bluuebunny/crossref_metadata_2025_split huggingface dataset:
Processing negative words in pun-humor: dynamic representation of mixed feelings blending amusement and negativity
Authors: Sun Yingying , Jiang Zhufang , Yin Xinyue , Li Xiaoqing , Chang Ruohan 
Published: November 2024

AbstractThis study aims to investigate whether amusement and negativity counteract each other or are jointly intensified during the online processing of negative keywords in pun-humor sentences, and how mixed feelings blending these two emotional states are dynamically experienced over time. Participants read three types of sentences that included the same negative words as keywords: pun-humor (negative words can generate humorous effects by resonating with the context), non-humor (negative words seamlessly align with the context), and nonsensical (negative words cannot be integrated with the context) sentences. The behavioral ratings revealed that compared with non-humor and nonsensical sentences, pun-humor sentences evoked stronger amusement and intensified negative feelings, indicating that pun-humor sentences containing negative keywords can effectively elicit mixed feelings that encompass conflicting emotional states. The ERP results showed that the N400 (300-500 ms) elicited by negative words in pun-humor sentences was comparable to that in non-humor sentences, suggesting that negative words were connected contextually in both sentence types. Besides, negative words elicited greater LPC (600-800 ms) in pun-humor sentences than in non-humor and nonsensical sentences, suggesting that pun-humor sentences require additional semantic processing and more elaborate emotional processing. Moreover, the representational similarity analysis (RSA) results revealed that in pun-humor sentences, the representation of negativity persisted for a longer duration, and it occurred and peaked earlier than that of amusement. This implies that within the dynamic representation of mixed feelings, negativity was experienced first, whereas amusement was subsequently felt within a brief period, during which negativity was not offset but rather continued to be represented over a longer time span, resulting in the simultaneous presence of both amused and negative feelings. Taken together, these findings show that mixed feelings elicited during the online processing of negative keywords in pun-humor sentences can be dynamically experienced in a way that aligns with the highly simultaneous pattern and that negativity can be experienced before amusement during the dynamic representation of mixed feelings.
Quantum Spin Resonance in Engineered Magneto-Sensitive Fluorescent Proteins Enables Multi-Modal Sensing in Living Cells
Authors: Abrahams Gabriel , Spreng Vincent , Štuhec Ana , Kempf Idris , James Jessica , Sechkar Kirill , Stacey Scott , Trelles-Fernandez Vicente , Antill Lewis M. , Ingaramo Maria , York Andrew , Tetienne Jean-Philippe , Timmel Christiane R. , Steel Harrison 
Published: November 2024

AbstractQuantum mechanical phenomena have been identified as fundamentally significant to an increasing number of biological processes. Simultaneously, quantum sensing is emerging as a cutting-edge technology for precision biosensing. However, biological based candidates for quantum-sensors have thus far been limited toin vitrosystems, are prone to light induced degradation, and require sophisticated experimental setups making high-throughput studies prohibitively complex. We recently created a new class of magneto-sensitive fluorescent proteins (MFPs) [1], which we now show overcome these challenges and represent the first biological quantum-based sensor that functions at physiological conditions and in living cells. Through directed evolution, we demonstrate the possibility of engineering these proteins to alter properties of their response to magnetic fields and radio frequencies. These effects are explained in terms of the spin correlated radical pair (SCRP) mechanism, involving the protein backbone and a bound flavin cofactor. Using this engineered system we demonstrate the first observation of a fluorescent protein exhibiting Optically Detected Magnetic Resonance (ODMR) in living bacterial cells at room temperature, at sufficiently high signal-to-noise to be detected in a single cell, paving the way for development of a new class ofin vivobiosensors. Magnetic resonance measurements using fluorescent proteins enable unprecedented technologies, for instance 3D spatial localisation of the fluorescence using gradient fields (i.e. Magnetic Resonance Imaging but using an endogenous probe). We further demonstrate the use of multiple variants of MFPs for multiplexing or lock-in amplification of fluorescence signals, opening a new approach to combining or extracting multiple signals from a biological measurement. Taken together, our results represent a new intersection of imaging and perhaps actuation modalities for engineered biological systems, based on and designed around understanding the quantum mechanical properties of MFPs.
Tissue-dependent nature of plant susceptibility: a comparative pathogenicity study of the systemic phytopathogenRalstonia pseudosolanacearumin eggplant and tomato seedlings through root and leaf
Authors: Bhuyan Shuvam , Jain Monika , Boruah Lakhyajit , Tara Tana Sun , Begum Shuhada , Dutta Lukapriya , Giri Shubhra Jyoti , Phukan Tarinee , Kabyashree Kristi , Mandal Manabendra , Ray Suvendra Kumar 
Published: November 2024

AbstractRalstonia pseudosolanacearumcauses a lethal bacterial wilt disease in many plant species, posing significant economic challenges. Although tomato has been a primary model host for investigating the pathogenicity and systemic infection of this bacterium, this manuscript presents a comparative pathogenicity study between two closely related solanaceous hosts, tomato and eggplant, revealing differential host responses to the same pathogen, specifically through leaves and roots. Interestingly, eggplant seedlings exhibited a significantly higher susceptibility to cotyledon leaf inoculation than tomato seedlings. In the case of tomato, a few seedlings escaped wilting (called escapees), which was usual at a high pathogen load, unlike the case of eggplant seedlings where escapees could not be observed even at a 100-fold lower pathogen concentration. The greater susceptibility of eggplant was further demonstrated by performing both single- and double-leaf inoculations in the seedlings. Surprisingly, root inoculations resulted in a significantly lower mortality for eggplant than for tomato seedlings. The contrasting susceptibility between the two hosts regarding root and leaf regions indicates the tissue-dependent nature of susceptibility. The study underscores the value of employing multiple host species to uncover new insights into pathogen behaviour and host-pathogen interactions.
CD47 predominates over CD24 as a macrophage immune checkpoint in cancer
Authors: Allen Juliet , Meglan Anna , Vaccaro Kyle , Velarde José , Chen Victor , Ribeiro Juliano , Blandin Jasmine , Gupta Sumeet , Mishra Ranjan , Ho Raymond , Love Jennifer , Reinhardt Ferenc , Bell George W. , Chen Jin , Weinberg Robert , Yang Dian , Weissman Jonathan , Weiskopf Kipp 
Published: November 2024

ABSTRACTMacrophages hold tremendous promise as effectors of cancer immunotherapy, but the best strategies to provoke these cells to attack tumors remain unknown. Here, we evaluated the therapeutic potential of targeting two distinct macrophage immune checkpoints: CD47 and CD24. We found that antibodies targeting these antigens could elicit maximal levels of phagocytosis when combined together in vitro. However, to our surprise, via unbiased genome-wide CRISPR screens, we found that CD24 primarily acts as a target of opsonization rather than an immune checkpoint. In a series of in vitro and in vivo genetic validation studies, we found that CD24 was neither necessary nor sufficient to protect cancer cells from macrophage phagocytosis in most mouse and human tumor models. Instead, anti-CD24 antibodies exhibit robust Fc-dependent activity, and as a consequence, they cause significant on-target hematologic toxicity in mice. To overcome these challenges and leverage our findings for therapeutic purposes, we engineered a collection of 77 novel bispecific antibodies that bind to a tumor antigen with one arm and engage macrophages with the second arm. We discovered multiple novel bispecifics that maximally activate macrophage-mediated cytotoxicity and reduce binding to healthy blood cells, including bispecifics targeting macrophage immune checkpoint molecules in combination with EGFR, TROP2, and CD71. Overall, our findings indicate that CD47 predominates over CD24 as a macrophage immune checkpoint in cancer, and that the novel bispecifics we created may be optimal immunotherapies to direct myeloid cells to eradicate solid tumors.
In silicotarget discovery for aromatic amino acid production inEscherichia coli
Authors: Fonseca André , Avendãno Leslie , Ferreira Sofia , Rocha Isabel 
Published: November 2024

AbstractAromatic amino acids (AAA) and derived compounds are rising on global market demand, which leads to the need of better production means. These compounds are usually produced by means of microbial cell factories. However, bacterial metabolism is complex and highly regulated, which complicates the discovery of new higher yield strains, optimized for the production of these compounds. Dynamic modelling has the capability to solve this problem by predicting metabolic behavior and helping to find targets for strain design. In this paper, a newEscherichia colidynamic model is presented. Evolutionary algorithm processes were used in order to find targets for metabolic engineering strategies for AAA increased production. The solutions obtained are compatible with strategies found in literature, while at the same time presenting new possible targets, not yet reported in literature.
Elevational and Oceanic Barriers Shape the Distribution, Dispersal and Diversity of Aotearoa’s Kapokapowai (Uropetala) Dragonflies
Authors: Tolman Ethan R. , Beatty Chris D. , Goodman Aaron , Ramchand Priscilla , McAllister Tara , Reyes Kelly , Zahara Akifa , Taveras Kassandra , Wade Vincent , Abbott John , Bybee Seth , Frandsen Paul B. , Guralnick Robert , Kohli Manpreet K. , Ware Jessica , Suvorov Anton 
Published: November 2024

AbstractMountains and islands provide an opportunity for studying the biogeography of diversification and population fragmentation. Aotearoa (New Zealand) is an excellent location to investigate both phenomena due to alpine emergence and oceanic separation. While it would be expected that separation across oceanic and elevation gradients are major barriers to gene flow in animals, including aquatic insects, such hypotheses have not been thoroughly tested in these taxa. Here, we show that mountains and oceanic separation function as semi-permeable barriers for Kapokapowai (Uropetala) dragonflies. Although Te Moana o Raukawa (Cook Strait), is likely responsible for some of the genetic structure observed, speciation has not yet occurred in populations separated by the strait. We find no evidence that they are an impervious barrier, but Kā Tiritiri-o-te-Moana (the Southern Alps) significantly restrict gene flow between named species. Our data support the hypothesis of an active colonization of Kā Tiritiri-o-te-Moana by the ancestral population of Kapokapowai, followed by a recolonization of the lowlands. These findings suggest that aquatic insects could be an exciting new frontier in the study of the biogeography and population fragmentation in the landscape of Aotearoa.
Neutrophil-chemoattractant CXCL5 induces lung barrier permeability in acute lung injury
Authors: Berger Sarah , Goekeri Cengiz , Pennitz Peter , Gutbier Birgitt , Michalick Laura , Hoffmann Karen , Lopez-Rodriguez Elena , Gluhovic Vladimir , Wienhold Sandra-Maria , Behrendt Ulrike , Taylor Alexander , Dietert Kristina , Kirsten Holger , Kunder Sandra , Mueller Kristina , Weigel Markus , Hain Torsten , Volkers Sarah M. , Weis Sebastian , Gruber Achim D. , Sander Leif E. , Kuebler Wolfgang M. ,   CAPSyS study group, Witzenrath Martin , Nouailles Geraldine 
Published: November 2024

ABSTRACTRationaleAcute lung injury is frequently caused by pneumonia, and severity correlates with inflammatory cell recruitment and lung barrier failure. Deciphering drug-targetable pathways is of clinical importance.ObjectivesInvestigation of paracrine and autocrine effects of epithelial-derived chemokine CXCL5 in acute lung injury.MethodsWe assessed the role of CXCL5 and related chemokines in patients with severe pneumonia and primary cells or cell lines challenged withStreptococcus pneumoniaeor exposed to mechanical stretch. Furthermore, we evaluated the role of CXCL5 inin vivomodels of acute lung injury through use ofCxcl5-deficient mice andin vitrohuman lung barrier models.ResultsPneumococcal infection and mechanical ventilation were associated with CXCL5 production in human subjects and in mice. CXCL5 was produced by bronchial and alveolar epithelial cells. The alveolar-epithelial barrier was protected in acute lung injury models inCxcl5-deficient mice, independent of alveolar neutrophil recruitment. Single-cell transcriptomics revealed enhanced cell junctional transcripts in epithelial, but not endothelial cells inCxcl5-deficient mice. Accordingly, CXCL5 exposure disrupted the barrier function of TNF-primed human primary alveolar epithelial cells, but not pulmonary microvascular endothelial cells.ConclusionsWe describe a novel function of CXCL5 in acute lung injury. Besides its recognized role in recruiting highly inflammatory cells such as neutrophils, CXCL5 increases alveolar-epithelial barrier permeability. Thus, in severe bacterial pneumonia, targeting of CXCL5 as adjunctive therapy to antibiotics may aid in reducing overshooting inflammation as well as stabilizing lung barrier function.
Mechanism of MCUB-dependent inhibition of mitochondrial calcium uptake
Authors: Rai Neeraj K. , Balynas Anthony M. , MacEwen Melissa JS , Bratt Ashley R. , Sancak Yasemin , Chaudhuri Dipayan 
Published: November 2024

ABSTRACTMitochondrial Ca2+levels are regulated to balance stimulating respiration against the harm of Ca2+overload. Contributing to this balance, the main channel transporting Ca2+into the matrix, the mitochondrial Ca2+uniporter, can incorporate a dominant-negative subunit (MCUB). MCUB is homologous to the pore-forming subunit MCU, but when present in the pore-lining tetramer, inhibits Ca2+transport. Here, using cell lines deleted of both MCU and MCUB, we identify three factors that contribute to MCUB-dependent inhibition. First, MCUB protein requires MCU to express. The effect is mediated via the N-terminal domain (NTD) of MCUB. Replacement of the MCUB NTD with the MCU NTD recovers autonomous expression but fails to rescue Ca2+uptake. Surprisingly, mutations to MCUB that affect interactions with accessory subunits or the conduction pore all failed to rescue Ca2+uptake, suggesting the mechanism of inhibition may involve global rearrangements. Second, using concatemeric tetramers with varying MCU:MCUB ratios, we find that MCUB incorporation does not abolish conduction, but rather inhibits Ca2+influx proportional to the amount of MCUB present in the channel. Reducing rather than abolishing Ca2+transport is consistent with MCUB retaining the highly-conserved selectivity filter DIME sequence. Finally, we apply live-cell Förster resonance energy transfer to establish that the endogenous stoichiometry is 2:2 MCU:MCUB. Taken together, our results suggest MCUB preferentially incorporates into nascent uniporters, and the amount of MCUB protein present linearly correlates with the degree of inhibition of Ca2+transport, creating a precise, tunable mechanism for cells to regulate mitochondrial Ca2+uptake.
Insights into the causes and consequences of DNA repeat expansions from 700,000 biobank participants
Authors: Hujoel Margaux L.A. , Handsaker Robert E. , Kamitaki Nolan , Mukamel Ronen E. , Rubinacci Simone , Palamara Pier F. , McCarroll Steven A. , Loh Po-Ru 
Published: November 2024

AbstractExpansions and contractions of tandem DNA repeats are a source of genetic variation in human populations and in human tissues: some expanded repeats cause inherited disorders, and some are also somatically unstable. We analyzed DNA sequence data, derived from the blood cells of >700,000 participants in UK Biobank and theAll of UsResearch Program, and developed new computational approaches to recognize, measure and learn from DNA-repeat instability at 15 highly polymorphic CAG-repeat loci. We found that expansion and contraction rates varied widely across these 15 loci, even for alleles of the same length; repeats at different loci also exhibited widely variable relative propensities to mutate in the germline versus the blood. The high somatic instability ofTCF4repeats enabled a genome-wide association analysis that identified seven loci at which inherited variants modulateTCF4repeat instability in blood cells. Three of the implicated loci contained genes (MSH3,FAN1, andPMS2) that also modulate Huntington’s disease age-at-onset as well as somatic instability of theHTTrepeat in blood; however, the specific genetic variants and their effects (instability-increasing or-decreasing) appeared to be tissue-specific and repeat-specific, suggesting that somatic mutation in different tissues—or of different repeats in the same tissue—proceeds independently and under the control of substantially different genetic variation. Additional modifier loci included DNA damage response genesATAD5andGADD45A. Analyzing DNA repeat expansions together with clinical data showed that inherited repeats in the 5’ UTR of the glutaminase (GLS)gene are associated with stage 5 chronic kidney disease (OR=14.0 [5.7–34.3]) and liver diseases (OR=3.0 [1.5–5.9]). These and other results point to the dynamics of DNA repeats in human populations and across the human lifespan.
Platelet Factor 4 (PF4) Regulates Hematopoietic Stem Cell Aging
Authors: Zhang Sen , Ayemoba Charles E. , Di Staulo Anna M. , Joves Kenneth , Patel Chandani M. , Leung Eva Hin Wa , Ong Sang-Ging , Nerlov Claus , Maryanovich Maria , Chronis Constantinos , Pinho Sandra 
Published: November 2024

AbstractHematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs. Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhancedin vivoreconstitution capacity, and balanced lineage output. Mechanistically, we identified LDLR and CXCR3 as the HSC receptors transmitting the PF4 signal, with double knockout mice showing exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to the youthful PF4 signaling, highlighting its potential for rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases.Key PointsAge-related attrition of the megakaryocytic niche and associated PF4 downregulation is a central mechanism in HSC aging.PF4 supplementation, acting on LDLR and CXCR3 receptors, rejuvenates the function of aged HSCs.
Visualization of a multi-turnover Cas9 after product release
Authors: Kiernan Kaitlyn A. , Taylor David W. 
Published: November 2024

AbstractWhile the most widely used CRISPR-Cas enzyme is theS. pyogenesCas9 endonuclease (Cas9), it exhibits single-turnover enzyme kinetics which leads to long residence times on product DNA. This blocks access to DNA repair machinery and acts as a major bottleneck during CRISPR-Cas9 gene editing. Although Cas9 can eventually be forcibly removed by extrinsic factors (translocating polymerases, helicases, chromatin modifying complexes, etc), the mechanisms contributing to Cas9 dissociation following cleavage remain poorly understood. Interestingly, it’s been shown that Cas9 can be more easily dislodged when complexes collide with the PAM-distal region of the Cas9 complex or when the strength of Cas9 interactions in this region are weakened. Here, we employ truncated guide RNAs as a strategy to weaken PAM-distal nucleic acid interactions and still support Cas9 activity. We find that guide truncation promotes much faster Cas9 turnover and used this to capture previously uncharacterized Cas9 reaction states. Kinetics-guided cryo-EM enabled us to enrich for rare, transient states that are often difficult to capture in standard workflows. From a single dataset, we examine the entire conformational landscape of a multi-turnover Cas9, including the first detailed snapshots of Cas9 dissociating from product DNA. We discovered that while the PAM-distal product dissociates from Cas9 following cleavage, tight binding of the PAM-proximal product directly inhibits re-binding of new targets. Our work provides direct evidence as to why Cas9 acts as a single-turnover enzyme and will guide future Cas9 engineering efforts.
Risk of evolution driven population-wide emergence of mpox: the paradoxic effect of moderate interventions
Authors: Nedényi F. , Benke J. M. , Szalai M. , Röst G. 
Published: November 2024

AbstractThe global mpox outbreak has recently been declared a public health emergency of international concern. In this paper, we investigate the spread of mpox primarily evolving and propagating within a core population before affecting the general population. A main public health concern is that through evolution, mpox gains the ability to widely spread in the entire population. We examine how effective various intervention strategies are in preventing this from happening. These non-pharmaceutical inter-ventions include reducing disease transmission in the core population, in the general population, or in both. Our analysis encompasses the optimal timing for these interventions, considering the effects of early versus late intervention and the potential impact of different mutation patterns on disease spread. Our findings highlight that effective early intervention can be achieved with lower intensity, while delayed intervention requires stronger measures. Notably, our results reveal an intriguing phenomenon where moderate intervention could lead to worse outcome than no intervention. This counterintuitive outcome arises because moderate restrictions may prolong transmission chains within the core group, leading to more opportunities for the pathogen to acquire mutations resulting in higher transmission potential in the general population. Consequently, a comprehensive understanding of the role of the core group in disease dynamics and the mutation patterns is crucial for developing tailored and effective public health strategies.