bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tim4 enables large peritoneal macrophages to cross-present tumor antigens at early stages of tumorigenesis
Authors: Joshi Sonal , Rodríguez Lucía López , Morosi Luciano Gastón , Amadio Roberto , Pachauri Manendra , Giacca Mauro , Piperno Giulia Maria , Benvenuti Federica 
Published: September 2023

SummaryCross-presentation of tumor antigens by subsets of macrophages at different stages along tumor progression may have divergent impacts on anti-tumoral immune responses. Here we show that TIM4+large peritoneal macrophages (LPM) avidly capture tumor cells and cross-present tumor-associated antigens at early stages of peritoneal infiltration by ovarian cancer cells. The phosphatidylserine (PS) receptor TIM4 promotes maximal uptake and triggers inflammatory and metabolic gene programs in combination with cytoskeletal remodeling and upregulation of transcriptional signatures related to antigen processing. At the cellular levels, TIM4 is recruited with F-actin at the phagocytic cup and translocates in nascent phagosomes, controlling the kinetic of phagosomal acidification and cargo degradation. TIM4 deletion abrogates cross-presentation of tumor-associated antigens and blunts expansion of effector CD8 T cells at tumor inception. In addition, targeting tumor antigens to LPM by PS liposomes can trigger CD8 T cell activation. Together these results suggest that TIM4 enables LPMs to scan the antigenic content of incoming tumor cells to promote immune surveillance by CD8 T cells and, at defined temporal windows, may be exploited for therapeutic purposes.
Gene Deletion of the PACAP/VIP Receptor, VPAC2R, Alters Glycemic Responses During Metabolic and Psychogenic Stress in Adult Female Mice
Authors: Kozlova Elena V. , Bishay Anthony E. , Denys Maximillian E. , Chinthirla Bhuvaneswari D. , Valdez Matthew C. , Spurgin Kurt A. , Krum Julia M. , Basappa Karthik R. , Curras-Collazo Margarita C. 
Published: September 2023

AbstractPituitary adenylate cyclase-activating polypeptide (PACAP) and the homologous peptide, vasoactive intestinal peptide (VIP), participate in glucose homeostasis using insulinotropic and counterregulatory processes. These opposing actions need further characterization, as does the role of VIP receptor 2 (VPAC2R) in the regulation of glucose metabolism. In this study, we examined the participation of VPAC2R on basal glycemia, fasted glucoregulatory hormones and on glycemia responses during metabolic and psychogenic stress using gene-deleted (Vipr2-/-) female mice. The mean basal glycemia was significantly greater inVipr2-/-in the fed state and after an 8h overnight fast as compared to wildtype (WT) mice. Insulin tolerance testing following a 5h fast (morning fast, 0.38 U/kg) indicated no effect of genotype. However, during a more intense metabolic challenge (8 h, ON fast, 0.25 U/kg),Vipr2-/-females displayed significantly impaired insulin hypoglycemia. During immobilization stress, the hyperglycemic response and plasma epinephrine levels were significantly elevated above basal inVipr2-/-, but not WT mice, in spite of similar stress levels of plasma corticosterone. Together, these results implicate the action of upregulated counterregulatory processes influenced by enhanced sympathoexcitation. Moreover, the suppression of plasma GLP-1 levels inVipr2-/-mice may have removed the inhibition on hepatic glucose production and the promotion of glucose disposal by GLP-1. qPCR analysis indicated deregulation of central gene markers of PACAP/VIP signaling inVipr2-/-: upregulated medullary tyrosine hydroxylase (Th) and downregulated hypothalamicVip. These results demonstrate a physiological role for VPAC2R in glucose metabolism, especially during insulin challenge and psychogenic stress, likely involving the participation of sympathoadrenal activity and/or metabolic hormones.
Diverse Plant-Parasitic Nematodes are Selectively Killed by Oxadiazole Thioether Pro-Nematicides
Authors: Knox Jessica , Burns Andrew R. , Cooke Brittany , Cammalleri Savina R. , Kitner Megan , Ching Justin , Castelli Jack M.P. , Puumala Emily , Snider Jamie , Koury Emily , Collins J.B. , Andersen Erik C. , Stagljar Igor , Cowen Leah E. , Lautens Mark , Zasada Inga , Roy Peter J. 
Published: September 2023

ABSTRACTLeft unchecked, plant-parasitic nematodes have the potential to devastate crops globally. Highly effective but non-selective nematicides are justifiably being phased-out, leaving farmers with limited options for managing nematode infestation. Here, we report our discovery of a 1,3,4-oxadiazole thioether scaffold called Cyprocide that selectively kills diverse plant-parasitic nematodes. Cyprocide is bioactivated into a lethal reactive electrophilic metabolite by specific nematode cytochrome P450 enzymes. Because Cyprocide fails to kill non-target organisms, we infer that the targeted lethality of this pro-nematicide derives from P450 substrate selectivity. Our findings demonstrate that Cyprocide is a selective nematicidal scaffold with broad-spectrum activity that holds the potential to help safeguard our global food supply.
The origin of secondary structure transitions and peptide self-assembly propensity in trifluoroethanol-water mixtures
Authors: Prasad Anup Kumar , Samajdar Rajarshi , Panwar Ajay Singh , Martin Lisandra L. 
Published: September 2023

AbstractThe formation of transient helical intermediates, implicated in the early-stages of amyloid formation in amyloidogenic peptides, is thought to be enhanced by membrane-peptide interactions. Uperin 3.5 is a seventeen-residue antimicrobial, amyloidogenic peptide that forms amyloid in phosphate buffered saline (PBS). The role of 2,2,2-trifluoroethanol (TFE) concentration, a known α-helical stabiliser, in modulating aggregation of Uperin 3.5 peptide in membrane-mimetic TFE:water mixtures was investigated. Thioflavin T (ThT) fluorescence assays showed complete inhibition of aggregation at higher concentrations of TFE (≥ 20% TFE:water v/v). However, a five-to-seven-fold increase in fibrillation kinetics was observed at 10% TFE:water mixtures in comparison to aggregation in a buffer. Further, aggregation in TFE:water mixtures was only observed upon addition of buffer. Interestingly, circular dichroism (CD) spectra showed the appearance of partial helical structures in 10% TFE:water, which transitioned to β-sheet rich structures only after addition of buffer. Microsecond time-scale molecular dynamics (MD) simulations of multiple U3.5 peptides in both salt-free and salt-containing TFE:water mixtures showed that changes in the local environment of peptide residues determined the structural transition and aggregation trajectories for U3.5. Consistent with experiments, the greatest extent of aggregation was observed for low TFE concentration (10% TFE:water simulations), characterised by faster formation of helical intermediates (oligomers). While the presence of 10% TFE efficiently induced partial helical structure in individual U3.5 peptides, it did not impede peptide-peptide interactions, thus enabling peptide aggregation. Addition of salt, screened like-charge repulsion between positively charged residues of different peptides, leading to stronger inter-peptide interactions. Significantly, the presence of salt determined subsequent structural transitions in the helical intermediates; either forming a predominantly α-helical oligomer in salt-free solutions or a β-sheet-rich oligomer in salt-containing solutions.
CDK6-mediated endothelial cell cycle acceleration drives arteriovenous malformations in hereditary hemorrhagic telangiectasia
Authors: Dinakaran Sajeth , Zhao Haitian , Tang Yuefeng , Wang Zhimin , Ruiz Santiago , Nomura-Kitabayashi Aya , Blanc Lionel , Faughnan Marie E. , Marambaud Philippe 
Published: September 2023

ABSTRACTIncreased endothelial cell (EC) proliferation is a hallmark of arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT). The underlying mechanism and disease relevance of this abnormal cell proliferative state of the ECs remain unknown. Here, we report the identification of a CDK6-driven mechanism of cell cycle progression deregulation directly involved in EC proliferation and HHT vascular pathology. Specifically, HHT mouse liver ECs exhibited defects in their cell cycle control characterized by a G1/S checkpoint bypass and acceleration of cell cycle speed. Phosphorylated retinoblastoma (p-RB1)—a marker of G1/S transition through the restriction point—significantly accumulated in ECs of HHT mouse retinal AVMs and HHT patient skin telangiectasias. Mechanistically, ALK1 loss of function increased the expression of key restriction point mediators, and treatment with palbociclib or ribociclib, two CDK4/6 inhibitors, blocked p-RB1 increase and retinal AVMs in HHT mice. Palbociclib also improved vascular pathology in the brain and slowed down endothelial cell cycle speed and EC proliferation. Specific deletion ofCdk6in ECs was sufficient to protect HHT mice from AVM pathology. Thus, CDK6-mediated endothelial cell cycle acceleration controls EC proliferation in AVMs and is a central determinant of HHT pathogenesis. We propose that clinically approved CDK4/6 inhibitors have repurposing potential in HHT.
Residual force depression is not related to positive muscle fascicle work during submaximal voluntary dorsiflexion contractions in humans
Authors: Raiteri Brent James , Lauret Leon , Hahn Daniel 
Published: September 2023

AbstractResidual force depression (rFD) following active muscle shortening is commonly assumed to strongly and linearly increase with increasing muscle work, but this has not been systematically tested during voluntary contractions in humans. Using dynamometry, we compared steady-state ankle joint torques (N=16) following tibialis anterior (TA) muscle-tendon unit (MTU) lengthening and shortening to the torque during submaximal voluntary fixed-end dorsiflexion reference contractions (REF) at a matched MTU length and EMG amplitude. B-mode ultrasound revealed that TA fascicle shortening amplitudes were significantly reduced (p<0.001) during MTU lengthening with no preload over small (LENsmall) and medium (LENmedium) amplitudes, respectively, relative to REF. MTU lengthening with a preload over a large (LENlargeP) amplitude significantly (p<0.001) increased fascicle shortening relative to REF, as well as stretch amplitudes relative to LENsmalland LENmedium(p≤0.001), but the significant (p≤0.028) steady-state fascicle force enhancement relative to REF was similar to LENsmalland LENmedium(3-5%). MTU shortening with and without a preload over small (SHOsmallP/SHOsmall) and large (SHOlargeP/SHOlarge) amplitudes significantly (p<0.001) increased positive fascicle and MTU work relative to REF, but significant (p≤0.006) rFD was observed in SHOsmallPand SHOlargeP(7-10%) only. rFD was linearly related to positive MTU work (rrm(47)=0.48,p<0.001), but not positive fascicle work (rrm(47)=0.16,p=0.277). Our findings indicate that MTU lengthening without substantial fascicle stretch enhances steady-state force output, which might be due to less shortening-induced rFD. Our findings also indicate that different amounts of positive fascicle and MTU work induce similar rFD, which cautions against using work to predict rFD during submaximal voluntary contractions.
Molecular and phenotypic blueprint of the hematopoietic compartment reveals proliferation stress as a driver of age-associated human stem cell dysfunctions
Authors: Lettera Emanuele , Scala Serena , Basso-Ricci Luca , Tavella Teresa , Volpe Lucrezia della , Furno Elena Lo , Kaufmann Kerstin B. , Garcia-Prat Laura , Quaranta Pamela , Hernandez Raisa Jofra , Murison Alex , Giannetti Kety , Aguilar-Navarro Alicia G. , Beretta Stefano , Conti Anastasia , Farina Giacomo , Flores-Figueroa Eugenia , Conte Pietro , Ometti Marco , Merelli Ivan , Xie Stephanie Z. , Aiuti Alessandro , Micco Raffaella Di 
Published: September 2023

AbstractHematopoietic stem/progenitor cell (HSPC) aging studies have been associated with myeloid skewing, reduced clonal output, and impaired regenerative capacity, but quantitative immunophenotypic and functional analysis across human aging is lacking. Here, we provide a comprehensive phenotypic, transcriptional, and functional dissection of human hematopoiesis across the lifespan. Although primitive HSPC numbers were stable during aging, overall cellularity was reduced, especially for erythroid and lymphoid lineages. Notably, HSPC from aged individuals had superior repopulating frequency than younger counterparts in xenografts; yet aged HSPC displayed epigenetic dysregulation of cell cycle, inflammatory signatures, and a reduced capacity to counteract activation-induced proliferative stress with concomitant accumulation of DNA damage and senescence-like features upon xenotransplantation. This phenotype was recapitulated by enforcing proliferative stressin vivoon cord blood (CB) HSPC. Overall, our work sheds light on dysregulated responses to activation-induced proliferation underlying HSPC aging and establishes CB xenotransplantation-based models as suitable for studying age-associated hematopoietic defects.
Trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer growth and immune suppression via phospholipid scramblase anoctamin 6 (ANO6)
Authors: Ogier Charline , Solomon Akino Mercy Charles , Lu Zhen , Recoules Ludmila , Klochkova Alena , Gabitova-Cornell Linara , Bayarmagnai Battuya , Restifo Diana , Surumbayeva Aizhan , Vendramini-Costa Débora B. , Deneka Alexander Y. , Francescone Ralph , Lilly Anna C. , Sipman Alyssa , Gardiner Jaye C. , Luong Tiffany , Franco-Barraza Janusz , Ibeme Nina , Cai Kathy Q. , Einarson Margret B. , Nicolas Emmanuelle , Efimov Andrei , Megill Emily , Snyder Nathaniel W. , Bousquet Corinne , Cros Jerome , Zhou Yunyun , Golemis Erica A. , Gligorijevic Bojana , Soboloff Jonathan , Fuchs Serge Y. , Cukierman Edna , Astsaturov Igor 
Published: September 2023

AbstractIn pancreatic ductal adenocarcinoma (PDAC), the fibroblastic stroma constitutes most of the tumor mass and is remarkably devoid of functional blood vessels. This raises an unresolved question of how PDAC cells obtain essential metabolites and water-insoluble lipids. We have found a critical role for cancer-associated fibroblasts (CAFs) in obtaining and transferring lipids from blood-borne particles to PDAC cells via trogocytosis of CAF plasma membranes. We have also determined that CAF-expressed phospholipid scramblase anoctamin 6 (ANO6) is an essential CAF trogocytosis regulator required to promote PDAC cell survival. During trogocytosis, cancer cells and CAFs form synapse-like plasma membranes contacts that induce cytosolic calcium influx in CAFs via Orai channels. This influx activates ANO6 and results in phosphatidylserine exposure on CAF plasma membrane initiating trogocytosis and transfer of membrane lipids, including cholesterol, to PDAC cells. Importantly, ANO6-dependent trogocytosis also supports the immunosuppressive function of pancreatic CAFs towards cytotoxic T cells by promoting transfer of excessive amounts of cholesterol. Further, blockade of ANO6 antagonizes tumor growth via disruption of delivery of exogenous cholesterol to cancer cells and reverses immune suppression suggesting a potential new strategy for PDAC therapy.
Improved Protein Model in SPICA Force Field
Authors: Yamada Teppei , Miyazaki Yusuke , Harada Shogo , Kumar Ashutosh , Vanni Stefano , Shinoda Wataru 
Published: September 2023

ABSTRACTThe previous version of the SPICA coarse-grained (CG) force field (FF) protein model focused primarily on membrane proteins and successfully reproduced the dimerization free energies of several transmembrane helices and stable structures of various membrane protein assemblies. However, that model had limited accuracy when applied to other proteins, such as intrinsically disordered proteins (IDPs) and peripheral proteins, because the dimensions of the IDPs in an aqueous solution were too compact, and protein binding on the lipid membrane surface was over-stabilized. To improve the accuracy of the SPICA FF model for the simulation of such systems, in this study we introduce protein secondary structure-dependent nonbonded interaction parameters to the backbone segments and re-optimize almost all nonbonded parameters for amino acids. The improved FF proposed here successfully reproduces the radius of gyration of various IDPs, the binding sensitivity of several peripheral membrane proteins, and the dimerization free energies of several transmembrane helices. The new model also shows improved agreement with experiments on the free energy of peptide association in water. In addition, an extensive library of nonbonded interactions between proteins and lipids, including various glycerophospholipids, sphingolipids, and cholesterol, allows the study of specific interactions between lipids and peripheral and transmembrane proteins. Hence, the new SPICA FF (version 2) proposed herein is applicable with high accuracy for simulating a wide range of protein systems.Graphical abstract
Warnings/Cautions when collecting Brassica diversity along a large climatic gradient
Authors: Falentin Cyril , Hadj-Arab Houria , Aissiou Fella , Bartoli Claudia , Bazan Giuseppe , Boudet Matéo , Bousset-Vaslin Lydia , Chwikhi Marwa , Coriton Olivier , Deniot Gwenaëlle , de Carvalho Julie Ferreira , Gay Laurène , Geraci Anna , Glory Pascal , Huteau Virginie , Ilahy Riadh , Ilardi Vincenzo , Jarillo José A. , Meglič Vladimir , Oddo Elisabetta , Pernas Mónica , Piñeiro Manuel , Pipan Barbara , Rhim Thouraya , Richer Vincent , Rizza Fulvia , Ronfort Joëlle , Rousseau-Gueutin Mathieu , Schicchi Rosario , Sinkovič Lovro , Taburel Maryse , Terzi Valeria , Théréné Sylvain , Tiret Mathieu , Tlili Imen , Badeck Franz Werner , Chèvre Anne-Marie 
Published: September 2023

AbstractAgriculture faces great challenges to overcome global warming and to improve system sustainability, requiring access to novel genetic diversity. So far, wild populations and local landraces remain poorly explored. This is notably the case for the two diploid species,Brassica oleraceaL. (CC, 2n=2x=18) andB. rapaL. (AA, 2n=2x=20). In order to explore genetic diversity in both species, we have collected numerous populations in their center of origin, the Mediterranean basin, on a large contrasting climatic and soil gradient from northern Europe to southern sub-Saharan regions. In these areas, we also collected 14 populations belonging to fiveB. oleraceaclosely related species. Before further genetic and agronomic investigations, we controlled the absence of species misidentification using flow cytometry, sequencing of species specific chloroplast genomic region, as well as cytogenetic analyses in case of unexpected results. Looking at the 102B. oleraceaand 146B. rapapopulations showing a good germination among the 112 and 154 populations collected, seventeen populations were misidentified. The most frequent mistake was a confusion of these diploid species withB. napus. Additionally forB. rapa, 2 autotetraploid populations were observed. Habitats of the collected wild populations and landraces are described in our work. This provides a unique plant material characterization that will pave the way for further analyses investigating the genomic regions involved in climatic and microbiota adaptation. This research is supported by the H2020 Prima project ‘BrasExplor’.
Tip Growth Defective1 interacts with the cellulose synthase complex to regulate cellulose synthesis in Arabidopsis thaliana
Authors: Lampugnani Edwin R , Persson Staffan , Khan Ghazanfar Abbas 
Published: September 2023

AbstractPlant cells possess robust and flexible cell walls composed primarily of cellulose, a polysaccharide that provides structural support and enables cell expansion. Cellulose is synthesised by the Cellulose Synthase A (CESA) catalytic subunits, which form cellulose synthase complexes (CSCs). While significant progress has been made in unravelling CSC function, the trafficking of CSCs and the involvement of post-translational modifications in cellulose synthesis remain poorly understood. In order to deepen our understanding of cellulose biosynthesis, this study utilised immunoprecipitation techniques with CESA6 as the bait protein to explore the CSC and its interactors. We successfully identified the core proteins of the CSC complex and discovered new potential interactors involved in CSC trafficking and the coordination of cell wall synthesis. Moreover, we identified TIP GROWTH DEFECTIVE 1 (TIP1) protein S-acyl transferases (PATs) as an interactor of the CSC complex. We confirmed the interaction between TIP1 and the CSC complex through multiple independent approaches. Further analysis revealed thattip1mutants exhibited stunted growth and reduced levels of crystalline cellulose in leaves. These findings suggest that TIP1 positively influences cellulose biosynthesis, potentially mediated by its role in the S-acylation of the CSC complex.
Interferon-α promotes neo-antigen formation and preferential HLA-B-restricted antigen presentation in pancreatic β-cells
Authors: Carré Alexia , Zhou Zhicheng , Perez-Hernandez Javier , Samassa Fatoumata , Lekka Christiana , Manganaro Anthony , Oshima Masaya , Liao Hanqing , Parker Robert , Nicastri Annalisa , Brandao Barbara , Colli Maikel L. , Eizirik Decio L. , Göransson Marcus , Burgos Morales Orlando , Anderson Amanda , Landry Laurie , Kobaisi Farah , Scharfmann Raphael , Marselli Lorella , Marchetti Piero , You Sylvaine , Nakayama Maki , Hadrup Sine R. , Kent Sally C. , Richardson Sarah J. , Ternette Nicola , Mallone Roberto 
Published: September 2023

AbstractInterferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but its effect on the repertoire of HLA Class I (HLA-I)-bound peptides presented by pancreatic β-cells is unknown. Using immunopeptidomics, we characterized the peptide/HLA-I presentation inin-vitroresting and IFN-α-exposed β-cells. IFN-α increased HLA-I expression and peptide presentation, including neo-sequences derived from alternative mRNA splicing, post-translational modifications - notably glutathionylation - and proteincis-splicing. This antigenic landscape relied on processing by both the constitutive and immune proteasome. The resting β-cell immunopeptidome was dominated by HLA-A-restricted ligands. However, IFN-α only marginally upregulated HLA-A and largely favored HLA-B, translating into a major increase in HLA-B-restricted peptides and into an increased activation of HLA-B-restricted vs. HLA-A-restricted CD8+T-cells. A preferential HLA-B hyper-expression was also observed in the islets of T1D vs. non-diabetic donors, and we identified islet-infiltrating CD8+T-cells from T1D donors reactive to HLA-B-restricted granule peptides. Thus, the inflammatory milieu of insulitis may skew the autoimmune response toward epitopes presented by HLA-B, hence recruiting a distinct T-cell repertoire that may be relevant to T1D pathogenesis.
Sperm Cell Painting: A Mechanism Driven Approach for Drug Discovery in Human Spermatozoa
Authors: Johnston Zoe C , Gruber Franz S , Myles Rachel , Kane Shruti V. , Richardson Anthony , Day David P. , Wilson Caroline , Read Kevin D. , Gilbert Ian H. , Martins da Silva Sarah , Barratt Christopher LR , Swedlow Jason R. 
Published: September 2023

ABSTRACTWe have adapted the cell painting assay developed by Carpenter and colleagues on cultured U2OS cells to human spermatozoa. In Sperm Cell Painting (SCP) we assemble an image-based quantitative fingerprint of the functional state of sperm. We use this assay to gain insight into the mechanism of action of compounds that modify sperm function and as a platform for contraceptive discovery.