drives inflammatory cardiac dysfunction
Authors: Simats A , Zhang S , Messerer D , Cao J , Chong F , Besson-Girard S , Carofiglio O , Filser S , Plesnila N , Braun C , Gökce Ö , Dichgans M , Hatakeyama K , Bonev B , Beltrán E , Schulz C , Liesz A 
Published: October 2023

AbstractThe enormous medical burden of stroke is not only due to the brain injury itself and the acute systemic effects, but is largely determined by chronic comorbidities that develop secondarily after stroke. We hypothesized that the high rate of comorbidity developing after a stroke might have a shared immunological cause, however, the chronic effects of brain injury on systemic immunity have so far been barely investigated. Here, we identified myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Using single-cell sequencing, we identified persistent pro-inflammatory transcriptomic changes in resident monocytes/macrophages in multiple organs one month after experimental ischemic brain injury, which was particularly abundant in the heart and associated with the development of cardiac fibrosis and diastolic dysfunction. A similar phenotype was seen in myocardial autopsy samples from stroke versus control patients. We observed chronic functional changes in myeloid hematopoiesis driven by post-stroke IL-1β-mediated epigenetic changes. These alterations could be transplanted to naïve recipient mice and were sufficient to induce cardiac dysfunction. By effectively blocking the trafficking of pro-inflammatory monocytes from the bone marrow to the heart using a dual CCR2/5 inhibitor, we successfully prevented post-stroke cardiac dysfunction. This approach holds promising potential as a novel immune-targeted secondary prevention therapy. We anticipate that the epigenetic immune reprogramming mechanisms detailed here for the brain-heart axis could be generalized to provide a novel framework for explaining the development of various comorbidities after acute tissue injury in remote organs.
Juxtacrine DLL4-NOTCH1 signaling between astrocytes drives neuroinflammation via the IL-6-STAT3 axis
Authors: Mora Pierre , Laisné Margaux , Bourguignon Célia , Rouault Paul , Gadeau Alain-Pierre , Renault Marie-Ange , Horng Sam , Couffinhal Thierry , Chapouly Candice 
Published: October 2023

AbstractUnder neuroinflammatory conditions, astrocytes acquire a reactive phenotype that drives acute inflammatory injury as well as chronic neurodegeneration. We hypothesized that astrocytic DLL4 may interact with its receptor NOTCH1 on neighboring astrocytes to regulate astrogliosis via downstream juxtacrine signaling pathways. Here we investigated the role of astrocytic DLL4 on neurovascular unit homeostasis under neuroinflammatory conditions. We probed for downstream effectors of the DLL4-NOTCH1 axis and targeted these for therapy in two models of CNS inflammatory disease. We first demonstrated that astrocytic DLL4 is upregulated during neuroinflammation, both in mice and humans, driving astrogliosis and subsequent blood brain barrier permeability and inflammatory infiltration. We then showed that the DLL4-mediated NOTCH1 signaling in astrocytes directly drives IL-6 levels, induces STAT3 phosphorylation promoting upregulation of astrocyte reactivity markers, pro-permeability factor secretion and consequent blood brain barrier destabilization. Finally we revealed that blocking DLL4 with antibodies improves experimental autoimmune encephalomyelitis symptoms in mice, identifying a potential novel therapeutic strategy for CNS autoimmune demyelinating disease. As a general conclusion, this study demonstrates that DLL4-NOTCH1 signaling is not only a key pathway in vascular development and angiogenesis, but also in the control of astrogliosis during neuroinflammation.
β-catenin inhibition disrupts the homeostasis of osteogenic/adipogenic differentiation leading to the development of glucocorticoid-induced osteonecrosis of femoral head
Authors: Xia Chenjie , Xu Huihui , Fang Liang , Chen Jiali , Yuan Wenhua , Fu Danqing , Wang Xucheng , He Bangjian , Xiao Luwei , Wu Chengliang , Tong Peijian , Chen Di , Wang Pinger , Jin Hongting 
Published: October 2023

AbstractGlucocorticoid-induced osteonecrosis of the femoral head (GONFH) is a common refractory joint disease characterized by bone damage and the collapse of femoral head structure. However, the exact pathological mechanisms of GONFH remain unknown. Here, we observed abnormal osteogenesis and adipogenesis associated with decreased β-catenin in the necrotic femoral head of GONFH patients. In vivo and in vitro studies further revealed that glucocorticoid exposure disrupted osteogenic/adipogenic differentiation of bone marrow mesenchymal cells (BMSCs) by inhibiting β-catenin signaling in glucocorticoid-induced GONFH rats. Col2+lineage largely contributes to BMSCs, and was found an osteogenic commitment in the femoral head through 9 months of lineage trace. Specific deletion ofβ-cateninin Col2+cells shifted their commitment from osteoblasts to adipocytes, leading to a full spectrum of disease phenotype of GONFH in adult mice. Overall, we uncover that β-catenin inhibition disrupting the homeostasis of osteogenic/adipogenic differentiation contributes to the development of GONFH, and identify an ideal genetic modified mouse model of GONFH.
Chemokine profiling of melanoma-macrophage crosstalk identifies CCL8 and CCL15 as prognostic factors in cutaneous melanoma
Authors: Barrio-Alonso Celia , Nieto-Valle Alicia , García-Martínez Elena , Gutiérrez-Seijo Alba , Parra-Blanco Verónica , Márquez-Rodas Iván , Avilés-Izquierdo José Antonio , Sánchez-Mateos Paloma , Samaniego Rafael 
Published: October 2023

AbstractDuring cancer evolution, tumor cells attract and dynamically interact with monocytes/macrophages. To find biomarkers of disease progression in human melanoma, we used unbiased RNA sequencing and secretome analyses of tumor-macrophage co-cultures. Pathway analysis of genes differentially modulated in human macrophages exposed to melanoma cells revealed a general upregulation of inflammatory hallmark gene sets, particularly chemokines. A selective group of chemokines, including CCL20, CCL15 and CCL8, was actively secreted upon melanoma-macrophage co-culture. Because we previously described the role of CCL20 in melanoma, we focused our study in CCL8 and CCL15, and confirmed that in vitro both chemokines contributed to melanoma survival, proliferation and 3D invasion, through CCR1 signaling. In vivo, both chemokines enhanced primary tumor growth, spontaneous lung metastasis and circulating tumor cell (CTC) survival and lung colonization in mouse xenograft models. Finally, we explored the clinical significance of CCL8 and CCL15 expression in human skin melanoma, screening a collection of 67 primary melanoma samples, by multicolor staining and quantitative image analysis of chemokine-chemokine receptor content at the single cell level. Primary skin melanomas displayed high CCR1 expression, but there was no difference in its level of expression between metastatic and non-metastatic cases. By contrast, the comparative analysis between these two clinically divergent groups showed a highly significant difference in the cancer cell content of CCL8 (P= 0.025) and CCL15 (P< 0.0001). Kaplan–Meier curves showed that high content of CCL8 or CCL15 in cancer cells correlated with shorter disease-free and overall survival (log-rank test, p< 0.001). Our results highlight the role of CCL8 and CCL15, which are highly induced by melanoma-macrophage interactions in biologically aggressive primary melanomas, and could be clinically applicable biomarkers for patient profiling.
Decoding the physics of observed actions in the human brain
Authors: Wurm Moritz F. , Erigüç Doruk Yiğit 
Published: October 2023

AbstractRecognizing goal-directed actions is a computationally challenging task, requiring not only the visual analysis of body movements, but also analysis of how these movements causally impact, and thereby induce a change in, those objects targeted by an action. We tested the hypothesis that the analysis of body movements and the effects they induce relies on distinct neural representations in superior and anterior inferior parietal lobe (SPL and aIPL). In four fMRI sessions, participants observed videos of actions (e.g. breaking stick, squashing plastic bottle) along with corresponding point-light-display stick figures, pantomimes, and abstract animations of agent-object interactions (e.g. dividing or compressing a circle). Cross-decoding between actions and animations revealed that aIPL encodes abstract representations of action effect structures independent of motion and object identity. By contrast, cross-decoding between actions and point-light-displays revealed that SPL is disproportionally tuned to body movements independent of visible interactions with objects. Lateral occipitotemporal cortex (LOTC) was sensitive to both action effects and body movements. Moreover, cross-decoding between pantomimes and animations suggests that right aIPL and LOTC represent action effects even in response to implied object interactions. These results demonstrate that parietal cortex and LOTC are tuned to physical action features, such as how body parts move in space relative to each other and how body parts interact with objects to induce a change (e.g. in position or shape/configuration). The high level of abstraction revealed by cross-decoding suggests a general neural code supporting mechanical reasoning about how entities interact with, and have effects on, each other.
Multimodal single-cell profiling of T cell specificity and reactivity in lung cancer
Authors: Bieberich Florian , Vazquez-Lombardi Rodrigo , Jin Huixin , Hong Kai-Lin , Herzig Petra , Trefny Marcel , Trüb Marta , Läubli Heinz , Lardinois Didier , Mertz Kirsten , Matter Matthias S. , Zippelius Alfred , Reddy Sai T. 
Published: October 2023

SUMMARYAdoptive transfer of autologous tumor-infiltrating lymphocyte T cells (TILs) offers one of the most promising approaches for cancer immunotherapy. However, high variability in patient responses highlight the need for an enhanced understanding of the transcriptional phenotypes of TILs and reactivity of their T cell receptors (TCR). Here, we employ single-cell multiomics approaches and TCR functional screening to investigate TILs from treatment-naive non-small cell lung cancer patients. This comprehensive analysis integrates scRNA-seq, scTCR-seq, and scATAC-seq, enabling a high-resolution examination of TILs within lung cancer tissue, as well as the adjacent non-tumor tissue. We apply a cellular functional screening platform to identify reactive TCRs that represent >1,000 TILs and have specificity towards a multitude of targets, including primary tumor cells, neoantigens, tumor-associated antigens, and viral antigens. Tumor-reactive TILs were primarily associated with dysfunctional phenotypes, whereas viral antigen-reactive TCRs were found in effector phenotype clusters. Key marker genes were identified and used to construct a tumor or viral reactivity score. Comparing clones shared in tumor and non-tumor tissue, a higher fraction of exhausted cells was observed in the tumor tissue, whereas non-tumor adjacent tissue possessed more effector cells, thus providing insight into potential sources for therapeutic T cells. Elucidating the specific T cell populations within TILs and their associated TCRs may support strategies to enhance the efficacy of TIL-based therapies.Graphical AbstractMultimodal single cell profiling and reactivity testing of TILs(A) CD8+T cells of treatment naive non-small cell lung cancer patients and adjacent lung tissue were isolated by fluorescence-activated cell sorting (FACS) and were then subjected to scRNA-seq + scTCR-seq or scATAC-seq. (B) TCRs were functionally screened using a cellular platform (TnT cells) and target cells (tumor cells, antigen-pulsed antigen-presenting cells, PBMCs) by flow cytometry and deep sequencing. (C) scRNA-seq + scATAC-seq allowed trajectory inference of transcription factors and genes along pseudotime. (D) Gene scores for tumor- and virus-reactivity were developed by combining functional reactivity and transcriptomic profiling for each CD8+T cell. (E) TIL scRNA-seq pre and post IL-2 treatment in tumor suspension displayed as alluvial plot shows change of clonal cell state composition.
JAK/STAT mediated insulin resistance in muscles is essential for effective immune response
Authors: McMullen Ellen , Strych Lukas , Chodáková Lenka , Krebs Amber , Dolezal Tomas 
Published: October 2023

AbstractThe metabolically demanding nature of immune response requires nutrients to be preferentially directed towards the immune system at the expense of peripheral tissues. We study the mechanisms by which this metabolic reprograming occurs using the parasitoid infection ofDrosophilalarvae. To overcome such an immune challenge hemocytes differentiate into lamellocytes, which encapsulate and melanize the parasitoid egg. Hemocytes acquire the energy for this process by expressing JAK/STAT ligands upd2 and upd3, which activates JAK/STAT signaling in muscles and redirects carbohydrates away from muscles in favor of immune cells. Absence of upd/JAK/STAT signaling leads to an impaired immune response and increased mortality. We demonstrate how JAK/STAT signaling in muscles leads to suppression of insulin signaling through activation of ImpL2, the inhibitor of Drosophila insulin like peptides. We reveal the crucial function of muscles during immune response and show the benefits of insulin resistance as an adaptive mechanism that is necessary for survival.
Employing a honeybee olfactory neural circuit as a novel gas sensor for the detection of human lung cancer biomarkers
Authors: Parnas Michael , Cox Elyssa , Sanchez Simon , Farnum Alexander , Lefevre Noël , Miller Sydney , Saha Debajit 
Published: October 2023

AbstractHuman breath contains biomarkers (odorants) that can be targeted for early disease detection. It is well known that honeybees have a keen sense of smell and can detect a wide variety of odors at low concentrations. Here, for the first time, we employ honeybee olfactory neuronal circuitry to classify human lung cancer volatile biomarkers and their mixtures at concentration ranges relevant to human breath, parts-per-billion to parts-per-trillion. Different lung cancer biomarkers evoked distinct spiking response dynamics in the honeybee antennal lobe neurons indicating that those neurons encoded biomarker-specific information. By investigating lung cancer biomarker-evoked population neuronal responses from the honeybee antennal lobe, we could classify individual human lung cancer biomarkers successfully (88% success rate). When we mixed six lung cancer biomarkers at different concentrations to create ‘synthetic lung cancer’ vs. ‘synthetic healthy breath’, honeybee population neuronal responses were also able to classify those complex breath mixtures successfully (100% success rate with a leave-one-trial-out method). Finally, we used separate training and testing datasets containing responses to the synthetic lung cancer and healthy breath mixtures. We identified a simple metric, the peak response of the neuronal ensemble, with the ability to distinguish synthetic lung cancer breath from the healthy breath with 86.7% success rate. This study provides proof-of-concept results that a powerful biological gas sensor, the honeybee olfactory system, can be used to detect human lung cancer biomarkers and their complex mixtures at biological concentrations.
Harnessing Landrace Diversity Empowers Wheat Breeding for Climate Resilience
Authors: Cheng Shifeng , Feng Cong , Wingen Luzie U. , Cheng Hong , Riche Andrew B. , Jiang Mei , Leverington-Waite Michelle , Huang Zejian , Collier Sarah , Orford Simon , Wang Xiaoming , Awal Rajani , Barker Gary , O’Hara Tom , Lister Clare , Siluveru Ajay , Quiroz-Chávez Jesús , Ramírez-González Ricardo H. , Bryant Ruth , Berry Simon , Bansal Urmil , Bariana Harbans S. , Bennett Malcolm J. , Bicego Breno , Bilham Lorelei , Brown James K.M. , Burridge Amanda , Burt Chris , Buurman Milika , Castle March , Chartrain Laetitia , Chen Baizhi , Denbel Worku , Elkot Ahmed F. , Fenwick Paul , Feuerhelm David , Foulkes John , Gaju Oorbessy , Gauley Adam , Gaurav Kumar , Hafeez Amber N. , Han Ruirui , Horler Richard , Hou Junliang , Iqbal Muhammad S. , Kerton Matthew , Kondic-Spica Ankica , Kowalski Ania , Lage Jacob , Li Xiaolong , Liu Hongbing , Liu Shiyan , Lovegrove Alison , Ma Lingling , Mumford Cathy , Parmar Saroj , Philp Charlie , Playford Darryl , Przewieslik-Allen Alexandra M. , Sarfraz Zareen , Schafer David , Shewry Peter R. , Shi Yan , Slafer Gustavo , Song Baoxing , Song Bo , Steele David , Steuernagel Burkhard , Tailby Phillip , Tyrrell Simon , Waheed Abdul , Wamalwa Mercy N. , Wang Xingwei , Wei Yanping , Winfield Mark , Wu Shishi , Wu Yubing , Wulff Brande B.H. , Xian Wenfei , Xu Yawen , Xu Yunfeng , Yuan Quan , Zhang Xin , Edwards Keith J. , Dixon Laura , Nicholson Paul , Chayut Noam , Hawkesford Malcolm J. , Uauy Cristobal , Sanders Dale , Huang Sanwen , Griffiths Simon 
Published: October 2023

AbstractBreeding crops resilient to climate change is urgently needed to help ensure food security. A key challenge is to harness genetic diversity to optimise adaptation, yield, stress resilience and nutrition. We examined the genetic and phenotypic diversity of the A.E. Watkins landrace collection of bread wheat (Triticum aestivum), a major global cereal, through whole-genome re-sequencing (827 Watkins landraces and 208 modern cultivars) and in-depth field evaluation spanning a decade. We discovered that modern cultivars are derived from just two of the seven ancestral groups of wheat, leaving five groups as previously untapped sources for breeding. This provides access to landrace-specific functional variations using structured germplasm, genotyping and informatics resources. Employing complementary genetic populations and approaches, we identified thousands of high-resolution quantitative trait loci (QTL) and significant marker–trait associations for major traits, revealing many Watkins-unique loci that can confer superior traits in modern wheat. Furthermore, we identified and functionally verified causative genes for climate-change adaptation, nutritional enhancement and resistance to wheat blast. Finally, we assessed the phenotypic effects of 44,338 Watkins-unique haplotypes, introgressed from 143 prioritised QTL in the context of modern cultivars, bridging the gap between landrace diversity and current breeding. This study establishes a framework for systematically utilising genetic diversity in crop improvement to achieve sustainable food security.