bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting protein-ligand neosurfaces using a generalizable deep learning approach
Authors: Marchand Anthony , Buckley Stephen , Schneuing Arne , Pacesa Martin , Gainza Pablo , Elizarova Evgenia , Neeser Rebecca M. , Lee Pao-Wan , Reymond Luc , Elia Maddalena , Scheller Leo , Georgeon Sandrine , Schmidt Joseph , Schwaller Philippe , Maerkl Sebastian J. , Bronstein Michael , Correia Bruno E. 
Published: March 2024

AbstractMolecular recognition events between proteins drive biological processes in living systems. However, higher levels of mechanistic regulation have emerged, where protein-protein interactions are conditioned to small molecules. Here, we present a computational strategy for the design of proteins that target neosurfaces, i.e. surfaces arising from protein-ligand complexes. To do so, we leveraged a deep learning approach based on learned molecular surface representations and experimentally validated binders against three drug-bound protein complexes. Remarkably, surface fingerprints trained only on proteins can be applied to neosurfaces emerging from small molecules, serving as a powerful demonstration of generalizability that is uncommon in deep learning approaches. The designed chemically-induced protein interactions hold the potential to expand the sensing repertoire and the assembly of new synthetic pathways in engineered cells.
A benchmarked, high-efficiency prime editing platform for multiplexed dropout screening
Authors: Cirincione Ann , Simpson Danny , Ravisankar Purnima , Solley Sabrina C. , Yan Jun , Singh Mona , Adamson Britt 
Published: March 2024

AbstractPrime editing installs precise edits into the genome with minimal unwanted byproducts, but low and variable editing efficiencies have complicated application of the approach to high-throughput functional genomics. Leveraging several recent advances, we assembled a prime editing platform capable of high-efficiency substitution editing across a set of engineered prime editing guide RNAs (epegRNAs) and corresponding target sequences (80% median intended editing). Then, using a custom library of 240,000 epegRNAs targeting >17,000 codons with 175 different substitution types, we benchmarked our platform for functional interrogation of small substitution variants (1-3 nucleotides) targeted to essential genes. Resulting data identified negative growth phenotypes for nonsense mutations targeted to ∼8,000 codons, and comparing those phenotypes to results from controls demonstrated high specificity. We also observed phenotypes for synonymous mutations that disrupted splice site motifs at 3′ exon boundaries. Altogether, we establish and benchmark a high-throughput prime editing approach for functional characterization of genetic variants with simple readouts from multiplexed experiments.
Tracking how attentional focusing in working memory benefits long-term memory
Authors: Wang Sisi , van Ede Freek 
Published: March 2024

AbstractHuman working memory serves as a key gateway to the formation of lasting memories in long-term memory. While it is well established how attentional focusing during working memory can prioritize internal representation for an imminent task, how such internal focusing affects subsequent long-term memory remains less understood. Here, we developed a two-stage visual working memory/long-term memory task in which we cued attention during working memory and tracked the dynamics of attentional deployment through a recently established gaze marker of internal focusing. Across two experiments, we found that attentional focusing in visual working memory reliably affects subsequent visual long-term memory, driven by a benefit to internally attended objects without a cost to unattended objects. Gaze biases associated with internal focusing revealed how this benefit was mediated by the speed – but not necessarily the degree – of attentional deployment, with faster attentional deployment predicting better subsequent memory. Together, these results highlight how attentional focusing in working memory benefits subsequent long-term memory, and uncover the dynamic processes that instill such lasting benefits – offering new insights into the catalyst function of attention in bridging working memory and long-term memory.
Spatial structure could explain the maintenance of alternative reproductive tactics in tree cricket males
Authors: Sadiq Mohammed Aamir , Bhat Ananda Shikhara , Guttal Vishwesha , Balakrishnan Rohini 
Published: March 2024

AbstractTrait polymorphisms are widespread in nature, and explaining their stable co-existence is a central problem in ecology and evolution. Alternative reproductive tactics, in which individuals of one or more sex exhibit discrete, discontinuous traits in response to reproductive competition, represent a special case of trait polymorphism in which the traits are often complex, behavioural, and dynamic. Thus, studying how alternative reproductive tactics are maintained may provide general insights into how complex trait polymorphisms are maintained in populations. We construct a spatially explicit individual-based model inspired from extensively collected empirical data to address the mechanisms behind the co-existence of three behavioural alternative reproductive tactics in males of a tree cricket (Oecanthus henryi). Our results show that the co-existence of these tactics over ecological time scales is facilitated by the spatial structure of the landscape they inhabit, which serves to equalize the otherwise unequal mating benefits of the three tactics. We also show that this co-existence is unlikely if spatial aspects of the system are not considered. Our findings highlight the importance of spatial dynamics in understanding ecological and evolutionary processes and underscore the power of integrative approaches that combine models inspired from empirical data.
Bettering of Learning Activity through Elevated P-Cresol Levels in the Brain: Insights from Active Avoidance Testing in Wistar Rats
Authors: Tevzadze Gigi , Kikvidze Zaal 
Published: March 2024

AbstractIt is established that p-cresol, a compound produced by bacterial colonies within the gastrointestinal tract of mammals, plays a contributory role in the manifestation of various mental disorders. Recently, our research demonstrated that diminishing p-cresol levels in the brain adversely impact the behavioral manifestation of cognitive abilities in rats. In this study, we aimed to investigate the impact of augmenting p-cresol levels in the brain on learning. The Active Avoidance Test was employed to assess learning capabilities. The results, with a high level of confidence, indicated that rats with an increased concentration of p-cresol in the brain exhibited superior task performance and accelerated learning compared to the control group.
Age pigment lipofuscin causes oxidative stress, lysosomal dysfunction, and pyroptotic cell death
Authors: Baldensperger Tim , Jung Tobias , Heinze Tom , Schwerdtle Tanja , Höhn Annika , Grune Tilman 
Published: March 2024

ABSTRACTAccumulation of the age pigment lipofuscin represents a ubiquitous hallmark of the aging process. However, our knowledge about cellular effects of lipofuscin accumulation is potentially flawed, because previous research mainly utilized highly artificial methods of lipofuscin generation. In order to address this tremendous problem, we developed a convenient protocol for isolation of authentic lipofuscin from human and equine cardiac tissue in high purity and quantity. Isolated lipofuscin aggregates contained elevated concentrations of proline and metals such as calcium or iron. The material was readily incorporated by fibroblasts and caused cell death at low concentrations (LC50= 5.0 µg/mL) via a pyroptosis-like pathway. Lipofuscin boosted mitochondrial ROS production and caused lysosomal dysfunction by lysosomal membrane permeabilization leading to reduced lysosome quantity and impaired cathepsin D activity. In conclusion, this is the first study utilizing authentic lipofuscin to experimentally validate the concept of the lysosomal-mitochondrial axis theory of aging and cell death.
HNF4α is a target of the Wnt/β-catenin pathway and regulates colorectal carcinogenesis
Authors: Sang Lei , Bai Weiyu , Lu Chenglu , Dong Rui , Hao Qinggang , Zhang Yingru , Sun Rongyuan , Shen Junling , Sun Yan , Sun Jianwei 
Published: March 2024

AbstractHepatocyte nuclear factor 4alpha (HNF4α) is a transcription factor involved in liver function. Dysregulation of HNF4α leads to hepatocarcinogenesis. However, the role and mechanism of HNF4α in colorectal cancer is still unknown. Here we demonstrate that HNF4α is upregulated in colorectal cancers. and HNF4α upregulation promotes colorectal tumorigenesis. Notably, expression levels of HNF4α are positively correlated with the Wnt/β-catenin signaling pathway in colorectal cancer patients. Further, we showed that HNF4α is transcriptionally activated by Wnt/β-catenin/TCF3 and is at least partially responsible for the oncognesis activity of the Wnt signaling in colorectal cancer. Our findings indicate that HNF4α is a direct target of that Wnt/β-catenin pathway and could play an important role in colorectal carcinogenesis.Author SummaryHere we demonstrate that HNF4α is upregulated in colorectal cancers and HNF4α upregulation promotes colorectal tumorigenesis. Notably, expression level of HNF4α are positively correlated with the Wnt/β-catenin pathway in colorectal cancer patients. Further, we showed that HNF4α is transcriptionally activated by Wnt/β-catenin/TCF3 and is at least partially responsible for the oncognesis activity of the Wnt signaling pathway in colorectal cancer.
Orthohantavirus Diversity in Central-East Argentina: Insights from Complete Genomic Sequencing on Phylogenetics, Geographic patterns and Transmission scenarios
Authors: Alonso Daniel Oscar , Kehl Sebastian , Coelho Rocio , Periolo Natalia , Poklepovich Tomas , Perez-Sautu Unai , Sanchez-Lockhart Mariano , Palacios Gustavo F. , Bellomo Carla , Martinez Valeria 
Published: March 2024

AbstractHantavirus Pulmonary Syndrome (HPS), characterized by its high fatality rate, poses a significant public health concern in the Americas. Phylogenetic relationships of orthohantaviruses in the country were inferred from partial genomic sequences. The objectives of this work were to report new complete viral genomes of the known viral variants associated with HPS cases in Central-East region of Argentina, to assess viral diversity, phylogenetic relationships, and to elucidate the geographic patterns of distribution of each variant. To accomplish this, a detailed analysis was conducted of the geographic distribution of reported cases within the most impacted province of the region. The phylogenetic analysis defined clearly separated clades in the country according to their geographic origin. Andes virus (ANDV) segregated from the rest of the sequences, and those representative from the Central East region, Buenos Aires (BAV) and Lechiguanas virus (LECV), were grouped in the same cluster but segregated in two different branches.ImportanceIn Argentina, most of the HPS cases were associated with ANDV and closely related viruses distributed in four endemic regions. This work focused on obtaining and studying the complete genome of the orthohantaviruses present in the Central East (CE) region (BAV and LECV). Both viruses were responsible for major and minor outbreaks of person- to-person transmission in the country, and the findings may pave the way to study the impact of genetic determinants of viral transmission and to consider the reclassification of the speciesOrthohantavirus andesense.
Cbf11 and Mga2 function as a single regulatory entity to activate transcription of lipid metabolism genes and promote mitotic fidelity in fission yeast
Authors: Marešová Anna , Grulyová Michaela , Hradilová Miluše , Zemlianski Viacheslav , Princová Jarmila , Převorovský Martin 
Published: March 2024

ABSTRACTWithin a eukaryotic cell, both lipid homeostasis and faithful cell cycle progression are meticulously orchestrated. The fission yeastSchizosaccharomyces pombeprovides a powerful platform to study the intricate regulatory mechanisms governing these fundamental processes. InS. pombe, the Cbf11 and Mga2 proteins are transcriptional activators of non-sterol lipid metabolism genes, with Cbf11 also known as a cell cycle regulator. Despite sharing a common set of target genes, little was known about their functional relationship. This study reveals that Cbf11 and Mga2 function together as a single regulatory entity critical for both lipid metabolism and mitotic fidelity. Deletion of either gene results in a similar array of defects, including slow growth, dysregulated lipid homeostasis, impaired cell cycle progression (cut phenotype), abnormal cell morphology, perturbed transcriptomic and proteomic profiles, and compromised response to the stressors camptothecin and thiabendazole. Remarkably, the double deletion mutant does not exhibit a more severe phenotype compared to the single mutants, suggesting that Cbf11 and Mga2 work together in the same pathway. In addition, ChIP-nexus analysis reveals that both Cbf11 and Mga2 bind to nearly identical positions within the promoter regions of target genes. Interestingly, Mga2 binding appears to be dependent on the presence of Cbf11 and Cbf11 likely acts as a tether to DNA, while Mga2 is needed to activate the target genes. In addition, the study explores the distribution of Cbf11 and Mga2 homologs across fungi. The presence of both Cbf11 and Mga2 homologs in Basidiomycota contrasts with Ascomycota, which mostly lack Cbf11 but retain Mga2. This suggests an evolutionary rewiring of the regulatory circuitry governing lipid metabolism and mitotic fidelity. In conclusion, this study offers compelling support for Cbf11 and Mga2 functioning jointly as a single regulator of lipid metabolism and mitotic fidelity in fission yeast.SUMMARY STATEMENTCbf11 and Mga2, transcriptional activators of non-sterol lipid metabolism genes, function as a single regulatory unit and are both required for proper cell cycle progression in the fission yeastSchizosaccharomyces pombe.
Structural basis for recognition of the FLAG-tag by anti-FLAG M2
Authors: Beugelink J. Wouter , Sweep Els , Janssen Bert J.C. , Snijder Joost , Pronker Matti F. 
Published: March 2024

AbstractThe FLAG-tag/anti-FLAG system is a widely used biochemical tool for protein detection and purification. Anti-FLAG M2 is the most popular antibody against the FLAG-tag, due to its ease of use, versatility, and availability in pure form or as bead conjugate. M2 binds N-terminal, C-terminal and internal FLAG-tags and binding is calcium-independent, but the molecular basis for the FLAG-tag specificity and recognition remains unresolved.Here we present an atomic resolution (1.17 Å) structure of the FLAG peptide in complex with the Fab of anti-FLAG M2, revealing key binding determinants. Five of the eight FLAG peptide residues form direct interactions with paratope residues. The FLAG peptide adopts a 310helix conformation in complex with the Fab. These structural insights allowed us to rationally introduce point mutations on both the peptide and antibody side. We tested these by surface plasmon resonance, leading us to propose a shorter yet equally binding version of the FLAG-tag for the M2 antibody.
Trafficking of Connexin36 (Cx36) in the early secretory pathway
Authors: Tetenborg Stephan , Ariakia Fatemeh , Martinez-Soler Elizabeth , Shihabeddin Eyad , Lazart Ignacio Cebrian , Miller Adam C. , O’Brien John 
Published: March 2024

AbstractGap junctions formed by the major neuronal connexin Cx36 function as electrical synapses in the nervous system and provide unique functions such as synchronizing activities or network oscillations. Although the physiological significance of electrical synapses for neuronal networks is well established, little is known about the pathways that regulate the transport of its main component: Cx36. Here we have used HEK293T cells as an expression system in combination with siRNA and BioID screens to study the transition of Cx36 from the ER to the cis Golgi. Our data indicate that the C-terminal tip of Cx36 is a key factor in this process, mediating binding interactions with two distinct components in the early secretory pathway: the COPII complex and the Golgi stacking protein Grasp55. The C-terminal amino acid valine serves as an ER export signal to recruit COPII cargo receptors Sec24A/B/C at ER exit sites, whereas the PDZ binding motif “SAYV” mediates an interaction with Grasp55. These two interactions have opposing effects in their respective compartments. While Sec24 subunits carry Cx36 out of the ER, Grasp55 stabilizes Cx36 in the Golgi as shown in over expression experiments. These early regulatory steps of Cx36 are expected to be essential for the formation, function, regulation and plasticity of electrical synapses in the developing and mature nervous system.
Role of 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase-3 in Maintaining Redox Homeostasis and DNA Repair in Non-Small Cell Lung Cancers Under EGFR-Targeting Therapy
Authors: Lypova Nadiia , Dougherty Susan M. , Clem Brian F. , Feng Jing , Yin Xinmin , Zhang Xiang , Li Xiaohong , Chesney Jason A. , Imbert-Fernandez Yoannis 
Published: March 2024

ABSTRACTThe efficacy of FDA-approved tyrosine kinase inhibitors (TKIs) targeting EGFR is limited due to the persistence of drug-tolerant cell populations, leading to therapy resistance. Non-genetic mechanisms, such as metabolic rewiring, play a significant role in driving lung cancer cells into the drug-tolerant state, allowing them to persist under continuous drug treatment. This study aimed to investigate the impact of the glycolytic regulator 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) on the metabolic adaptivity of lung cancer cells to EGFR TKI therapies. Using two EGFR-driven non-small cell lung cancer cell lines, PC9 and HCC827, we analyzed metabolic changes in cells exposed to EGFR inhibitors and evaluated the effect of PFKFB3 inhibition on metabolic adaptations during TKI treatment. Our results indicate that PFKFB3-mediated glycolysis sustains ATP production upon TKI treatment. Metabolomics studies revealed that PFKFB3 inhibition in TKI-treated cells limits glucose utilization in glycolysis, TCA cycle, and polyol pathway. Additionally, we show that pharmacological inhibition of PFKFB3 overcomes TKI-driven redox capacity by diminishing the expression of glutathione peroxidase 4 (GPX4), which in turn, exacerbates oxidative stress. Our study also revealed that PFKFB3 contributes to DNA oxidation and damage by controlling the expression of DNA-glycosylases involved in base excision repair. In TKI-treated cells, PFKFB3 inhibition reduced ATM expression and limited DNA damage repair, increasing sensitivity to DNA integrity insults.In summary, our results suggest that inhibiting PFKFB3 can be an effective strategy to eradicate cancer cells surviving under EGFR-TKI therapy before they enter the drug-resistant state.STATEMENT OF IMPLICATIONTargeting PFKFB3 can improve the efficacy of EGFR-targeting TKIs by restricting non-genetic adaptations embraced by drug-tolerant cells.
Proton Free Induction Decay MRSI at 7T in the Human Brain Using an Egg-Shaped Modified Rosette K-Space Trajectory
Authors: Blömer Simon , Hingerl Lukas , Marjańska Małgorzata , Bogner Wolfgang , Motyka Stanislav , Hangel Gilbert , Klauser Antoine , Andronesi Ovidiu C , Strasser Bernhard 
Published: March 2024

1.Abstract1.1PurposeProton (1H)-MRSI via spatial-spectral encoding poses high demands on gradient hardware at ultra-high fields and high-resolutions. Rosette trajectories help alleviate these problems, but at reduced SNR-efficiency due to their k-space densities not matching any desired k-space filter. We propose modified rosette trajectories, which more closely match a Hamming filter, and thereby improve SNR performance while still staying within gradient hardware limitations and without prolonging scan time.1.2MethodsAnalytical and synthetic simulations were validated with phantom and in vivo measurements at 7 T. The rosette and modified rosette trajectories were measured in five healthy volunteers in six minutes in a 2D slice in the brain. A 3D sequence was measured in one volunteer within 19 minutes. The SNR, linewidth, CRLBs, lipid contamination and data quality of the proposed modified rosette trajectory were compared to the rosette trajectory.1.3ResultsUsing the modified rosette trajectories, an improved k-space weighting function was achieved resulting in an increase of up to 12% in SNR compared to rosette’s dependent on the two additional trajectory parameters. Similar results were achieved for the theoretical SNR calculation based on k-space densities, as well as when using the pseudo-replica method for simulated, in-vivo and phantom data. The CRLBs improved slightly, but non-significantly for the modified rosette trajectories, while the linewidths and lipid contamination remained similar.1.4ConclusionBy improving the rosette trajectory’s shape, modified rosette trajectories achieved higher SNR at the same scan time and data quality.
Time-varying reproduction number estimation: Fusing compartmental models with generalised additive models
Authors: Pang Xiaoxi , Han Yang , Tessier Elise , Abdul Aziz Nurin , Pellis Lorenzo , House Thomas , Hall Ian 
Published: March 2024

AbstractThe reproduction number, the mean number of secondary cases infected by each primary case, is a central metric in infectious disease epidemiology, and played a key role in the COVID-19 pandemic response. This is because it gives an indication of the effort required to control the disease. Beyond the well-knownbasicreproduction number, there are two natural versions, namely thecontrolandeffectivereproduction numbers. As behaviour, population immunity and viral characteristics can change with time, these reproduction numbers can vary over time and in different regions.Real world data can be complex, for example with daily variation in numbers due to weekend surveillance biases as well as natural stochastic noise. As such, in this work we consider a Generalised Additive Model to smooth real data through the explicit incorporation of day-of-the-week effects, to provide a simple measure of the time-varying growth rate associated with the data.Converting the resulting spline into an estimator for both the control and effective reproduction numbers requires assumptions on a model structure, which we here assume to be a compartmental model. The reproduction numbers calculated are based on both simulated and real world data, and are compared with estimates from an already existing tool.The derived method for estimating the time-varying reproduction number is effective, efficient and comparable to other methods. It provides a useful alternative approach, which can be included as part of a toolbox of models, that is particularly apt at smoothing out day-of-the-week effects in surveillance.