bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stability of SARS-CoV-2 spike antigens against mutations
Authors: De la Fuente Ildefonso M. , Malaina Iker , Fedetz Maria , Chruszcz Maksymilian , Grandes Gontzal , Targoni Oleg , Lozano-Pérez Antonio A. , Shteyer Eyal , Ya’acov Ami Ben , de la Cámara Agustín Gómez , Borobia Alberto M. , Carrasco-Pujante Jose , Pijoan Jose Ignacio , Bringas Carlos , Pérez-Yarza Gorka , Ouro Alberto , Crawford Michael J. , Shoshan-Barmatz Varda , Zhurov Vladimir , López José I. , Knafo Shira , Tary-Lehmann Magdalena , Gabaldón Toni , Grbic Miodrag 
Published: October 2022

SummaryModern health care needs preventive vaccines and therapeutic treatments with stability against pathogen mutations to cope with current and future viral infections. At the beginning of the COVID-19 pandemic, our analytic and predictive tool identified a set of eight short SARS-CoV-2 S-spike protein epitopes that had the potential to persistently avoid mutation. Here a combination of genetic, Systems Biology and protein structure analyses confirm the stability of our identified epitopes against viral mutations. Remarkably, this research spans the whole period of the pandemic, during which 93.9% of the eight peptides remained invariable in the globally predominant 43 circulating variants, including Omicron. Likewise, the selected epitopes are conserved in 97% of all 1,514 known SARS-CoV-2 lineages. Finally, experimental analyses performed with these short peptides showed their specific immunoreactivity. This work opens a new perspective on the design of next-generation vaccines and antibody therapies that will remain reliable against future pathogen mutations.HighlightsOur novel method predicts SARS-CoV-2 epitopes that are stable against future mutationsGenetic analyses (performed 2 years after epitopes were identified) validate the stability of the identified peptidesThese epitopes remained invariable in 97% of all 1,514 known SARS-CoV-2 lineages93.9% of such peptides were conserved in the 43 variants of most interest, including OmicronGraphical Abstract
ACSM1 and ACSM3 regulate prostate cancer fatty acid metabolism to promote tumour growth and constrain ferroptosis
Authors: Shrestha Raj , Nassar Zeyad D. , Hanson Adrienne R. , Iggo Richard , Townley Scott L. , Dehairs Jonas , Mah Chui Yan , Helm Madison , Ghodsi Mohammadreza , Pickering Marie , Watt Matthew J. , Quek Lake-Ee , Hoy Andrew J. , Tilley Wayne D. , Swinnen Johannes V. , Butler Lisa M. , Selth Luke A. 
Published: October 2022

ABSTRACTProstate tumours are highly reliant on lipids for energy, growth and survival. Activity of the androgen receptor (AR) is associated with reprogramming of lipid metabolic processes in prostate cancer, although the molecular underpinnings of this relationship remain to be fully elucidated. Here, we identified Acyl-CoA Synthetase Medium Chain Family Members 1 and 3 (ACSM1 and ACSM3) as AR-regulated mediators of prostate cancer metabolism and growth. ACSM1 and ACSM3 are upregulated in prostate tumours compared to non-malignant tissues and other cancer types. Both enzymes enhanced proliferation and protected PCa cells from deathin vitro, while silencing ACSM3 led to reduced tumour growth in an orthotopic xenograft model. We show that ACSM1 and ACSM3 are major regulators of the PCa lipidome and enhance energy production via fatty acid oxidation. Metabolic dysregulation caused by loss of ACSM1/3 led to mitochondrial oxidative stress, lipid peroxidation and cell death by ferroptosis. Conversely, over-expression of ACSM1/3 enabled PCa cells to survive toxic doses of medium chain fatty acids and promoted resistance to ferroptosis-inducing drugs and AR antagonists. Collectively, these studies uncover a new link between AR and lipid metabolism and position ACSM1 and ACSM3 as key players in prostate cancer progression and therapy resistance.
A Leaky Human Colon Model Reveals Uncoupled Apical/Basal Cytotoxicity in EarlyClostridioides difficileToxin Exposure
Authors: Ok Meryem T. , Liu Jintong , Bliton R. Jarrett , Hinesley Caroline M. , San Pedro Ekaterina Ellyce T. , Breau Keith A. , Gomez-Martinez Ismael , Burclaff Joseph , Magness Scott T. 
Published: October 2022

ABSTRACTBackground & AimsClostridioides difficile(C. difficile) toxins A (TcdA) and B (TcdB) cause antibiotic-associated colitis and increase morbidity and mortality. Accurate in vitro models are necessary to detect early toxicity kinetics, investigate disease etiology, and develop pre-clinical models for new therapies. Properties of cancer cell lines and 3D organoids inherently limit these efforts. Here, we develop adult stem cell-derived monolayers of differentiated human colonic epithelium (hCE) with barrier function, investigate the impact of toxin application to apical/basal aspects of monolayers, and evaluate whether a leaky epithelial barrier enhances toxicity.MethodsSingle-cell RNA-sequencing (scRNAseq) mappedC. difficile-relevant genes to cell lineages across the human gut. Transcriptomics informed timing of stem cell differentiation to achieve in vitro colonocyte maturation like that observed in vivo. Transepithelial electrical resistance (TEER) and fluorescent dextran permeability assays measured cytotoxicity as barrier loss post-toxin exposure. Leaky epithelial barriers were induced with diclofenac.ResultsscRNAseq demonstrated broad and variable toxin receptor expression across the human gut lineages. Absorptive colonocytes displayed generally enhanced toxin receptor, Rho GTPase, and cell junction expression. 21-day differentiated Caco-2 cells remained immature whereas hCE monolayers were similar to mature colonocytes. hCE monolayers exhibited high barrier function after 1-day differentiation. Basal TcdA/B application to monolayers caused more toxicity and apoptosis than apical exposure. Diclofenac induced leaky hCE monolayers and enhanced toxicity of apical TcdB exposure.ConclusionsApical/basal toxicities are uncoupled with more rapid onset and increased magnitude of basal toxicity. Leaky paracellular junctions enhance toxicity of apical TcdB exposure. hCE monolayers represent a physiologically relevant and sensitive culture system to evaluate the impact of microbial toxins on gut epithelium.
Candida albicanspromotes neutrophil extracellular trap formation and leukotoxic hypercitrullination via the peptide toxin candidalysin
Authors: Unger Lucas , Backman Emelie , Amulic Borko , Ponce-Garcia Fernando M. , Yellagunda Sujan , Krüger Renate , von Bernuth Horst , Bylund Johan , Hube Bernhard , Naglik Julian R. , Urban Constantin F. 
Published: October 2022

AbstractThe cytolytic peptide toxin candidalysin is secreted by the invasive, hyphal form of the human fungal pathogen,Candida albicans. Candidalysin is essential for inducing host cell damage during mucosal and systemicC. albicansinfections, resulting in neutrophil recruitment. Neutrophil influx toC. albicans-infected tissue is critical for limiting fungal growth and preventing the fungal dissemination. Here, we demonstrate that candidalysin secreted by hyphae promotes the stimulation of neutrophil extracellular traps (NETs), while synthetic candidalysin triggers a distinct mechanism for NET-like structures (NLS), which are more compact and less fibrous than canonical NETs. Candidalysin activates NADPH oxidase and calcium influx, with both processes contributing to morphological changes in neutrophils resulting in NLS formation. NLS are induced by leukotoxic hypercitrullination, which is governed by protein arginine deaminase 4 activation via calcium influx and initiation of intracellular signalling events. However, activation of signalling by candidalysin does not suffice to trigger downstream events essential for NET formation, as demonstrated by lack of lamin A/C phosphorylation, an event required for activation of cyclin-dependent kinases that are crucial for NET release. Interestingly, exposure to candidalysin does not immediately restrict the capability of neutrophils to produce reactive oxygen species (ROS), nor to phagocytose particles. Instead, candidalysin triggers ROS production, calcium influx and subsequent activation of downstream signalling that drive morphological alteration and the formation of NLS in a dose- and time-dependent manner. Notably, candidalysin-triggered NLS demonstrate anti-Candidaactivity, which is resistant to nuclease treatment and dependent on the deprivation of Zn2+. This study reveals thatC. albicanshyphae releasing candidalysin concurrently trigger canonical NETs and NLS, which together form a fibrous sticky network that entanglesC. albicanshyphae and inhibits their growth. Importantly, this explains discrepancies of previous studies demonstrating that neutrophil-derived extracellular chromatin structures triggered byC. albicanscan be both dependent and independent of ROS. Our data also demonstrate that while candidalysin hampers neutrophil function, the toxin also increases the capability of neutrophils to entangle hyphae and to restrict their growth, reflecting the importance of human neutrophils in controlling the dissemination ofC. albicans.
The potentiative cytotoxic effect of IGF1R and EGFR inhibition on the Head and Neck Cancer Proteome
Authors: Hall Sarah , Lehman Christine E. , Wulfkuhle Julia , Petricoin Emanuel F. , Bekiranov Stefan , Dolatshahi Sepideh , Jameson Mark J. , Gioeli Daniel 
Published: October 2022

AbstractHead and neck cancers are the sixth most common cancer worldwide. Combinatorial targeted therapy has the potential to reduce drug resistance and increase cytotoxicity to head and neck squamous cell carcinoma (HNSCC). Using drug combinations is especially important when targeting the epidermal growth factor receptor (EGFR) since we previously demonstrated that activation of the insulin-like growth factor 1 receptor (IGF1R) is a mechanism for resistance against EGFR inhibition and that a combination of an IGF1R inhibitor, BMS754807, and an EGFR inhibitor, BMS599626, robustly inhibited the growth of HNSCC cell linesin vitro. To examine the mechanism of cytotoxicity, we performed protein pathway activation mapping via reverse phase protein array (RPPA) analysis of 145 proteins and phosphoproteins in five HNSCC cell lines to map key proteins and phosphoproteins important in tumorigenesis. By performing principal component analysis, calculating log fold changes, and constructing protein networks, we were able to provide evidence to support the hypothesis that the combination of IGF1R and EGFR inhibitors has a potentiative effect on inhibiting receptor tyrosine kinase signaling. The effects of the individual drugs are amplified, demonstrating that the combination more robustly inhibits the pathways of both receptors.
Phylogenomic analysis of the understudiedNeisseriaceaespecies reveals a poly- and paraphyleticKingellagenus
Authors: Morreale Daniel P. , St Geme Joseph W. , Planet Paul J. 
Published: October 2022

AbstractTaxonomic classification and phylogenetic analysis of theNeisseriaceaefamily has focused on the pathogensNeisseria meningitidisandNeisseria gonorrhoeae. Less is known about the relationships of commensalNeisseriaspecies and otherNeisseriaceaegenera, raising the possibility that the phylogeny of this family may not agree with taxonomy. In this study we used available nucleotide sequences and a phylogenetic approach to assess theKingellagenus and its relatives. We found that this genus is both paraphyletic and polyphyletic.Kingella potusis more closely related toNeisseria bacilliformisthan otherKingellaspecies. TheAlysiellaandSimonsiellagenera form a distinct clade within theKingellagenus that is closely related to the pathogensK. kingaeandK. negevensis. We find a phylogenetic relationship betweenConchiformibius,Alysiella,Simonsiella, andKingella, which we name the CASK clade. Finally, we define the gene sets that differentiate each genus of the CASK clade from one another and from the rest of theNeisseriaceaefamily.ImportanceUnderstanding the evolutionary relationships between the species in theNeisseriaceaehas been a persistent challenge in bacterial systematics due to high recombination rates in these species. Previous studies of this family have focused onN. meningitidisandN. gonorrhoeae. However, previously understudiedNeisseriaceaespecies are gaining new attention, withK. kingaenow recognized as a common human pathogen and withAlysiellaandSimonsiellabeing unique in the bacterial world as multicellular organisms. A better understanding of the genomic evolution of theNeisseriaceaecan lead to identification of the specific genes and traits that characterize the remarkable diversity of this family.
TCID50 Measurements of anti-viral efficacy on metal printed masks and plastic surfaces
Authors: Bilynsky Colette S.M. , Taylor Kishana , Anand Megha , Wayne Elizabeth 
Published: October 2022

AbstractThe SARS-CoV-2 pandemic has created a need for effective personal protective equipment (PPE) to prevent viral spread. PPE like face masks contain the spread of virus-filled droplets and thus reduce infection rates, has been a critical tool in stopping the spread of SARS-CoV-2. PET plastic barriers have also been used in public settings to reduce face to face viral transmission. However, in some cases, they have provided additional contact with the virus due to contamination. In order study, we evaluated the effectiveness of face masks and PET plastics coated in different metals in reducing viral load. We compared PPE printed with silver, copper, or zinc for their ability to inactivate live human coronavirus HCoV 229E. Our results show that silver and copper have significant anti-viral efficacy when printed on nonwoven fabric compared to the controls. The metal-printed PET showed around 70% anti-viral efficacy with any formulations, with copper performing the best. This work builds more data to support the development of metal printed materials for enhanced protection against coronaviruses.
Role of spike in the pathogenic and antigenic behavior of SARS-CoV-2 BA.1 Omicron
Authors: Chen Da-Yuan , Kenney Devin , Chin Chue Vin , Tavares Alexander H. , Khan Nazimuddin , Conway Hasahn L. , Liu GuanQun , Choudhary Manish C. , Gertje Hans P. , O’Connell Aoife K. , Kotton Darrell N. , Herrmann Alexandra , Ensser Armin , Connor John H. , Bosmann Markus , Li Jonathan Z. , Gack Michaela U. , Baker Susan C. , Kirchdoerfer Robert N. , Kataria Yachana , Crossland Nicholas A. , Douam Florian , Saeed Mohsan 
Published: October 2022

AbstractThe recently identified, globally predominant SARS-CoV-2 Omicron variant (BA.1) is highly transmissible, even in fully vaccinated individuals, and causes attenuated disease compared with other major viral variants recognized to date1–7. The Omicron spike (S) protein, with an unusually large number of mutations, is considered the major driver of these phenotypes3,8. We generated chimeric recombinant SARS-CoV-2 encoding the S gene of Omicron in the backbone of an ancestral SARS-CoV-2 isolate and compared this virus with the naturally circulating Omicron variant. The Omicron S-bearing virus robustly escapes vaccine-induced humoral immunity, mainly due to mutations in the receptor-binding motif (RBM), yet unlike naturally occurring Omicron, efficiently replicates in cell lines and primary-like distal lung cells. In K18-hACE2 mice, while Omicron causes mild, non-fatal infection, the Omicron S-carrying virus inflicts severe disease with a mortality rate of 80%. This indicates that while the vaccine escape of Omicron is defined by mutations in S, major determinants of viral pathogenicity reside outside of S.
Vector diversity and malaria prevalence: global trends and local determinants
Authors: Hoi Amber Gigi , Gilbert Benjamin , Mideo Nicole 
Published: October 2022

AbstractIdentifying determinants of global infectious disease burden is a central goal of disease ecology. While it is widely accepted that host diversity structures parasite diversity and prevalence across large spatial scales, the influence of vector diversity on disease risk has rarely been examined despite the role of vectors as obligatory intermediate hosts for many parasites. Malaria, for instance, can be transmitted by over 70 species of mosquitoes, but the impact of this diversity on malaria risk remains unclear. Further, such relationships are likely dependent on the context in which disease transmission occurs, as arthropod life history and behavior are highly sensitive to environmental factors such as temperature. We studied the relationship between vector diversity, malaria prevalence, and environmental attributes using a unique dataset we curated by integrating several open-access sources. Globally, the association between vector species richness and malaria prevalence differed by latitude, indicating that this relationship is strongly dependent on underlying environmental conditions. Structural equation models further revealed different processes by which the environment impacts vector community assemblage and function, and subsequently disease prevalence, in different regions. In Africa, the environment exerted a top-down influence on disease through its role in shaping vector communities, whereas in Southeast Asia, disease prevalence is influenced by more complex interactions between the physical and socioeconomic environment (i.e., rainfall and GDP) and vector diversity across sites. This work highlights the key role of vector diversity in structuring disease distribution at large spatial scales and offers crucial insights to vector management and disease control.Significance statementThe global health threat from persistent and emerging vector-borne diseases continues to increase and is exacerbated by rapid environmental and societal change. Predicting how disease burden will shift in response to these changes necessitates a clear understanding of existing determinants of disease risk. We focused on an underappreciated potential source of variation in disease burden – vector diversity – and its role in structuring global malaria distribution. Our work revealed that vector diversity influences malaria prevalence and that the strength and nature of this association strongly depend on local environmental context. Extending disease transmission theory, surveillance, and control to embrace heterogeneity in vector community structure and function across space and time is an asset in the fight against vector-borne diseases.
ULTRAFAST STRUCTURAL CHANGES DIRECT THE FIRST MOLECULAR EVENTS OF VISION
Authors: Gruhl Thomas , Weinert Tobias , Rodrigues Matthew , Milne Christopher J , Ortolani Giorgia , Nass Karol , Nango Eriko , Sen Saumik , Johnson Philip J M , Cirelli Claudio , Furrer Antonia , Mous Sandra , Skopintsev Petr , James Daniel , Dworkowski Florian , Båth Petra , Kekilli Demet , Ozerov Dmitry , Tanaka Rie , Glover Hannah , Bacellar Camila , Brünle Steffen , Casadei Cecilia M , Diethelm Azeglio D , Gashi Dardan , Gotthard Guillaume , Guixà-González Ramon , Joti Yasumasa , Kabanova Victoria , Knopp Gregor , Lesca Elena , Ma Pikyee , Martiel Isabelle , Mühle Jonas , Owada Shigeki , Pamula Filip , Sarabi Daniel , Tejero Oliver , Tsai Ching-Ju , Varma Niranjan , Wach Anna , Boutet Sébastien , Tono Kensuke , Nogly Przemyslaw , Deupi Xavier , Iwata So , Neutze Richard , Standfuss Jörg , Schertler Gebhard FX , Panneels Valerie 
Published: October 2022

AbstractVision is initiated by the rhodopsin family of light-sensitive G protein-coupled receptors (GPCRs). A photon is absorbed by the 11-cisretinal chromophore of rhodopsin which isomerises within 200 femtoseconds to the all-transconformation, thereby initiating the cellular signal transduction processes that ultimately lead to vision. However, the intramolecular mechanism by which the photoactivated retinal induces the activation events inside rhodopsin remains elusive. In this work, we use ultrafast time-resolved crystallography at room temperature to determine how an isomerised twistedall-transretinal stores the photon energy required to initiate protein conformational changes associated with the formation of the G protein-binding signalling state. The distorted retinal at 1 ps time-delay of photoactivation has pulled away from half of its numerous interactions with its binding pocket, and the excess of the photon energy is released through an anisotropic protein breathing motion in the direction of the extracellular space. Strikingly, the very early structural motions in the protein side chains of rhodopsin appear in regions involved in later stages of the conserved Class A GPCR activation mechanism. Our work sheds light on the earliest stages of vision in vertebrates and points to fundamental aspects of the molecular mechanisms of agonist-mediated GPCR activation.
Dietary omega-3 fatty acid deficiency from pre-pregnancy to lactation affects expression of genes involved in neurogenesis of the offspring
Authors: Srinivas Vilasagaram , Varma Saikanth , Kona Suryam Reddy , Ibrahim Ahamed , Duttaroy Asim K , Basak Sanjay 
Published: October 2022

AbstractMaternal n-3 PUFA (omega-3) deficiency can affect brain developmentin uteroand postnatally. Despite the evidence, the impacts of n-3 PUFA deficiency on the expression of neurogenesis genes in the postnatal brain remained elusive. Since postnatal brain development requires PUFAs via breast milk, we examined the fatty acid composition of breast milk and hippocampal expression of neurogenesis genes in n-3 PUFA deficient 21d mice. In addition, expression of fatty acid desaturases, elongases, signalling receptors of free fatty acids, insulin and leptin, and glucose transporters were measured. Among the genes involved in neurogenesis, the expression of brain-specific tenascin-R (TNR) was downregulated to a greater extent (∼31 folds), followed by adenosine A2A receptor (A2AAR), dopamine receptor D2 (DRD2), glial cell line-derived neurotrophic factor (GDNF) expression in the n-3 PUFA deficient hippocampus (p<0.05). Increasing dietary LA to ALA (50:1) elevated ARA to DHA ratio by ∼8 folds in the n-3 PUFA deficient breast milk, with an overall increase of total n-6/n-3 PUFAs by ∼15:1 (p<0.05) compared to n-3 PUFA sufficient (LA to ALA: 2:1) diet. The n-3 PUFA deficient brain exhibited upregulation of FADS1, FADS2, ELOVL2, ELOVL5, ELOVL6, GPR40, GPR120, LEPR, IGF1 and downregulation of GLUT1, GLUT3, and GLUT4 mRNA expression (p<0.05). Maternal n-3 PUFA deficiency affects the expression of key neurogenesis genes in the offspring with concomitant expression of desaturases and elongases genes suggesting the importance of dietary n-3 PUFA for neurodevelopment.