bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reading of ingroup politicians’ smiles triggers smiling in the corner of one’s eyes
Authors: Fino Edita , Menegatti Michela , Avenanti Alessio , Rubini Monica 
Published: August 2023

AbstractCapturing political support from spontaneous smile reactions detected in others’ faces can be used to gauge electorate preference. But will a smile elicited in the corner of one’s eye while reading of a favored politician smiling indicate positive disposition and political support for target candidates? From an embodied simulation perspective, we tested whether reading of an ingroup or outgroup politician smiling would trigger morphologically different smiles in faces of readers. In a reading task in the laboratory, participants were presented with subject-verb phrases describing left and right-wing politicians smiling or frowning while their facial muscular reactions were measured via electromyography (EMG) recording from the zygomaticus major (ZM, lip puller muscle), orbicularis oculi (OO, eye corner muscle) and the corrugator supercili (CS, wrinkler of the eyebrows). We expected and found that participants responded with a smile detected at the lip puller (ZM) and eye corner (OO) facial muscles when exposed to portrayals of smiling politicians of same political orientation, and reported more positive emotions towards these latter. When reading about outgroup politicians smiling, there was a weaker activation of the lip corner (ZM) muscle and no activation of the eye corner (OO) muscle, while emotions reported towards outgroup politicians were significantly more negative. Also, a more enhanced frown response (CS) was found for ingroup compared to outgroup politicians’ frown expressions. Present findings suggest that a politician’s smile may go a long way to influence electorates through both non-verbal and verbal pathways. They add another layer to our understanding of how language and social information shape embodied effects in a highly nuanced manner.
GetPrimers: a generalized PCR-based genetic targeting primer designer enabling easy and standardized targeted gene modification across multiple systems
Authors: Miao Zepu , Wang Haiting , Tu Xinyu , Huang Zhengshen , Huang Shujing , Zhang Xinxin , Wang Fan , Huang Zhishen , Li Huihui , Jiao Yue , Gao Song , Zhou Zhipeng , Shan Chun-Min , Li Jing , Yue Jia-Xing 
Published: August 2023

AbstractGenetic targeting (e.g., gene knockout and tagging) based on polymerase chain reaction (PCR) is a simple yet powerful approach for studying gene functions. Although originally developed in classic budding and fission yeast models, the same principle applies to other eukaryotic systems with efficient homologous recombination. One-step-PCR-based genetic targeting is conventionally used but the sizes of the homologous arms that it generates for recombination-mediated genetic targeting are usually limited. Alternatively, gene targeting can also be performed via fusion PCR, which can create homologous arms that are orders of magnitude larger, therefore substantially increases the efficiency of recombination-mediated genetic targeting. Here we present GetPrimers (https://www.evomicslab.org/app/getprimers/), a generalized computational framework and web tool to assist automatic targeting and verification primer design for both one-step-PCR-based and fusion-PCR-based genetic targeting experiments. Moreover, GetPrimers by design runs for any given genetic background of any species with full genome scalability. Therefore, GetPrimers is capable of empowering high-throughput functional genomics assays at multi-population and multi-species levels. Comprehensive experimental validations have been performed for targeting and verification primers designed by GetPrimers across multiple organism systems and experimental setups. We anticipate GetPrimers to become a highly useful and popular tool to facilitate easy and standardized gene modification across multiple systems.Take AwaysDeveloped GetPrimers for generalized primer design of PCR-based genetic targeting.GetPrimers shines with its high versatility and genome-wide scalability.GetPrimers was validated across multiple organisms and experimental setups.
Mapping Natural Product Biosynthetic Hotspots: Prioritizing Conservation for Medicinal Resources
Authors: Fahmi Muhamad , Takanashi Kojiro , Kakei Yusuke , Kubota Yasuhiro , Kanemoto Keiichiro 
Published: August 2023

AbstractBackgroundNatural products (NPs) are vital for promoting human health. Given the increasing threats of biodiversity loss and ecosystem degradation, understanding the geographical hotspots of NPs is essential to strategically prioritize areas for conservation, ensuring the sustained availability of these invaluable medicinal resources.MethodsWe constructed a global diversity map for 1,434 woody angiosperm species, each represented by existing genomic or transcriptomic data. We curated a list of 166 enzymes essential for the biosynthesis and structural diversity of NPs, and identified geographical hotspots of NPs by averaging enzyme presence across the grids. We also examined the distribution pattern of each enzyme. To gain deeper insights into NP distribution patterns, we performed a comparative analysis of enzyme groups responsible for the biosynthesis of two pharmacologically significant compounds with distinct biosynthetic pathways, shikonin derivatives and benzylisoquinoline alkaloids.FindingsOur study reveals a correlation between NP hotspots and biodiversity hotspots, with a subset of markers displaying unique, region-specific patterns. Comparative analysis of enzymes for shikonin derivatives and benzylisoquinoline alkaloids biosynthetic pathways shows similar pattern, with the former demonstrating a unique and region-specific distribution.InterpretationOur findings emphasize the importance of preserving biodiversity hotspots for sustaining NP-based medicinal resources. Additionally, the specific distribution of certain enzyme markers, such as those related to shikonin derivatives, suggests that some NPs may necessitate targeted conservation strategies. This study provides a foundational roadmap for identifying the geographical hotspots of NPs and developing targeted conservation strategies.FundingJapan Society for the Promotion of Science through the Grant-in-Aid for Scientific Research (A) 20H00651.
Stress granule dysfunction via chromophore-associated light inactivation
Authors: Koizumi Takumi , Fujimoto Ai , Kawaguchi Haruka , Kurosaki Tsumugi , Kitamura Akira 
Published: August 2023

AbstractStress granules (SGs) are cytoplasmic condensates composed of various proteins and RNAs that protect translation-associated machinery from harmful conditions during stress. However, the method of spatio-temporal inactivation of condensates such as SGs in live cells to study cellular phenotypes is still in the process of being demonstrated. Here, we show that the inactivation of SG by chromophore-associated light inactivation (CALI) using a genetically encoded red fluorescence protein (SuperNova-Red) as a photosensitizer leads to differences in cell viability during recovery from hyperosmotic stress. CALI delayed the disassembly kinetics of SGs during recovery from hyperosmotic stress. Consequently, CALI could inactivate the SGs, and the cellular fate due to SGs could be analyzed. Furthermore, CALI is an effective spatiotemporal knockdown method for intracellular condensates/aggregates and would contribute to the elucidation of importance of such condensates/aggregates.
Ikzf1 association with Foxp3 for Foxp3-dependent gene repression in Treg cells: induction of autoimmunity and tumor immunity by disrupting the association
Authors: Ichiyama Kenji , Long Jia , Kobayashi Yusuke , Horita Yuji , Kinoshita Takeshi , Nakamura Yamami , Kominami Chizuko , Georgopoulos Katia , Sakaguchi Shimon 
Published: August 2023

SUMMARYThe transcription factor Foxp3 specifically expressed in regulatory T (Treg) cells controls Treg function by repressing some genes and activating others. We have shown here that the transcription factor Ikzf1 associates with Foxp3 via its exon 5 (called IkE5) and that conditional deletion ofIkE5up-regulated the genes, includingIfng, normally repressed by Foxp3 upon TCR stimulation.IkE5-deletion in Treg cells indeed incurred IFN-γ overproduction, which destabilized Foxp3 expression and impaired suppressive function, consequently producing fatal systemic autoimmune diseases and evoking strong anti-tumor immunity. In addition, pomalidomide, which degrades IKZF1 and IKZF3, induced IFN-γ overproduction in human Treg cells. Mechanistically, the Foxp3/Ikzf1/Ikzf3 complex exerted gene-repressing function by competing with epigenetic co-activators, such as p300 and NFAT1, for binding to the target gene loci via chromatin remodeling. Collectively, the association of Ikzf1 with Foxp3 is essential for repressive function of Foxp3, and can be targeted to control autoimmunity and tumor immunity.
Characterization and Genome Sequencing of a Novel Lytic Bacteriophage Infecting Hospital-Associated Carbapenem-ResistantKlebsiella pneumoniaeStrain from Dhaka, Bangladesh
Authors: Khan Fahad , Salman Bhuiyan Mohammad Sami , Tabassum Syeda Naushin , Abrar Hossain Md. Sakib , Rahman Aura , Sadique Abdus , Jaber Abdullah All , Shams Fariza , Bhandare Sudhakar , Hossain Maqsud 
Published: August 2023

AbstractBackgroundMultidrug-resistant bacterial pathogens pose a grave threat to global health, withKlebsiella pneumoniaebeing a particular concern due to its hypervariable extracellular matrix capsule and frequent development of extended-spectrum β-lactamases and other antibiotic defenses. TreatingK. pneumoniae-induced infections with antibiotics is becoming increasingly challenging, necessitating the development of new approaches to address this problem. Phages have emerged as a promising alternative to antibiotics due to their high host specificity, abundance in nature, and evolvability. However, their host specificity makes it difficult to target highly diverse bacterial species using phage therapy.MethodsIn this study, aK. pneumoniaebacteriophage was characterized using double-agar overlay (DLA), host range testing, and Oxford Nanopore Technologies (ONT) MinION long-read sequencer for whole genome sequencing.ResultsThe phage was isolated from a hospital sewage drain and showed activity against multi-drug resistantK. pneumoniae, and showed extensive activity againststrains from Dhaka, Bangladesh. Sequence analysis confirmed that the phage belonged to the familySiphoviridae, subfamily UnclassifiedWebervirus.ConclusionThe findings of this study highlight the potential of sewage samples as a rich source of bacteriophages against medically important pathogens. Further studies on the biological characteristics of thisK. pneumoniaebacteriophage could yield valuable insights into the development of a potential therapeutic agent forK. pneumoniaespecific infections. It is worth noting that although the viruses were only found in sewage from places with increasing reports ofK. pneumoniaeinfections, such as public hospitals, they hold promise for addressing the growing problem of multidrug-resistant bacterial pathogens.
Mitochondrial complex I as a diagnostic and therapeutic target in a mouse model of tauopathy
Authors: Wong Jia Hui , Vincent Anselm S. , Khanapur Shivashankar , Rong Tang Jun , Ramasamy Boominathan , Hartimath Siddesh , Cheng Peter , Tsukada Hideo , Robins Edward G , Goggi Julian L , Barron Anna M. 
Published: August 2023

AbstractDysfunction of the energy producing organelle of the cell, mitochondria, plays a pivotal role in Alzheimer’s disease (AD). We have recently used a novel positron emission tomographic (PET) imaging tracer targeting mitochondrial complex I (MC-I) to visualize mitochondrial abnormalities in the brains of living tau transgenic (TauTg) mice. MC-I mediates the first and limiting step in oxidative phosphorylation, the primary source of neuronal energy production. Here we used MC-I-PET to test if inhibition of mutant tau expression through transgene suppression with doxycycline could reverse mitochondrial defects in a mouse model of tauopathy and evaluate the efficacy of a MC-I-targeted candidate therapeutic, Mdivi-1. We found that late-stage suppression of mutant tau did not rescue mitochondrial deficits measuredin vivoby MC-I-PET, despite reduced burden of tauopathy and neuroinflammation. These findings demonstrate that mitochondrial dysfunction may continue even if tauopathy is halted, particularly if initiated at late-stage disease. Further, we demonstrate the potential application of MC-I-PET for monitoring therapeutic efficacy, surprisingly finding detrimental effects of the mitochondrial-targeted candidate therapeutic, Mdivi-1, in TauTg mice. These findings directly contrast with the beneficial effects of Mdivi-1 observed in other models of neurodegeneration. Together, our findings highlight the need for clinical endpoints measuring mitochondrial damage in addition to markers of tauopathy in the assessment of disease prognosis and efficacy of candidate therapeutics and demonstrates the potential application of MC-I-PET to meet this need.
Structural basis of allosteric modulation of metabotropic glutamate receptor activation and desensitization
Authors: Strauss Alexa , Gonzalez-Hernandez Alberto J. , Lee Joon , Abreu Nohely , Selvakumar Purushotham , Salas-Estrada Leslie , Kristt Melanie , Marx Dagan C. , Gilliland Kristen , Melancon Bruce J. , Filizola Marta , Meyerson Joel , Levitz Joshua 
Published: August 2023

AbstractThe metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled receptors which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) to transmembrane domains (TMDs) to drive intracellular signaling. Pharmacologically, mGluRs can be targeted either at the LBDs by glutamate and synthetic orthosteric compounds or at the TMDs by allosteric modulators. Despite the potential of allosteric TMD-targeting compounds as therapeutics, an understanding of the functional and structural basis of their effects on mGluRs is limited. Here we use a battery of approaches to dissect the distinct functional and structural effects of orthosteric versus allosteric ligands. We find using electrophysiological and live cell imaging assays that both agonists and positive allosteric modulators (PAMs) can drive activation and desensitization of mGluRs. The effects of PAMs are pleiotropic, including both the ability to boost the maximal response to orthosteric agonists and to serve independently as desensitization-biased agonists across mGluR subtypes. Conformational sensors reveal PAM-driven inter-subunit re-arrangements at both the LBD and TMD. Motivated by this, we determine cryo-electron microscopy structures of mGluR3 in the presence of either an agonist or antagonist alone or in combination with a PAM. These structures reveal PAM-driven re-shaping of intra- and inter-subunit conformations and provide evidence for a rolling TMD dimer interface activation pathway that controls G protein and beta-arrestin coupling.Highlights-Agonists and PAMs drive mGluR activation, desensitization, and endocytosis-PAMs are desensitization-biased and synergistic with agonists-Four combinatorial ligand conditions reveal an ensemble of full-length mGluR structures with novel interfaces-Activation and desensitization involve rolling TMD interfaces which are re-shaped by PAM
Neutron crystallographic refinement withREFMAC5 of theCCP4 suite
Authors: Catapano Lucrezia , Long Fei , Yamashita Keitaro , Nicholls Robert A. , Steiner Roberto A. , Murshudov Garib N. 
Published: August 2023

AbstractHydrogen (H) atoms are abundant in macromolecules and often play critical roles in enzyme catalysis, ligand recognition processes, and protein-protein interactions. However, their direct visualisation by diffraction techniques is challenging. Macromolecular X-ray crystallography affords the localisation of the most ordered H atoms at (sub-)atomic resolution (around 1.2 Å or higher), that is not often attainable. Differently, neutron diffraction methods enable the visualisation of most H atoms, typically in the form of deuterium (D) atoms at much more common resolution values (better than 2.5 Å). Thus, neutron crystallography, although technically demanding, is often the method of choice when direct information on protonation states is sought.REFMAC5 of the Collaborative Computational Project No. 4 (CCP4) is a program for the refinement of macromolecular models against X-ray crystallographic and cryo-EM data. This contribution describes its extension to include the refinement of structural models obtained from neutron crystallographic data. Stereochemical restraints with accurate bond distances between H atoms and their parent atom nuclei are now part of theCCP4 Monomer Library, the source of prior chemical information used in refinement. One new feature for neutron data analysis inREFMAC5 is the refinement of the protium/deuterium (1H/D) fraction. This parameter describes the relative1H/D contribution to neutron scattering for H atoms. The newly developedREFMAC5algorithms were tested by performing the (re-)refinement of several entries available in the PDB and of one novel structure (FutA) by using either (i) neutron data-only or (ii) neutron data supplemented by external restraints to a reference X-ray crystallographic structure. Re-refinement withREFMAC5afforded models characterised byR-factor values that are consistent with, and in some cases better than, the originally deposited values. The use of external reference structure restraints during refinement has been observed to be a valuable strategy especially for structures at medium-low resolution.SynopsisThe macromolecular refinement packageREFMAC5 of theCCP4 suite has been extended with the incorporation of algorithms for neutron crystallography.
A spatially constrained independent component analysis jointly informed by structural and functional network connectivity
Authors: Fouladivanda Mahshid , Iraji Armin , Wu Lei , van Erp Theodorus G.M. , Belger Aysenil , Hawamdeh Faris , Pearlson Godfrey D. , Calhoun Vince D. 
Published: August 2023

AbstractThere are a growing number of neuroimaging studies motivating joint structural and functional brain connectivity. Brain connectivity of different modalities provides insight into brain functional organization by leveraging complementary information, especially for brain disorders such as schizophrenia. In this paper, we propose a multi-modal independent component analysis (ICA) model that utilizes information from both structural and functional brain connectivity guided by spatial maps to estimate intrinsic connectivity networks (ICNs). Structural connectivity is estimated through whole-brain tractography on diffusion-weighted MRI (dMRI), while functional connectivity is derived from resting-state functional MRI (rs-fMRI). The proposed structural-functional connectivity and spatially constrained ICA (sfCICA) model estimates ICNs at the subject level using a multi-objective optimization framework. We evaluated our model using synthetic and real datasets (including dMRI and rs-fMRI from 149 schizophrenia patients and 162 controls). Multi-modal ICNs revealed enhanced functional coupling between ICNs with higher structural connectivity, improved modularity, and network distinction, particularly in schizophrenia. Statistical analysis of group differences showed more significant differences in the proposed model compared to the unimodal model. In summary, the sfCICA model showed benefits from being jointly informed by structural and functional connectivity. These findings suggest advantages in simultaneously learning effectively and enhancing connectivity estimates using structural connectivity.
Goblet cell invasion promotes breaching of respiratory epithelia by an opportunistic human pathogen
Authors: Swart A. Leoni , Laventie Benoît-Joseph , Sütterlin Rosmarie , Junne Tina , Yu Xiao , Karagkiozi Evdoxia , Okujava Rusudan , Jenal Urs 
Published: August 2023

SummaryWhile commensal bacteria generally respect natural barriers of the human body, pathogens are able to breach epithelia, invade deeper tissue layers and cause life-threatening infections.Pseudomonas aeruginosa, an opportunistic human pathogen, is a leading cause of severe hospital-acquired pneumonia, with mortality rates as high as 50% in mechanically ventilated patients1–3. Effective colonization and breaching of lung mucosa are hallmarks ofP. aeruginosapathogenesis4. Although virulence factors and behavioral strategies ofP. aeruginosahave been described5,6, it has remained unclear how this pathogen disseminates on functional mucosal surfaces, how it avoids mucociliary clearance and how it invades the tissue barrier. Using fully differentiated human lung epithelia, we demonstrate thatP. aeruginosaefficiently spreads on the apical tissue surface before it breaches epithelia by specifically invading mucus secreting goblet cells. Internalization leads to host cell death and expulsion and the formation of ruptures of the epithelial barrier. Rupture sites are rapidly colonized by extracellular bacteria through active chemotaxis, leading to increasing tissue damage and successful pathogen translocation to the unprotected basolateral side of the epithelium. We show that cell invasion is promoted by two Type-6 toxin secretion systems (T6SS), while Type-3 (T3SS) mediates cell death of infected goblet cells. T3SS mutants invade goblet cells normally, but internalized bacteria fail to trigger goblet cell expulsion and instead show unrestrained intracellular replication. While the effective shedding of infected host cells reveals potent tissue protection mechanisms, the discovery of an intracellular lifestyle ofP. aeruginosain human lung epithelia provides new entry points into investigating the intersection of antibiotic and immune mechanisms during lung infections. By demonstrating thatP. aeruginosauses a combination of specific virulence factors and collective behavior to invade goblet cells and breach the lung tissue barrier from within, these studies reveal novel mechanisms underlying lung infection dynamics under physiological conditions.
Degeneracy in negative feedback (NFBL) and incoherent feedforward (IFFL) loops: Adaptation and resonance
Authors: Ventura Alejandra C. , Rotstein Horacio G. 
Published: August 2023

AbstractDegeneracy in dynamic models refers to these situations where multiple combinations of parameter values produce identical patterns for the observable variable. We investigate this phenomenon in two qualitatively different adaptive circuit mechanisms: nonlinear feedback loop (NFBL) and incoherent feedback loop (IFFL). We use minimal models of these circuit types together with analytical calculations, regular perturbation analysis, dynamical systems tools and numerical simulations. In response to constant (or step-constant) inputs, NFBLs and IFFLs produce and overshoot allowing the observable variable to return to a value closer to baseline than the peak (adaptation). We identify the dynamic principles underlying the emergence of degeneracy in adaptive patterns both within and across circuit types in representative NFBL and IFFL models in terms of biologically plausible parameters. We identify the conditions under which degeneracy persists in response to oscillatory inputs with arbitrary frequencies, giving rise to resonance and phasonance degeneracy. This naturally extends to the response of adaptive systems to time-dependent inputs within a relatively large class. By using phase-plane analysis, we provide a mechanistic, dynamical systems-based interpretation of degeneracy. Our results have implication for the understanding of adaptive systems, for the relationship between adaptive and resonant/phasonant systems, for the understanding of complex biochemical circuits, for neuronal computation, and for the development of methods for circuit and dynamical systems reconstruction based on experimental or observational data.