bluuebunny/crossref_metadata_2025_split huggingface dataset:
NRP1 transduces mechanical stress inhibition via LATS1/YAP in hypertrophic scars
Authors: Li Mengzhi , Wang Peng , Li Jingting , Zhou Fei , Huang Shixin , Qi Shaohai , Shu Bin 
Published: September 2023

AbstractHypertrophic scar (HS) is an abnormal fibrous hyperplasia of the skin caused by excessive tissue repair in response to skin burns and trauma, which restricts physical function and impairs patients’ quality of life. Numerous studies have shown that pressure garment therapy (PGT) is an effective treatment for preventing hypertrophic scars. Herein, we found that mechanical stress stimulates the neuropilin 1 (NRP1) expression through screening GSE165027, GSE137210, and GSE120194 from Gene Expression Omnibus (GEO) database and bioinformatics analysis. We verified this stimulation in the human hypertrophic scar, pressure culture cell model, and rat tail-scar model. Mechanical compression increased LATS1 and pYAP enrichment, thus repressing the expression of YAP. Functionally, the knockdown of NRP1 promoted the expression of LATS1, thus decreasing the expression of YAP and inhibiting endothelial cell proliferation. Furthermore, co-immunoprecipitation analysis confirmed that NRP1 binds to YAP, and mechanical compression disrupted this binding, which resulted in the promotion of YAP relocation to nuclear. In conclusion, our results indicated that NRP1 transduces mechanical force inhibition by inhibiting YAP expression. Mechanical pressure can release YAP bound to NRP1, which explains the phenomenon that mechanical stress increases YAP in the nucleus. Strategies targeting NRP1 may promote compression therapy with optimal and comfortable pressures.
MYC Deregulation and PTEN Loss Model Tumor and Stromal Heterogeneity of Aggressive Triple-Negative Breast Cancer
Authors: Doha Zinab O. , Wang Xiaoyan , Calistri Nicholas L. , Eng Jennifer , Daniel Colin J. , Ternes Luke , Kim Eun Na , Pelz Carl , Munks Michael , Betts Courtney , Kwon Sunjong , Bucher Elmar , Li Xi , Waugh Trent , Tatarova Zuzana , Blumberg Dylan , Ko Aaron , Kirchberger Nell , Pietenpol Jennifer A. , Sanders Melinda E. , Langer Ellen M. , Dai Mu-Shui , Mills Gordon , Chin Koei , Chang Young Hwan , Coussens Lisa M. , Gray Joe W. , Heiser Laura M. , Sears Rosalie C. 
Published: September 2023

AbstractTriple-negative breast cancer (TNBC) patients have a poor prognosis and few treatment options. Mouse models of TNBC are important for development of new therapies, however, few mouse models represent the complexity of TNBC. Here, we develop a female TNBC murine model by mimicking two common TNBC mutations with high co-occurrence: amplification of the oncogene MYC and deletion of the tumor suppressor PTEN. This Myc;Ptenfl model develops heterogeneous triple-negative mammary tumors that display histological and molecular features commonly found in human TNBC. Our research involves deep molecular and spatial analyses on Myc;Ptenfl tumors including bulk and single-cell RNA-sequencing, and multiplex tissue-imaging. Through comparison with human TNBC, we demonstrate that this genetic mouse model develops mammary tumors with differential survival and therapeutic responses that closely resemble the inter- and intra-tumoral and microenvironmental heterogeneity of human TNBC, providing a pre-clinical tool for assessing the spectrum of patient TNBC biology and drug response.
Global fossil fuel reduction pathways under different climate mitigation strategies and ambitions
Authors: Achakulwisut Ploy , Erickson Peter , Guivarch Céline , Schaeffer Roberto , Brutschin Elina , Pye Steve 
Published: September 2023

AbstractThe mitigation scenarios database of the Intergovernmental Panel on Climate Change’s Sixth Assessment Report is an important resource for informing policymaking on energy transitions. However, there is a large variety of models, scenario designs, and resulting outputs. Here we analyse the scenarios consistent with limiting warming to 2 °C or below regarding the speed, trajectory, and feasibility of different fossil fuel reduction pathways. In scenarios limiting warming to 1.5 °C with no or limited overshoot, global coal, oil, and natural gas supply (intended for all uses) decline on average by 95%, 62%, and 42%, respectively, from 2020 to 2050, but the long-term role of gas is highly variable. Higher-gas pathways are enabled by higher carbon capture and storage (CCS) and carbon dioxide removal (CDR), but are likely associated with inadequate model representation of regional CO2 storage capacity and technology adoption, diffusion, and path-dependencies. If CDR is constrained by limits derived from expert consensus, the respective modelled coal, oil, and gas reductions become 99%, 70%, and 84%. Our findings suggest the need to adopt unambiguous near- and long-term reduction benchmarks in coal, oil, and gas production and use alongside other climate mitigation targets.
CSF proteome profiling reveals biomarkers to discriminate dementia with Lewy bodies from Alzheimer´s disease
Authors: del Campo Marta , Vermunt Lisa , Peeters Carel F. W. , Sieben Anne , Hok-A-Hin Yanaika S. , Lleó Alberto , Alcolea Daniel , van Nee Mirrelijn , Engelborghs Sebastiaan , van Alphen Juliette L. , Arezoumandan Sanaz , Chen-Plotkin Alice , Irwin David J. , van der Flier Wiesje M. , Lemstra Afina W. , Teunissen Charlotte E. 
Published: September 2023

AbstractDiagnosis of dementia with Lewy bodies (DLB) is challenging and specific biofluid biomarkers are highly needed. We employed proximity extension-based assays to measure 665 proteins in the cerebrospinal fluid (CSF) from patients with DLB (n = 109), Alzheimer´s disease (AD,n = 235) and cognitively unimpaired controls (n = 190). We identified over 50 CSF proteins dysregulated in DLB, enriched in myelination processes among others. The dopamine biosynthesis enzyme DDC was the strongest dysregulated protein, and could efficiently discriminate DLB from controls and AD (AUC:0.91 and 0.81 respectively). Classification modeling unveiled a 7-CSF biomarker panel that better discriminate DLB from AD (AUC:0.93). A custom multiplex panel for six of these markers (DDC, CRH, MMP-3, ABL1, MMP-10, THOP1) was developed and validated in independent cohorts, including an AD and DLB autopsy cohort. This DLB CSF proteome study identifies DLB-specific protein changes and translates these findings to a practicable biomarker panel that accurately identifies DLB patients, providing promising diagnostic and clinical trial testing opportunities.
Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses
Authors: Chapman Nathaniel S. , Hulswit Ruben J. G. , Westover Jonna L. B. , Stass Robert , Paesen Guido C. , Binshtein Elad , Reidy Joseph X. , Engdahl Taylor B. , Handal Laura S. , Flores Alejandra , Gowen Brian B. , Bowden Thomas A. , Crowe James E. 
Published: September 2023

AbstractThe zoonotic Rift Valley fever virus (RVFV) can cause severe disease in humans and has pandemic potential, yet no approved vaccine or therapy exists. Here we describe a dual-mechanism human monoclonal antibody (mAb) combination against RVFV that is effective at minimal doses in a lethal mouse model of infection. We structurally analyze and characterize the binding mode of a prototypical potent Gn domain-A-binding antibody that blocks attachment and of an antibody that inhibits infection by abrogating the fusion process as previously determined. Surprisingly, the Gn domain-A antibody does not directly block RVFV Gn interaction with the host receptor low density lipoprotein receptor-related protein 1 (LRP1) as determined by a competitive assay. This study identifies a rationally designed combination of human mAbs deserving of future investigation for use in humans against RVFV infection. Using a two-pronged mechanistic approach, we demonstrate the potent efficacy of a rationally designed combination mAb therapeutic.
Single-cell isotope tracing reveals functional guilds of bacteria associated with the diatom Phaeodactylum tricornutum
Authors: Mayali Xavier , Samo Ty J. , Kimbrel Jeff A. , Morris Megan M. , Rolison Kristina , Swink Courtney , Ramon Christina , Kim Young-Mo , Munoz-Munoz Nathalie , Nicora Carrie , Purvine Sam , Lipton Mary , Stuart Rhona K. , Weber Peter K. 
Published: September 2023

AbstractBacterial remineralization of algal organic matter fuels algal growth but is rarely quantified. Consequently, we cannot currently predict whether some bacterial taxa may provide more remineralized nutrients to algae than others. Here, we quantified bacterial incorporation of algal-derived complex dissolved organic carbon and nitrogen and algal incorporation of remineralized carbon and nitrogen in fifteen bacterial co-cultures growing with the diatom Phaeodactylum tricornutum at the single-cell level using isotope tracing and nanoSIMS. We found unexpected strain-to-strain and cell-to-cell variability in net carbon and nitrogen incorporation, including non-ubiquitous complex organic nitrogen utilization and remineralization. We used these data to identify three distinct functional guilds of metabolic interactions, which we termed macromolecule remineralizers, macromolecule users, and small-molecule users, the latter exhibiting efficient growth under low carbon availability. The functional guilds were not linked to phylogeny and could not be elucidated strictly from metabolic capacity as predicted by comparative genomics, highlighting the need for direct activity-based measurements in ecological studies of microbial metabolic interactions.
Assembly mechanism of a Tad secretion system secretin-pilotin complex
Authors: Tassinari Matteo , Rudzite Marta , Filloux Alain , Low Harry H. 
Published: September 2023

AbstractThe bacterial Tight adherence Secretion System (TadSS) assembles surface pili that drive cell adherence, biofilm formation and bacterial predation. The structure and mechanism of the TadSS is mostly unknown. This includes characterisation of the outer membrane secretin through which the pilus is channelled and recruitment of its pilotin. Here we investigate RcpA and TadD lipoprotein from Pseudomonas aeruginosa. Light microscopy reveals RcpA colocalising with TadD in P. aeruginosa and when heterologously expressed in Escherichia coli. We use cryogenic electron microscopy to determine how RcpA and TadD assemble a secretin channel with C13 and C14 symmetries. Despite low sequence homology, we show that TadD shares a similar fold to the type 4 pilus system pilotin PilF. We establish that the C-terminal four residues of RcpA bind TadD - an interaction essential for secretin formation. The binding mechanism between RcpA and TadD appears distinct from known secretin-pilotin pairings in other secretion systems.
Variation in spatial dependencies across the cortical mantle discriminates the functional behaviour of primary and association cortex
Authors: Leech Robert , Vos De Wael Reinder , Váša František , Xu Ting , Austin Benn R. , Scholz Robert , Braga Rodrigo M. , Milham Michael P. , Royer Jessica , Bernhardt Boris C. , Jones Emily J. H. , Jefferies Elizabeth , Margulies Daniel S. , Smallwood Jonathan 
Published: September 2023

AbstractRecent theories of cortical organisation suggest features of function emerge from the spatial arrangement of brain regions. For example, association cortex is located furthest from systems involved in action and perception. Association cortex is also ‘interdigitated’ with adjacent regions having different patterns of functional connectivity. It is assumed that topographic properties, such as distance between regions, constrains their functions, however, we lack a formal description of how this occurs. Here we use variograms, a quantification of spatial autocorrelation, to profile how function changes with the distance between cortical regions. We find function changes with distance more gradually within sensory-motor cortex than association cortex. Importantly, systems within the same type of cortex (e.g., fronto-parietal and default mode networks) have similar profiles. Primary and association cortex, therefore, are differentiated by how function changes over space, emphasising the value of topographical features of a region when estimating its contribution to cognition and behaviour.
HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer
Authors: Neubert Emily N. , DeRogatis Julia M. , Lewis Sloan A. , Viramontes Karla M. , Ortega Pedro , Henriquez Monique L. , Buisson Rémi , Messaoudi Ilhem , Tinoco Roberto 
Published: September 2023

AbstractChronic infections and cancers evade the host immune system through mechanisms that induce T cell exhaustion. The heterogeneity within the exhausted CD8+ T cell pool has revealed the importance of stem-like progenitor (Tpex) and terminal (Tex) exhausted T cells, although the mechanisms underlying their development are not fully known. Here we report High Mobility Group Box 2 (HMGB2) protein expression is upregulated and sustained in exhausted CD8+ T cells, and HMGB2 expression is critical for their differentiation. Through epigenetic and transcriptional programming, we identify HMGB2 as a cell-intrinsic regulator of the differentiation and maintenance of Tpex cells during chronic viral infection and in tumors. Despite Hmgb2−/− CD8+ T cells expressing TCF-1 and TOX, these master regulators were unable to sustain Tpex differentiation and long-term survival during persistent antigen. Furthermore, HMGB2 also had a cell-intrinsic function in the differentiation and function of memory CD8+ T cells after acute viral infection. Our findings show that HMGB2 is a key regulator of CD8+ T cells and may be an important molecular target for future T cell-based immunotherapies.
Simultaneously ultrafast and robust two-dimensional flash memory devices based on phase-engineered edge contacts
Authors: Yu Jun , Wang Han , Zhuge Fuwei , Chen Zirui , Hu Man , Xu Xiang , He Yuhui , Ma Ying , Miao Xiangshui , Zhai Tianyou 
Published: September 2023

AbstractAs the prevailing non-volatile memory (NVM), flash memory offers mass data storage at high integration density and low cost. However, due to the ‘speed-retention-endurance’ dilemma, their typical speed is limited to ~microseconds to milliseconds for program and erase operations, restricting their application in scenarios with high-speed data throughput. Here, by adopting metallic 1T-LixMoS2 as edge contact, we show that ultrafast (10–100 ns) and robust (endurance>106 cycles, retention>10 years) memory operation can be simultaneously achieved in a two-dimensional van der Waals heterostructure flash memory with 2H-MoS2 as semiconductor channel. We attribute the superior performance to the gate tunable Schottky barrier at the edge contact, which can facilitate hot carrier injection to the semiconductor channel and subsequent tunneling when compared to a conventional top contact with high density of defects at the metal interface. Our results suggest that contact engineering can become a strategy to further improve the performance of 2D flash memory devices and meet the increasing demands of high speed and reliable data storage.
Dual hypoxia-responsive supramolecular complex for cancer target therapy
Authors: Guo Jian-Shuang , Li Juan-Juan , Wang Ze-Han , Liu Yang , Yue Yu-Xin , Li Hua-Bin , Zhao Xiu-He , Sun Yuan-Jun , Ding Ya-Hui , Ding Fei , Guo Dong-Sheng , Wang Liang , Chen Yue 
Published: September 2023

AbstractThe prognosis with pancreatic cancer is among the poorest of any human cancer. One of the important factors is the tumor hypoxia. Targeting tumor hypoxia is considered a desirable therapeutic option. However, it has not been translated into clinical success in the treatment of pancreatic cancer. With enhanced cytotoxicities against hypoxic pancreatic cancer cells, BE-43547A2 (BE) may serve as a promising template for hypoxia target strategy. Here, based on rational modification, a BE prodrug (NMP-BE) is encapsulated into sulfonated azocalix[5]arene (SAC5A) to generate a supramolecular dual hypoxia-responsive complex NMP-BE@SAC5A. Benefited from the selective load release within cancer cells, NMP-BE@SAC5A markedly suppresses tumor growth at low dose in pancreatic cancer cells xenograft murine model without developing systemic toxicity. This research presents a strategy for the modification of covalent compounds to achieve efficient delivery within tumors, a horizon for the realization of safe and reinforced hypoxia target therapy using a simple approach.
Arabidopsis TCP4 transcription factor inhibits high temperature-induced homeotic conversion of ovules
Authors: Lan Jingqiu , Wang Ning , Wang Yutao , Jiang Yidan , Yu Hao , Cao Xiaofeng , Qin Genji 
Published: September 2023

AbstractAbnormal high temperature (HT) caused by global warming threatens plant survival and food security, but the effects of HT on plant organ identity are elusive. Here, we show that Class II TEOSINTE BRANCHED 1/CYCLOIDEA/ PCF (TCP) transcription factors redundantly protect ovule identity under HT. The duodecuple tcp2/3/4/5/10/13/17/24/1/12/18/16 (tcpDUO) mutant displays HT-induced ovule conversion into carpelloid structures. Expression of TCP4 in tcpDUO complements the ovule identity conversion. TCP4 interacts with AGAMOUS (AG), SEPALLATA3 (SEP3), and the homeodomain transcription factor BELL1 (BEL1) to strengthen the association of BEL1 with AG-SEP3. The tcpDUO mutant synergistically interacts with bel1 and the ovule identity gene seedstick (STK) mutant stk in tcpDUO bel1 and tcpDUO stk. Our findings reveal the critical roles of Class II TCPs in maintaining ovule identity under HT and shed light on the molecular mechanisms by which ovule identity is determined by the integration of internal factors and environmental temperature.
Synchronization in collectively moving inanimate and living active matter
Authors: Riedl Michael , Mayer Isabelle , Merrin Jack , Sixt Michael , Hof Björn 
Published: September 2023

AbstractWhether one considers swarming insects, flocking birds, or bacterial colonies, collective motion arises from the coordination of individuals and entails the adjustment of their respective velocities. In particular, in close confinements, such as those encountered by dense cell populations during development or regeneration, collective migration can only arise coordinately. Yet, how individuals unify their velocities is often not understood. Focusing on a finite number of cells in circular confinements, we identify waves of polymerizing actin that function as a pacemaker governing the speed of individual cells. We show that the onset of collective motion coincides with the synchronization of the wave nucleation frequencies across the population. Employing a simpler and more readily accessible mechanical model system of active spheres, we identify the synchronization of the individuals’ internal oscillators as one of the essential requirements to reach the corresponding collective state. The mechanical ‘toy’ experiment illustrates that the global synchronous state is achieved by nearest neighbor coupling. We suggest by analogy that local coupling and the synchronization of actin waves are essential for the emergent, self-organized motion of cell collectives.
High performance mechano-optoelectronic molecular switch
Authors: Yang Zhenyu , Cazade Pierre-André , Lin Jin-Liang , Cao Zhou , Chen Ningyue , Zhang Dongdong , Duan Lian , Nijhuis Christian A. , Thompson Damien , Li Yuan 
Published: September 2023

AbstractHighly-efficient molecular photoswitching occurs ex-situ but not to-date inside electronic devices due to quenching of excited states by background interactions. Here we achieve fully reversible in-situ mechano-optoelectronic switching in self-assembled monolayers (SAMs) of tetraphenylethylene molecules by bending their supporting electrodes to maximize aggregation-induced emission (AIE). We obtain stable, reversible switching across >1600 on/off cycles with large on/off ratio of (3.8 ± 0.1) × 103 and 140 ± 10 ms switching time which is 10-100× faster than other approaches. Multimodal characterization shows mechanically-controlled emission with UV-light enhancing the Coulomb interaction between the electrons and holes resulting in giant enhancement of molecular conductance. The best mechano-optoelectronic switching occurs in the most concave architecture that reduces ambient single-molecule conformational entropy creating artificially-tightened supramolecular assemblies. The performance can be further improved to achieve ultra-high switching ratio on the order of 105 using tetraphenylethylene derivatives with more AIE-active sites. Our results promise new applications from optimized interplay between mechanical force and optics in soft electronics.
Cell microparticles loaded with tumor antigen and resiquimod reprogram tumor-associated macrophages and promote stem-like CD8+ T cells to boost anti-PD-1 therapy
Authors: Zhang Xiaoqiong , Wei Zhaohan , Yong Tuying , Li Shiyu , Bie Nana , Li Jianye , Li Xin , Liu Haojie , Xu Hang , Yan Yuchen , Zhang Bixiang , Chen Xiaoping , Yang Xiangliang , Gan Lu 
Published: September 2023

AbstractThe durable response rate to immune checkpoint blockade such as anti-programmed cell death-1 (PD-1) antibody remains relatively low in hepatocellular carcinoma (HCC), mainly depending on an immunosuppressive microenvironment with limited number of CD8+ T cells, especially stem-like CD8+ T cells, in tumor tissues. Here we develop engineered microparticles (MPs) derived from alpha-fetoprotein (AFP)-overexpressing macrophages to load resiquimod (R848@M2pep-MPsAFP) for enhanced anti-PD-1 therapy in HCC. R848@M2pep-MPsAFP target and reprogram immunosuppressive M2-like tumor-associated macrophages (TAMs) into M1-like phenotype. Meanwhile, R848@M2pep-MPsAFP-reprogrammed TAMs act as antigen-presenting cells, not only presenting AFP antigen to activate CD8+ T cell-mediated antitumor immunity, but also providing an intra-tumoral niche to maintain and differentiate stem-like CD8+ T cells. Combination immunotherapy with anti-PD-1 antibody generates strong antitumor immune memory and induces abundant stem-like CD8+ T cell proliferation and differentiation to terminally exhausted CD8+ T cells for long-term immune surveillance in orthotopic and autochthonous HCC preclinical models in male mice. We also show that the R848-loaded engineered MPs derived from macrophages overexpressing a model antigen ovalbumin (OVA) can improve anti-PD-1 therapy in melanoma B16-OVA tumor-bearing mice. Our work presents a facile and generic strategy for personalized cancer immunotherapy to boost anti-PD-1 therapy.
High-throughput screening of BAM inhibitors in native membrane environment
Authors: Rath Parthasarathi , Hermann Adrian , Schaefer Ramona , Agustoni Elia , Vonach Jean-Marie , Siegrist Martin , Miscenic Christian , Tschumi Andreas , Roth Doris , Bieniossek Christoph , Hiller Sebastian 
Published: September 2023

AbstractThe outer membrane insertase of Gram-negative bacteria, BAM, is a key target for urgently needed novel antibiotics. Functional reconstitutions of BAM have so far been limited to synthetic membranes and with low throughput capacity for inhibitor screening. Here, we describe a BAM functional assay in native membrane environment capable of high-throughput screening. This is achieved by employing outer membrane vesicles (OMVs) to present BAM directly in native membranes. Refolding of the model substrate OmpT by BAM was possible from the chaperones SurA and Skp, with the required SurA concentration three times higher than Skp. In the OMVs, the antibiotic darobactin had a tenfold higher potency than in synthetic membranes, highlighting the need for native conditions in antibiotics development. The assay is successfully miniaturized for 1536-well plates and upscaled using large scale fermentation, resulting in high-throughput capacities to screen large commercial compound libraries. Our OMV-based assay thus lays the basis for discovery, hit validation and lead expansion of antibiotics targeting BAM.