bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combinatorial immune refocusing within the influenza hemagglutinin head elicits cross-neutralizing antibody responses
Authors: Dosey Annie , Ellis Daniel , Boyoglu-Barnum Seyhan , Syeda Hubza , Saunders Mason , Watson Michael , Kraft John C. , Pham Minh N. , Guttman Miklos , Lee Kelly K. , Kanekiyo Masaru , King Neil P. 
Published: May 2023

SUMMARYThe head domain of influenza hemagglutinin (HA) elicits potently neutralizing yet mostly strain-specific antibodies during infection and vaccination. Here we evaluated a series of immunogens that combined several immunofocusing techniques for their ability to enhance the functional breadth of vaccine-elicited immune responses. We designed a series of “trihead” nanoparticle immunogens that display native-like closed trimeric heads from the HAs of several H1N1 influenza viruses, including hyperglycosylated variants and hypervariable variants that incorporate natural and designed sequence diversity at key positions in the periphery of the receptor binding site (RBS). Nanoparticle immunogens displaying triheads or hyperglycosylated triheads elicited higher HAI and neutralizing activity against vaccine-matched and -mismatched H1 viruses than corresponding immunogens lacking either trimer-stabilizing mutations or hyperglycosylation, indicating that both of these engineering strategies contributed to improved immunogenicity. By contrast, mosaic nanoparticle display and antigen hypervariation did not significantly alter the magnitude or breadth of vaccine-elicited antibodies. Serum competition assays and electron microscopy polyclonal epitope mapping revealed that the trihead immunogens, especially when hyperglycosylated, elicited a high proportion of antibodies targeting the RBS, as well as cross-reactive antibodies targeting a conserved epitope on the side of the head. Our results yield important insights into antibody responses against the HA head and the ability of several structure-based immunofocusing techniques to influence vaccine-elicited antibody responses.HIGHLIGHTSGeneralization of trihead antigen platform to several H1 hemagglutinins, including hyperglycosylated and hypervariable variantsTrimer-stabilizing mutations in trihead nanoparticle immunogens lead to lower levels of non-neutralizing antibody responses in both mice and rabbitsHyperglycosylated triheads elicit higher antibody responses against broadly neutralizing epitopes
Ouvrai: Opening access to remote VR studies of human behavioral neuroscience
Authors: Cesanek Evan , Shivkumar Sabyasachi , Ingram James N. , Wolpert Daniel M. 
Published: May 2023

AbstractModern virtual reality (VR) devices offer 6 degree-of-freedom kinematic data with high spatial and tem-poral resolution, making them powerful tools for research on sensorimotor and cognitive functions. We introduce Ouvrai, an open-source solution that facilitates the design and execution of remote VR studies, capitalizing on the surge in VR headset ownership. This tool allows researchers to develop sophisticated experiments using cutting-edge web technologies like the WebXR Device API for browser-based VR, with-out compromising on experimental design. Ouvrai’s features include easy installation, intuitive JavaScript templates, a component library managing front- and back-end processes, and a streamlined workflow. It also integrates APIs for Firebase, Prolific, and Amazon Mechanical Turk and provides data processing utilities for analysis. Unlike other tools, Ouvrai remains free, with researchers managing their web hosting and cloud database via personal Firebase accounts. Through three distinct motor learning experiments, we confirm Ouvrai’s efficiency and viability for conducting remote VR studies.
Cancer driver genes and opportunities for precision oncology revealed by whole genome sequencing 10,478 cancers
Authors: Kinnersley Ben , Sud Amit , Everall Andrew , Cornish Alex J. , Chubb Daniel , Culliford Richard , Gruber Andreas , Lärkeryd Adrian , Mitsopoulos Costas ,   Genomics England Research Consortium, Wedge David , Houlston Richard 
Published: May 2023

ABSTRACTIdentifying cancer driver genes is key for delivering the vision of precision oncology. The falling cost of whole genome sequencing (WGS) potentially makes WGS an attractive single all-encompassing test to identify cancer drivers in a patient, which may not be captured by standard panel testing but are targetable by small molecules. We analysed WGS data on 10,478 patients spanning 35 cancer types recruited to the UK 100,000 Genomes Project. We identified 330 driver genes, including 74 which are novel to any cancer. Across all cancer types 16% of the patients would be eligible for a currently approved therapy. Computational chemogenomic analysis of cancer mutations identified 96 additional targets of compounds that are potentially active and represent candidates for future clinical trials, expanding opportunities for improved patient care.
Concomitant effects of orchiectomy and intermittent hypoxia on hepatic oxidative stress, expression of flavin-containing monooxygenases and transcriptomic profile in mice
Authors: Ganouna-Cohen Gauthier , Marcouiller François , Beauparlant Charles Joly , Droit Arnaud , Belaidi Elise , Bairam Aida , Joseph Vincent 
Published: May 2023

AbstractIntermittent hypoxia induces oxidative stress and alters hepatic metabolism, likely underlying the association of sleep apnea with non-alcoholic fatty liver disease. In male patients with sleep apnea, metabolic or liver diseases, the levels of testosterone are reduced, and in patients with metabolic diseases, low levels of testosterone are associated with oxidative stress. To assess potential interactions between testosterone and IH on hepatic oxidative stress we used sham-operated or orchiectomized (ORX) mice exposed to normoxia (Nx) or IH (6% O2, 12 cycles/h, 12h/day) for 2 weeks. The activity of prooxidant (NADPH oxidase – NOX), antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase – SOD, Cat, GPx), lipid peroxidation (MDA concentration) and the total concentration of glutathione (GSH) were measured in liver. IH induced a prooxidant profile of enzyme activity (lower SOD activity and higher NOX/SOD and NOX/Cat activity ratio) without altering hepatic MDA and GSH content. Using RNA sequencing followed by a pathway enrichment analysis we identified putative hepatic genes underlying the interactions between IH and testosterone. ORX and IH altered the expression of genes involved in oxidoreductase activities, cytochromes dependent pathways, and glutathione metabolism. Among the genes upregulated in ORX-IH mice, the flavin-containing monooxygenases (FMO) are particularly relevant since these are potent hepatic antioxidant that could help prevent overt oxidative stress in ORX-IH mice.Graphical Abstract
Serine synthesis pathway upregulated by E-cadherin is essential for the proliferation and metastasis of breast cancers
Authors: Lee Geonhui , Wong Claudia , Cho Anna , West Junior J. , Crawford Ashleigh J. , Russo Gabriella C. , Si Bishwa Ranjan , Kim Jungwoo , Hoffner Lauren , Jang Cholsoon , Jung Moonjung , Leone Robert D. , Konstantopoulos Konstantinos , Ewald Andrew J. , Wirtz Denis , Jeong Sangmoo 
Published: May 2023

AbstractThe loss of E-cadherin (E-cad), an epithelial cell adhesion molecule, has been implicated in the epithelial-mesenchymal transition (EMT), promoting invasion and migration of cancer cells and, consequently, metastasis. However, recent studies have demonstrated that E-cad supports the survival and proliferation of metastatic cancer cells, suggesting that our understanding of E-cad in metastasis is far from comprehensive. Here, we report that E-cad upregulates thede novoserine synthesis pathway (SSP) in breast cancer cells. The SSP provides metabolic precursors for biosynthesis and resistance to oxidative stress, critically beneficial for E-cad-positive breast cancer cells to achieve faster tumor growth and more metastases. Inhibition of PHGDH, a rate-limiting enzyme in the SSP, significantly and specifically hampered the proliferation of E-cad-positive breast cancer cells and rendered them vulnerable to oxidative stress, inhibiting their metastatic potential. Our findings reveal that E-cad adhesion molecule significantly reprograms cellular metabolism, promoting tumor growth and metastasis of breast cancers.
Comparative electric and ultrastructural studies of cable bacteria reveal new components of conduction machinery
Authors: Digel Leonid , Justesen Mads L. , Bonné Robin , Fransaert Nico , Wouters Koen , Jensen Pia B. , Plum-Jensen Lea E. , Marshall Ian P. G. , Nicolas-Asselineau Louison , Drace Taner , Bøggild Andreas , Hansen John L. , Schramm Andreas , Bøjesen Espen D. , Nielsen Lars P. , Manca Jean V. , Boesen Thomas 
Published: May 2023

AbstractCable bacteria encompass at least two genera, and they are known to vary greatly in habitat preferences and filament thickness. We systematically investigated variations and similarities in cellular structures and electrical properties of different cable bacteria strains. Using SEM, TEM, STEM-EDX and ToF-SIMS, we characterized shared features of cable bacteria, such as inner and outer membranes, surface layer and cell junction architecture, as well as strain specific features, like the number and size of periplasmic conductive fibers (PCFs). Our data indicates that the PCFs are organized as loose stranded rope-like structures. With spatially resolved elemental analysis we detected nickel-containing co-factors within the PCF of cable bacteria strains in both genera suggesting a conserved conduction mechanism. Electrical conductivity of different cable bacteria strains showed a range of values covering three orders of magnitude indicating an unknown metabolic adaptation. Using cryogenic electron tomography we discovered multiple polar chemosensory arrays, abundant cytoplasmic inner membrane-attached vesicles (IMVs), polysomes and inner membrane invaginations that shed light on cable bacteria metabolism including complex motility control mechanisms, localized protein synthesis, and membrane remodeling. We propose that the IMVs discovered in this work are novel metabolic hubs closely connected to the unique conductive fiber structure of cable bacteria.
Pupil size predicts the onset of exploration in brain and behavior
Authors: Shourkeshti Akram , Marrocco Gabriel , Jurewicz Katarzyna , Moore Tirin , Ebitz R. Becket 
Published: May 2023

AbstractIn uncertain environments, intelligent decision-makers exploit actions that have been rewarding in the past, but also explore actions that could be even better. Several neuromodulatory systems are implicated in exploration, based, in part, on work linking exploration to pupil size–a peripheral correlate of neuromodulatory tone and index of arousal. However, pupil size could instead track variables that make exploration more likely, like volatility or reward, without directly predicting either exploration or its neural bases. Here, we simultaneously measured pupil size, exploration, and neural population activity in the prefrontal cortex while two rhesus macaques explored and exploited in a dynamic environment. We found that pupil size under constant luminance specifically predicted the onset of exploration, beyond what could be explained by reward history. Pupil size also predicted disorganized patterns of prefrontal neural activity at both the single neuron and population levels, even within periods of exploitation. Ultimately, our results support a model in which pupil-linked mechanisms promote the onset of exploration via driving the prefrontal cortex through a critical tipping point where prefrontal control dynamics become disorganized and exploratory decisions are possible.
Chaperone-driven entropic separation of amyloid nanofilament bundles
Authors: Vilar Jose M. G. , Rubi J. Miguel , Saiz Leonor 
Published: May 2023

AbstractThe disassembly of misfolded protein aggregates is a requirement for the proper functioning of cells. It has implications in multiple neuropathologies, such as Alzheimer’s and Parkinson’s diseases. The active unbundling of fibrillar aggregates has recently been identified as a key, rate-limiting step in the disassembly process. Yet, the nature of the underlying molecular mechanism remains an outstanding question. Here, we develop a coarse-grained computational approach from the atomistic structural information and show that the interactions of molecules tethered to fibrils lead to entropic forces consistent with the unbundling process observed in amyloid α-synuclein disaggregation by Hsp70. We uncover two main types of entropic effects, categorized as intra- and inter-protofilament, which are differentially affected by the system parameters and conditions. Our results show that only highly efficient chaperone systems can overcome the free energy cost of the lateral association between two protofilaments. Through the analysis of cryo-electron tomography and high-speed atomic force microscopy data, we find that co-chaperone networks and ATP hydrolysis are needed to achieve the conditions for highly efficient entropic force generation. We highlight the implications of these results for the design of targeted therapies for the underlying neuropathologies.
Development and validation of a high throughput screening platform to enable target identification in skeletal muscle cells from Duchenne Muscular Dystrophy (DMD) patients
Authors: Hariharan Santosh , Lorintiu Oana , Lee Chia-Chin , Duchemin-Pelletier Eve , Li Xianfeng , Healy Aileen , Doyonnas Regis , Selig Luc , Poydenot Pauline , Ventre Erwann , Weston Andrea , Owens Jane , Christoforou Nicolas 
Published: May 2023

ABSTRACTDuchenne muscular dystrophy (DMD) is a progressive and fatal muscle degenerating disease caused by dystrophin deficiency. Effective methods for drug discovery for the treatment of DMD requires systems to be physiologically relevant, scalable, and effective. To this end, the Myoscreen platform offers a scalable and physiologically relevant system for generating and characterizing patient-derived myotubes. Morphological profiling is a powerful technique involving the simultaneous measurement of hundreds of morphological parameters from fluorescence microscopy images and using machine learning to predict cellular activity. Here, we describe combining the Myoscreen platform and high dimensional morphological profiling to accurately predict a phenotype associated with the lack of Dystrophin expression in patient derived myotubes. Using this methodology, we evaluated a series of Dystrophin-associated protein complex (DAPC) candidates and identified that the combination of Utrophin and α- Sarcoglycan yielded highest morphological differences between DMD and non-DMD donors. Finally, we validated this methodology by knocking down Dystrophin expression in non-DMD cells as well as introducing Dystrophin expression in DMD cells. Knocking down Dystrophin in non- DMD cells shifted their morphological profile to one that is similar to DMD cells while introducing Dystrophin in DMD cells shifted their morphological profile towards non-DMD cells. In conclusion, we have developed a platform that accurately predicts the DMD disease phenotype in a disease relevant cell type. Ultimately this platform may have wide applications in the drug development process include identification of disease modifier genes, screening of novel therapeutic moieties, and as a potency assay for future therapeutics.
Cone Synaptic function is modulated by the leucine rich repeat (LRR) adhesion molecule LRFN2
Authors: Hasan Nazarul , Gregg Ronald G. 
Published: May 2023

ABSTRACTDaylight vision is mediated by cone photoreceptors in vertebrates, which synapse with bipolar cells (BCs) and horizontal (HCs) cells. This cone synapse is functionally and anatomically complex, connecting to 8 types of depolarizing (DBC) BCs and 5 types of hyperbolizing BCs (HBCs). The dendrites of DBCs and HCs cells make invaginating ribbon synapses with the cone axon terminal, while HBCs form flat synapses with the cone pedicles. The molecular architecture that underpins this organization is relatively poorly understood. To identify new proteins involved in synapse formation and function we used an unbiased proteomic approach and identified LRFN2 (Leucine-rich repeat and fibronectin III domain-containing 2) as a component of the DBC signaling complex. LRFN2 interacts with TRPM1 and is selectively expressed at cone terminals and co-localizes with PNA, and other DBC signalplex members. In the absence of LRFN2 the cone-mediated photopic electroretinogram b-wave amplitude is reduced. In LRFN2 deficient mice, the synaptic markers: LRIT3, ELFN2, mGluR6, TRPM1 and GPR179 are properly localized. Similarly, LRFN2 expression and localization is not dependent on these synaptic proteins. These data demonstrate that LRFN2 likely interacts with TRPM1 and its absence compromises normal synaptic transmission between cones and cone DBCs cells.Significance StatementSignaling between cone photoreceptors and the downstream bipolar cells is critical to normal vision. Cones synapse with 13 different types of bipolar cells forming an invaginating ribbon synapses with 8 types, and flat synapse with 5 types, to form one of the most complex synapses in the brain. In this report a new protein, LRFN2 (Leucine-rich repeat and fibronectin III domain-containing 2), was identified that is expressed on the cones synapses. UsingLrfn2knockout mice we show LRFN2 is required for the normal cone signaling.
Efficient and accurate prediction of protein structure using RoseTTAFold2
Authors: Baek Minkyung , Anishchenko Ivan , Humphreys Ian R. , Cong Qian , Baker David , DiMaio Frank 
Published: May 2023

AbstractAlphaFold2 and RoseTTAFold predict protein structures with very high accuracy despite substantial architecture differences. We sought to develop an improved method combining features of both. The resulting method, RoseTTAFold2, extends the original three-track architecture of RoseTTAFold over the full network, incorporating the concepts of Frame-aligned point error, recycling during training, and the use of a distillation set from AlphaFold2. We also took from AlphaFold2 the idea of structurally coherent attention in updating pair features, but using a more computationally efficient structure-biased attention as opposed to triangle attention. The resulting model has the accuracy of AlphaFold2 on monomers, and AlphaFold2-multimer on complexes, with better computational scaling for large proteins and complexes. This excellent performance is achieved without hallmark features of AlphaFold2, invariant point attention and triangle attention, indicating that these are not essential for high accuracy prediction. Almost all recent work on protein structure prediction has re-used the basic AlphaFold2 architecture; our results show that excellent performance can be achieved with a broader class of models, opening the door for further exploration.
Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue
Authors: Du Junwei , Sudlow Leland C. , Shahverdi Kiana , Zhou Haiying , Michie Megan , Schindler Thomas H. , Mitchell Joshua D. , Mollah Shamim , Berezin Mikhail Y. 
Published: May 2023

AbstractOxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. At high cumulative dosage, the negative effect of oxaliplatin on the heart becomes evident and is linked to a growing number of clinical reports. The aim of this study was to determine how chronic oxaliplatin treatment causes the changes in energy-related metabolic activity in the heart that leads to cardiotoxicity and heart damage in mice. C57BL/6 male mice were treated with a human equivalent dosage of intraperitoneal oxaliplatin (0 and 10 mg/kg) once a week for eight weeks. During the treatment, mice were followed for physiological parameters, ECG, histology and RNA sequencing of the heart. We identified that oxaliplatin induces strong changes in the heart and affects the heart’s energy-related metabolic profile. Histological post-mortem evaluation identified focal myocardial necrosis infiltrated with a small number of associated neutrophils. Accumulated doses of oxaliplatin led to significant changes in gene expression related to energy related metabolic pathways including fatty acid (FA) oxidation, amino acid metabolism, glycolysis, electron transport chain, and NAD synthesis pathway. At high accumulative doses of oxaliplatin, the heart shifts its metabolism from FAs to glycolysis and increases lactate production. It also leads to strong overexpression of genes in NAD synthesis pathways such asNmrk2. Changes in gene expression associated with energy metabolic pathways can be used to develop diagnostic methods to detect oxaliplatin-induced cardiotoxicity early on as well as therapy to compensate for the energy deficit in the heart to prevent heart damage.Significance StatementThis study uncovers the detrimental impact of chronic oxaliplatin treatment on heart metabolism in mice, linking high accumulative dosages to cardiotoxicity and heart damage. By identifying significant changes in gene expression related to energy metabolic pathways, the findings pave the way for the development of diagnostic methods to detect oxaliplatin-induced cardiotoxicity at an early stage. Furthermore, these insights may inform the creation of therapies that compensate for the energy deficit in the heart, ultimately preventing heart damage and improving patient outcomes in cancer treatment.
Young gene HP6/Umbrea is dispensable for viability and fertility
Authors: Grill Sherilyn , Riley Ashley , Selvaraj Monica , Lehmann Ruth 
Published: May 2023

AbstractStudies of the young gene Heterochromatin Protein 6 (HP6) have challenged the dogma that essential functions are only seen in genes with a long evolutionary history. Based on its prominent expression in Drosophila germ cells, we asked if HP6 might play a role in germline development. Surprisingly, we found that CRISPR-generated HP6 null mutants are viable and fertile. We identified an independent lethal allele and an RNAi off-target effect that prevented accurate interpretation of HP6 essentiality in previous studies. We found that the vast majority of young essential genes were viable when tested with orthologous methods. Together our data call into question the frequency with which young genes gain essential functions.