bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contributions of tactile information to the sense of agency and its metacognitive representations
Authors: Charalampaki Angeliki , Ciston Anthony Buck , Filevich Elisa 
Published: December 2023

AbstractWe compared the contribution of tactile information to other sources of information in our representations of agency. Participants (N = 40) reached with their right hand toward a ridged plate with a specific orientation and saw online feedback that could match or differ from their action in one of three ways: the physical plate’s orientation, the action’s timing, or the hand’s position in space. Absolute subjective ratings revealed that an increased mismatch in tactile information led to a diminished sense of agency, similar to what has been reported for spatial and temporal mismatches. Further, estimations of metacognitive efficiency revealed similar M-ratios in the identification of tactile violation predictions as compared to temporal violations (but lower than spatial). These findings emphasize the importance of tactile information in shaping our experience of acting voluntarily, and show how this important component can be experimentally probed.Statement of RelevanceThe sense of agency is the feeling that we are the authors of our actions. It is essential not only for the control we assert over our bodies but also for how we interact with interfaces like a computer or a mobile phone. Despite the central role of touch in our daily activities, the role of tactile information in forming our sense of agency is often overlooked. In this project, we used a novel experimental design that allowed us to compare the role of tactile information relative to two other sources of information that have been previously reported to affect our agency, namely temporal and spatial information of the action. We provide evidence for the first time that tactile information is crucial for our subjective experience of agency and a tool to study this role further.
AAV-mediated expression of mouse or human GLDC normalises metabolic biomarkers in a GLDC-deficient mouse model of Non-Ketotic Hyperglycinemia
Authors: Leung Kit-Yi , Santos Chloe , De Castro Sandra C.P. , Diaz Diana Gold , Copp Andrew J. , Waddington Simon , Greene Nicholas DE 
Published: December 2023

AbstractNon-Ketotic Hyperglycinemia (NKH) is a rare inborn error of metabolism caused by impaired function of the glycine cleavage system (GCS) and characterised by accumulation of glycine in body fluids and tissues. NKH is an autosomal recessive condition and the majority of affected individuals carry mutations inGLDC(glycine decarboxylase). Current treatments for NKH are not effective or curative. As a monogenic condition with known genetic causation, NKH is potentially amenable to gene therapy. An AAV9-based expression vector was designed to target sites of GCS activity. Using an ubiquitous promoter to drive expression of a GFP reporter, transduction of liver and brain was confirmed following intra-venous and/or intra-cerebroventricular administration to neonatal mice. Using the same capsid and promoter with transgenes to express mouse or human GLDC, vectors were then tested in a GLDC-deficient mice that provide a model of NKH. GLDC-deficient mice exhibited elevated plasma glycine concentration and accumulation of glycine in liver and brain tissues as previously observed. Moreover, the folate profile indicated suppression of folate one carbon metabolism (FOCM) in brain tissue, as found at embryonic stages, and reduced abundance of FOCM metabolites including betaine and choline. Neonatal administration of vector achieved reinstatement ofGLDCmRNA and protein expression in GLDC-deficient mice. Treated GLDC-deficient mice showed significant lowering of plasma glycine, confirming functionality of vector expressed protein. AAV9-GLDC treatment also led to lowering of brain tissue glycine, and normalisation of the folate profile indicating restoration of glycine-derived one-carbon supply. These findings support the hypothesis that AAV-mediated gene therapy may offer potential in treatment of NKH.
Production of single-cell-protein (SCP) / poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) matrices through fermentation of archaeaHaloferax mediterranei
Authors: Unis Razan , Gnaim Rima , Kashyap Mrinal , Shamis Olga , Gnayem Nabeel , Gozin Michael , Liberzon Alexander , Gnaim Jallal , Golberg Alexander 
Published: December 2023

AbstractThe idea ofin-situintegrating poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) sieves in a single-cell protein (SCP) represents a promising approach to enhance the properties of microbial biomass as protein alternatives. Archaea SCP/PHBV matrix was successfully produced with a concentration of 8.0 ± 0.1 g L-1and a productivity of 11.1 mg L-1h-1usingHaloferax mediterranei. This was achieved by employing 30 g L-1of enzymatically hydrolyzed bread waste (BW) and 200 g L-1of red sea salt at 42 °C and with shaking at 150 rpm for 3 days. The amino acid profile of the SCP/PHBV matrix revealed a total amino acid content of 358 g kg-1, including 147 g kg-1of essential amino acids. The protein quality of theH. mediterraneiSCP/PHBV matrix was assessed using thein-vitroenzyme digestion method, indicating a high-quality protein with anin-vitrodigestibility value of 0.91 and a protein digestibility-corrected amino acid score (PDCAAS) of 0.78. The PHBV component (36.0 ± 6.3% w/w) in the SCP/PHBV matrix consisted of a copolymer of 3-hydroxybutyrate and 3- hydroxyvalerate in a 91:9 mol% ratio, respectively. The simultaneous production of PHBV polymeric sieves within theH. mediterraneiSCP/PHBV matrix provides an alternative protein source with enhanced physicochemical and thermal properties.HighlightsSCP/PHBV matrices were produced from wasted bread by archaeaH. mediterranei.This is the first report that explored the production and properties of SCP/PHBV.The presence of PHBV in SCP affected its physicochemical and thermal properties.SCP/PHBV with high-quality protein was achieved with a PDCAAS value of 0.78.Graphical abstract
Unraveling molecular basis for reduced neuraminidase inhibitors susceptibility in highly pathogenic avian influenza A (H5N1) viruses isolated from chickens in India
Authors: Kumar Naveen , Sood Richa , Gupta Chhedi Lal , Bhatia Sandeep , Kumar Manoj , Nagarajan S. , Tosh C. , Murugkar H.V. , Sanyal Aniket 
Published: December 2023

AbstractThe increasing resistance cases in influenza viruses to different classes of antiviral drugs, necessitates the in-depth analysis of molecular interactions governing reduced susceptibility to these drugs. This study explores the molecular basis of neuraminidase inhibitors resistance in avian H5N1 influenza viruses identified in our previous research. Using comprehensive modeling and docking tools, we investigated two isolates—A/chicken/India/85459/2008 (N294S) and A/chicken/WestBengal/142121/2008 (E119A + I117V). The N294S mutation conferred oseltamivir resistance while retaining zanamivir susceptibility, whereas the E119A + I117V mutations led to zanamivir resistance while reducing oseltamivir susceptibility. Molecular interactions analysis unveiled varied fitness levels, hydrogen bonding, and affinity transitions associated with N294S and E119A + I117V mutations. This study provides crucial insights into molecular interactions responsible for reduced susceptibility to neuraminidase inhibitors, which is essential for optimizing antiviral strategies and pandemic preparedness.
The histone methyltransferase SETD2 regulates HIV expression and latency through a post-transcriptional mechanism
Authors: Bussey-Sutton Cameron , Ward Airlie , Turner Anne-Marie W , Peterson Jackson J , Emery Ann , Longoria Arturo SR , Margolis David M , Strahl Brian D , Browne Edward P 
Published: December 2023

AbstractHIV can enter a state of transcriptional latency in CD4 T cells, allowing the virus to evade the host immune system and persist during antiretroviral therapy. Thus, understanding the mechanisms that drive HIV latency, and developing strategies to reactivate viral expression in latently infected cells, are key goals for achieving a cure for HIV. The full spectrum of mechanisms behind the regulation of HIV expression and latency are unclear but include covalent modifications to cellular histones that are associated with the integrated provirus. Here we investigate the role of the SETD2 histone methyltransferase, which deposits H3K36 trimethylation (H3K36me3) cotranscriptionally at genes, in HIV infection. We show that prevention of H3K36me3 through addition of a potent and selective inhibitor of SETD2 (EPZ-719) in human T cells leads to reduced post-integration viral gene expression and accelerated the emergence of a latently infected pool within a population of infected cells. CRISPR/Cas9-mediated knockout of SETD2 in HIV infected primary CD4 T cells confirmed the role of SETD2 in HIV expression. Intriguingly, EPZ-719 exposure also enhanced responsiveness of latently infected cells to latency reversal with the HDAC inhibitor vorinostat. Transcriptomic profiling of EPZ-719 exposed HIV-infected cells identified numerous cellular pathways impacted by EPZ-719. Finally, we show SETD2 inhibition does not affect HIV viral transcription, but instead leads to a shift in the pattern of viral RNA splicing – a result that would be predicted to reduce HIV expression. These results identify SETD2 and H3K36me3 as novel regulators of HIV expression and latency through a post-transcriptional mechanism.
Synergistic Effects of Sulopenem in Combination with Cefuroxime or Durlobactam againstMycobacterium abscessus
Authors: Dousa Khalid M. , Shin Eunjeong , Kurz Sebastian G. , Plummer Mark , Nantongo Mary , Bethel Christopher R. , Taracila Magdalena A. , Nguyen David C. , Kreiswirth Barry N. , Daley Charles L. , Remy Kenneth E. , Holland Steven M. , Bonomo Robert A. 
Published: December 2023

ABSTRACTMycobacterium abscessus(Mab) affects patients with immunosuppression, Cystic Fibrosis (CF), or underlying structural lung diseases. Additionally,Mabposes clinical challenges due to its resistance to multiple antibiotics. Herein, we investigated the synergistic effect of dual β-lactams [sulopenem and cefuroxime (CXM)] or the combination of sulopenem and CXM with a β-lactamase inhibitors [BLI; avibactam (AVI) or durlobactam (DUR)]. The sulopenem-CXM combination yielded low minimum inhibitory concentration MIC values for 54 clinicalMabisolates and ATCC19977 (MIC50and MIC90≤ 0.25 μg/mL). Similar synergistic effects were observed in time-kill studies conducted at concentrations achievable in clinical settings. Sulopenem-CXM outperformed monotherapy, yielding ∼1.5 Log10CFU/mL reduction during 10 days. Addition of BLIs enhanced this antibacterial effect, resulting in additional reduction of CFUs (∼3 Log10for sulopenem-CXM and AVI and ∼4 Log10for sulopenem-DUR). Exploration of the potential mechanisms of the synergy focused on their interactions with L,D-transpeptidases (LDTs; LDTMab1–LDTMab4), Penicillin-Binding-Protein B (PBP-B), and D,D-Carboxypeptidase (DDC). Acyl complexes identified via mass spectrometry analysis, demonstrated the binding of sulopenem with LdtMab2-LdtMab4, DDC, and PBP B, and CXM with LdtMab2and PBP-B. Molecular docking suggested formation of a covalent adduct between sulopenem and LdtMab2after the nucleophilic attack of the cysteine residue at the β-lactam carbonyl carbon, leading to the cleavage of the β-lactam ring, and the establishment of a thioester bond linking the LdtMab2with sulopenem. In conclusion, we demonstrated the biochemical basis of the synergy of sulopenem-CXM with or without BLI. These findings potentially broaden selection of oral therapeutic agents to combatMab.
Comparative genomics and the salivary transcriptome of the redbanded stink bug shed light on its high damage potential to soybean
Authors: Walt Hunter K. , King Jonas G. , Towles Tyler B. , Ahn Seung-Joon , Hoffmann Federico G. 
Published: December 2023

ABSTRACTThe redbanded stink bug,Piezodorus guildinii(Westwood) (Hemiptera: Pentatomidae), is a significant soybean pest in the Americas, inflicting more physical damage on soybean than other native stink bugs. Studies suggest that its heightened impact is attributed to the aggressive digestive properties of its saliva. Despite its agricultural importance, the factors driving its greater ability to degrade plant tissues have remained unexplored in a genomic evolutionary context. In this study, we hypothesized that lineage-specific gene family expansions have increased the dosage of digestive genes expressed in the salivary glands. To investigate this, we annotated a previously published genome assembly of the redbanded stink bug and performed a comparative genomic analysis on 11 hemipteran species and reconstructed patterns of gene duplication, gain, and loss in the redbanded stink bug. We also performed RNA-seq on the redbanded stink bug’s salivary tissues, along with the rest of the body without salivary glands. We identified hundreds of differentially expressed salivary genes, including a subset lost in other stink bug lineages but retained and expressed in the redbanded stink bug’s salivary glands. These genes were significantly enriched with protein families involved in proteolysis, potentially explaining the redbanded stink bug’s heightened damage to soybeans. Contrary to our hypothesis, we found no support for an increased dosage of digestive genes in the salivary glands of the redbanded stink bug. Nonetheless, these results provide insight into the evolution of this important crop pest, establishing a link between its genomic history and its agriculturally important physiology.SIGNIFICANCE STATEMENTThe redbanded stink bug, an important soybean pest in the Americas, inflicts greater damage to soybean due to higher salivary digestion. We employed comparative genomics and analyses of the salivary transcriptome to explore this and found that the differential retention of ancestral salivary genes may explain this phenomenon better than gene gains or duplications in the redbanded stink bug genome. We identify a distinct set of genes in the salivary gland that were differentially retained and expressed in the redbanded stink bug lineage, demonstrating enrichment in proteolytic function. This discovery offers a potential explanation for the redbanded stink bug’s elevated damage to soybean crops.
Targetable leukemia dependency on noncanonical PI3Kγ signaling
Authors: Luo Qingyu , Raulston Evangeline G. , Prado Miguel A. , Wu Xiaowei , Gritsman Kira , Yan Kezhi , Booth Christopher A. G. , Xu Ran , van Galen Peter , Doench John G. , Shimony Shai , Long Henry W. , Neuberg Donna S. , Paulo Joao A. , Lane Andrew A. 
Published: December 2023

AbstractPhosphoinositide 3-kinase gamma (PI3Kγ) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and activation of phosphoinositide 3-kinase regulatory subunit 5 (PIK3R5), which encodes a regulatory subunit of PI3Kγ and stabilizes the active enzymatic complex. Mechanistically, we identify p21 (RAC1) activated kinase 1 (PAK1) as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency independently of Akt kinase. PI3Kγ inhibition dephosphorylates PAK1, activates a transcriptional network of NFκB-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukemias with activatedPIK3R5, either at baseline or by exogenous inflammatory stimulation. Notably, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Taken together, our study reveals a targetable dependency on PI3Kγ/PAK1 signaling that is amenable to near-term evaluation in patients with acute leukemia.
A Boundary Element Method of Bidomain Modeling for Predicting Cellular Responses to Electromagnetic Fields
Authors: Czerwonky David M. , Aberra Aman S. , Gomez Luis J. 
Published: December 2023

AbstractObjectiveCommonly used cable equation-based approaches for determining the effects of electromagnetic fields on excitable cells make several simplifying assumptions that could limit their predictive power. Bidomain or “whole” finite element methods have been developed to fully couple cells and electric fields for more realistic neuron modeling. Here, we introduce a novel bidomain integral equation designed for determining the full electromagnetic coupling between stimulation devices and the intracellular, membrane, and extracellular regions of neurons.MethodsOur proposed boundary element formulation offers a solution to an integral equation that connects the device, tissue inhomogeneity, and cell membrane-induced E-fields. We solve this integral equation using first-order nodal elements and an unconditionally stable Crank-Nicholson time-stepping scheme. To validate and demonstrate our approach, we simulated cylindrical Hodgkin-Huxley axons and spherical cells in multiple brain stimulation scenarios.Main ResultsComparison studies show that a boundary element approach produces accurate results for both electric and magnetic stimulation. Unlike bidomain finite element methods, the bidomain boundary element method does not require volume meshes containing features at multiple scales. As a result, modeling cells, or tightly packed populations of cells, with microscale features embedded in a macroscale head model, is made computationally tractable, and the relative placement of devices and cells can be varied without the need to generate a new mesh.SignificanceDevice-induced electromagnetic fields are commonly used to modulate brain activity for research and therapeutic applications. Bidomain solvers allow for the full incorporation of realistic cell geometries, device E-fields, and neuron populations. Thus, multi-cell studies of advanced neuronal mechanisms would greatly benefit from the development of fast-bidomain solvers to ensure scalability and the practical execution of neural network simulations with realistic neuron morphologies.
Plant infection by the necrotrophic fungusBotrytisrequires actin-dependent generation of high invasive turgor pressure
Authors: Müller Tobias , Bronkhorst Jochem , Müller Jonas , Safari Nassim , Hahn Matthias , Sprakel Joris , Scheuring David 
Published: December 2023

AbstractThe devastating pathogenBotrytis cinereainfects a broad spectrum of host plants, causing great socio-economic losses. The necrotrophic fungus rapidly kills plant cells, nourishing their walls and cellular contents. To this end, necrotrophs secretes a cocktail of cell wall degrading enzymes, phytotoxic proteins and metabolites. Additionally, many fungi produce specialized invasion organs that generate high invasive pressures to force their way into the plant cell. However, for most necrotrophs, includingBotrytis, the biomechanics of penetration and its contribution to virulence are poorly understood. Here we use a combination of quantitative micromechanical imaging and CRISPR-Cas guided mutagenesis to show thatBotrytisuses substantial invasive pressure, in combination with strong surface adherence, for penetration. We found that the fungus establishes a unique mechanical geometry of penetration that develops over time during penetration events, and which is actin cytoskeleton dependent. Furthermore, interference of force generation by blocking actin polymerization was found to decreaseBotrytisvirulence, indicating that also for necrotrophs, mechanical pressure is important in host colonization. Our results demonstrate for the first time mechanistically how a necrotrophic fungus such asBotrytisemploys this “brute force” approach, in addition to the secretion of lytic proteins and phytotoxic metabolites, to overcome plant host resistance.
Hybrid adaptation is hampered by Haldane’s sieve
Authors: Bautista Carla , Gagnon-Arsenault Isabelle , Utrobina Mariia , Fijarczyk Anna , Bendixsen Devin P. , Stelkens Rike , Landry Christian R. 
Published: December 2023

AbstractHybrids between species exhibit plastic genomic architectures that foster phenotypic diversity. Their genomic instability also incurs costs, potentially limiting adaptation. When challenged to evolve in an environment containing a UV mimetic drug, yeast hybrids have reduced adaptation rates compared to parents. We hypothesized that this reduction could result from a faster accumulation of genomic changes, but we found no such association. Alternatively, we proposed that hybrids might lack access to adaptive mutations occurring in the parents, yet, we identified mutations in the same genes (PDR1 and YRR1), suggesting similar molecular adaptation mechanisms. However, mutations in these genes tended to be homozygous in the parents but heterozygous in the hybrids. We hypothesized that a lower rate of loss of heterozygosity (LOH) in hybrids could limit fitness gain. Using genome editing, we demonstrated that mutations display incomplete dominance, requiring homozygosity to show full impact and to circumvent Haldane’s sieve, which favors the fixation of dominant mutations. We used frozen ‘fossils’ to track genotype frequency dynamics and confirmed that LOH occurs at a slower pace in hybrids than in parents. Together, these findings show that Haldane’s sieve slows down adaptation in hybrids, revealing an intrinsic constraint of hybrid genomic architecture that can limit the role of hybridization in adaptive evolution.
Powdery mildew infection induces a non-canonical route to storage lipid formation at the expense of host thylakoid lipids to fuel its spore production
Authors: Jaenisch J. , Xue H. , Schläpfer J. , McGarrigle E.R. , Louie K. , Northen T.R. , Wildermuth M.C. 
Published: December 2023

ABSTRACTPowdery mildews are obligate biotrophic fungi that manipulate plant metabolism to supply lipids, particularly during fungal asexual reproduction when fungal lipid demand is extensive. The mechanism for host response to fungal lipid demand has not been resolved. We found storage lipids, triacylglycerols (TAGs), increase by 3.5-fold in powdery mildew-infected tissue. In addition, lipid bodies, not observable in uninfected mature leaves, are present in both cytosol and chloroplasts at the infection site. This is concurrent with decreased thylakoid membrane lipids and thylakoid disassembly. Together, these findings indicate that the powdery mildew induces localized thylakoid membrane degradation to promote storage lipid formation. Genetic analyses show the canonical ER pathway for TAG synthesis does not support powdery mildew spore production. Instead, Arabidopsis DIACYLGLYCEROL ACYLTRANSFERASE 3 (DGAT3), shown to be chloroplast-localized and to be largely responsible for powdery mildew-induced chloroplast TAGs, promotes fungal asexual reproduction. Powdery mildew-induced leaf TAGs are enriched in thylakoid associated fatty acids, which are also present in the produced spores. This research provides new insights on obligate biotrophy and plant lipid metabolism plasticity and function. Furthermore, by understanding how photosynthetically active leaves can be converted into TAG producers, more sustainable and environmentally benign plant oil production could be facilitated.