bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of a minimal biomarker profile in head-and-neck squamous cell carcinoma tumors
Authors: Sanchez-Diaz Laura , Navas Lola E. , Suarez-Martinez Elisa , Felipe-Abrio Blanca , Fernández-Rozadilla Ceres , Verdugo-Sivianes Eva M , Celis-Romero Manuel A. , Chaves-Conde Manuel , Chiara Maria-Dolores , Garcia-Mayea Yoelsis , LLeonart Matilde E. , Garcia-Heredia Jose Manuel , Muñoz-Galvan Sandra , Carracedo Angel , Rodrigo Juan P. , Carnero Amancio 
Published: November 2021

AbstractAlthough important advances have been made in the knowledge of the molecular mechanisms leading to the development, of head and neck squamous cell carcinoma (HNSCC), only PDL1 is used for the immunotherapy (pemborlizumab) treatment in the first line of metastatic or recurrent disease. There are no other molecular biomarkers currently used in clinical practice. The objective of the study was to identify transcriptional alterations in patients with oral cavity cancer that identify gene networks responsible for resistance to treatment and prognosis. To identify possible targets for the treatment or prevention of these tumors, we screened for changes in transcription of genes that were recurrently altered in patients and that successfully stratify tumoral and non-tumoral samples, as well as patient survival, based on expression levels. The gene panels are primarily related to the cell cycle, DNA damage response, cytokine signaling and the immune system but also to the embryonic stem cell core. Validation of these panels in an independent cohort led to the identification of three non-interconnected genes, WDR66, SERPINH1 and ZNF622, that can predict patient survival and are differentially expressed in 3D cultures from HNSCC primary cell lines. These genes are related to stemness phenotype are transcriptional targets of the pluripotency transcription factors Sox2 and c-Myc. Our results suggest that WDR66, SERPINH1 and ZNF622 con-stitute a minimal signature of stemness transcriptional targets able to predict the prognosis of HNSCC tumors.Simple SummaryThe objective of the study was to identify transcriptional alterations in patients with oral cavity cancer to possibly identify gene networks responsible for resistance to treatment and prognosis. We identify bioinformatically gene panels are primarily related to the cell cycle, DNA damage response, cytokine signaling and the immune system but also to the embryonic stem cell core. Validation of these panels in patients independent cohorts led to the identification of three non-interconnected genes, WDR66, SERPINHl and ZNF622, that can predict patient survival and are differentially expressed in cancer stem cells cultures from HNSCC. These genes are related to stemness phenotype and epithelial-to-mesenchymal transition and are transcriptional targets of the pluripotency transcription factors Sox2 and c-Myc.
Maternal diet disrupts the placenta-brain axis in a sex-specific manner
Authors: Ceasrine Alexis M , Devlin Benjamin A , Bolton Jessica L. , Green Lauren A. , Jo Young Chan , Huynh Carolyn , Patrick Bailey , Washington Kamryn , Sanchez Cristina L. , Joo Faith , Brayan Campos-Salazar A. , Lockshin Elana R. , Kuhn Cynthia , Murphy Susan K. , Simmons Leigh Ann , Bilbo Staci D. 
Published: November 2021

SUMMARYHigh maternal weight is associated with a number of detrimental outcomes in offspring, including increased susceptibility to neurological disorders such as anxiety, depression, and communicative disorders (e.g. autism spectrum disorders)1–8. Despite widespread acknowledgement of sex-biases in the prevalence, incidence, and age of onset of these disorders, few studies have investigated potential sex-biased mechanisms underlying disorder susceptibility. Here, we use a mouse model to demonstrate how maternal high-fat diet, one contributor to overweight, causes endotoxin accumulation in fetal tissue, and subsequent perinatal inflammation influences sex-specific behavioral outcomes in offspring. In male high-fat diet offspring, increased macrophage toll like receptor 4 signaling results in excess phagocytosis of serotonin neurons in the developing dorsal raphe nucleus, decreasing serotonin bioavailability in the fetal and adult brain. Bulk sequencing from a large cohort of matched first trimester human fetal brain, placenta, and maternal decidua samples reveals sex-specific transcriptome-wide changes in placenta and brain tissue in response to maternal triglyceride accumulation (a proxy for dietary fat content). Further, we find that fetal brain serotonin levels decrease as maternal dietary fat intake increases in males only. These findings uncover a microglia-dependent mechanism through which maternal diet may impact offspring susceptibility for neuropsychiatric disorder development in a sex-specific manner.
A novel mechanism of bulk cytoplasmic transport by cortical dynein in Drosophila ovary
Authors: Lu Wen , Lakonishok Margot , Serpinskaya Anna S. , Gelfand Vladimir I. 
Published: November 2021

AbstractCytoplasmic dynein, a major minus-end directed microtubule motor, plays essential roles in eukaryotic cells. Drosophila oocyte growth is mainly dependent on the contribution of cytoplasmic contents from the interconnected sister cells, nurse cells. We have previously shown that cytoplasmic dynein is required for Drosophila oocyte growth, and assumed that it transports cargoes along microtubule tracks from nurse cells to the oocyte. Here we report that instead transporting cargoes along microtubules into the oocyte, cortical dynein actively moves microtubules in nurse cells and from nurse cells to the oocyte via the cytoplasmic bridges, the ring canals. We demonstrate this microtubule movement is sufficient to drag even inert cytoplasmic particles through the ring canals to the oocyte. Furthermore, replacing dynein with a minus-end directed plant kinesin linked to the actin cortex is sufficient for transporting organelles and cytoplasm to the oocyte and driving its growth. These experiments show that cortical dynein can perform bulk cytoplasmic transport by gliding microtubules along the cell cortex and through the ring canals to the oocyte. We propose that the dynein-driven microtubule flow could serve as a novel mode of cargo transport for fast cytoplasmic transfer to support rapid oocyte growth.
After the Haiti 2021 Earthquake: Triage and treatment data for a cohort of patients transported for higher level of care
Authors: Edwards Kelly , Ellis David , Oaks Cory , Mann SGM Clayton W. , DeGennaro Vincent 
Published: November 2021

AbstractIntroOn August 14, a magnitude 7.2 earthquake occurred in the South of Haiti, killing over 2,200 people and leaving at least 12,000 injured. On August 17th, a joint task force coordinated the triage, treatment, and transport for patients arriving at the Port-au-Prince airport from the South.MethodsFrom August 17th-27th, approximately 243 patients were encountered at the Port-au-Prince airport. For the first three days of operations, written notes, reports, and various chat logs from WhatsApp were used to compile this data.Results243 patents were encountered at the airport Triage and Treatment from August 17 to August 27. Orthopedic injuries were the most common presenting injury with 20% of patients having a pelvis fracture (the most prevalent injury). Of the 174 with known transfer destinations, 118 (68%) were transported to one of three tertiary care hospitals, with 99 going via ground ambulance to the two in Port au Prince, and 19 going via HAA helicopter to Mirebalais. Once treatment operations were initiated, 106 patients received some form of treatment at the airport while awaiting transport.DiscussionInteragency coordination was the key to rapid scale up. To address the most prevalent patient issues, a treatment bundle was conceptualized a few days into operations that consisted of IV fluids, analgesia, IV antibiotics, wound debridement and cleaning, and tetanus prophylaxis.
Three-dimensional structure of kinetochore-fibers in human mitotic spindles
Authors: Kiewisz Robert , Fabig Gunar , Conway William , Baum Daniel , Needleman Daniel , Müller-Reichert Thomas 
Published: November 2021

AbstractDuring cell division, kinetochore microtubules (KMTs) provide a physical linkage between the chromosomes and the rest of the spindle. KMTs in mammalian cells are organized into bundles, so-called kinetochore-fibers (k-fibers), but the ultrastructure of these fibers is currently not well characterized. Here we show by large-scale electron tomography that each k-fiber in HeLa cells in metaphase is composed of approximately nine KMTs, only half of which reach the spindle pole. Our comprehensive reconstructions allowed us to analyze the three-dimensional (3D) morphology of k-fibers and their surrounding MTs in detail. We found that k-fibers exhibit remarkable variation in circumference and KMT density along their length, with the pole-proximal side showing a broadening. Extending our structural analysis then to other MTs in the spindle, we further observed that the association of KMTs with non-KMTs predominantly occurs in the spindle pole regions. Our 3D reconstructions have implications for KMT growth and k-fiber self-organization models as covered in a parallel publication applying complementary live-cell imaging in combination with biophysical modeling (Conway et al., 2022). Finally, we also introduce a new visualization tool allowing an interactive display of our 3D spindle data that will serve as a resource for further structural studies on mitosis in human cells.
Susceptibility of sheep to experimental co-infection with the ancestral lineage of SARS-CoV-2 and its alpha variant
Authors: Gaudreault Natasha N. , Cool Konner , Trujillo Jessie D. , Morozov Igor , Meekins David A. , McDowell Chester , Bold Dashzeveg , Carossino Mariano , Balaraman Velmurugan , Mitzel Dana , Kwon Taeyong , Madden Daniel W. , Artiaga Bianca Libanori , Pogranichniy Roman M. , Roman-Sosa Gleyder , Wilson William C. , Balasuriya Udeni B. R. , García-Sastre Adolfo , Richt Juergen A. 
Published: November 2021

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for a global pandemic that has had significant impacts on human health and economies worldwide. SARS-CoV-2 is highly transmissible and the cause of coronavirus disease 2019 (COVID-19) in humans. A wide range of animal species have also been shown to be susceptible to SARS-CoV-2 infection by experimental and/or natural infections. Domestic and large cats, mink, ferrets, hamsters, deer mice, white-tailed deer, and non-human primates have been shown to be highly susceptible, whereas other species such as mice, dogs, pigs, and cattle appear to be refractory to infection or have very limited susceptibility. Sheep (Ovis aries) are a commonly farmed domestic ruminant that have not previously been thoroughly investigated for their susceptibility to SARS-CoV-2. Therefore, we performed in vitro and in vivo studies which consisted of infection of ruminant-derived cell cultures and experimental challenge of sheep to investigate their susceptibility to SARS-CoV-2. Our results showed that sheep-derived cell cultures support SARS-CoV-2 replication. Furthermore, experimental challenge of sheep demonstrated limited infection with viral RNA shed in nasal and oral swabs primarily at 1-day post challenge (DPC), and also detected in the respiratory tract and lymphoid tissues at 4 and 8 DPC. Sero-reactivity was also observed in some of the principal infected sheep but not the contact sentinels, indicating that transmission to co-mingled naïve sheep was not highly efficient; however, viral RNA was detected in some of the respiratory tract tissues of sentinel animals at 21 DPC. Furthermore, we used challenge inoculum consisting of a mixture of two SARS-CoV-2 isolates, representatives of the ancestral lineage A and the B.1.1.7-like alpha variant of concern (VOC), to study competition of the two virus strains. Our results indicate that sheep show low susceptibility to SARS-CoV-2 infection, and that the alpha VOC outcompeted the ancestral lineage A strain.
Orthogonal control of gene expression in plants using synthetic promoters and CRISPR-based transcription factors
Authors: Kar Shaunak , Bordiya Yogendra , Rodriguez Nestor , Kim Junghyun , Gardner Elizabeth C. , Gollihar Jimmy , Sung Sibum , Ellington Andrew D. 
Published: November 2021

AbstractBackgroundThe construction and application of synthetic genetic circuits is frequently improved if gene expression can be orthogonally controlled, relative to the host. In plants, orthogonality can be achieved via the use of CRISPR-based transcription factors that are programmed to act on natural or synthetic promoters. The construction of complex gene circuits can require multiple, orthogonal regulatory interactions, and this in turn requires that the full programmability of CRISPR elements be adapted to non-natural and non-standard promoters that have few constraints on their design. Therefore, we have developed synthetic promoter elements in which regions upstream of the minimal 35S CaMV promoter are designed from scratch to interact via programmed gRNAs with dCas9 fusions that allow activation of gene expression.ResultsA panel of three, mutually orthogonal promoters that can be acted on by artificial gRNAs bound by CRISPR regulators were designed. Guide RNA expression targeting these promoters was in turn controlled by either Pol III (U6) or ethylene-inducible Pol II promoters, implementing for the first time a fully artificial Orthogonal Control System (OCS). Following demonstration of the complete orthogonality of the designs, the OCS was tied to cellular metabolism by putting gRNA expression under the control of an endogenous plant signaling molecule, ethylene. The ability to form complex circuitry was demonstrated via the ethylene-driven, ratiometric expression of fluorescent proteins in single plants.ConclusionsThe design of synthetic promoters is highly generalizable to large tracts of sequence space, allowing Orthogonal Control Systems of increasing complexity to potentially be generated at will. The ability to tie in several different basal features of plant molecular biology (Pol II and Pol III promoters, ethylene regulation) to the OCS demonstrates multiple opportunities for engineering at the system level. Moreover, given the fungibility of the core 35S CaMV promoter elements, the derived synthetic promoters can potentially be utilized across a variety of plant species.
Resistance profiling of Aspergillus fumigatus to olorofim indicates absence of intrinsic resistance and unveils the molecular mechanisms of acquired olorofim resistance
Authors: Buil Jochem B. , Oliver Jason D. , Law Derek , Baltussen Tim , Zoll Jan , Hokken Margriet W.J. , Tehupeiory-Kooreman Marlou , Melchers Willem J.G. , Birch Mike , Verweij Paul E. 
Published: November 2021

AbstractOlorofim (F901318) is a new antifungal currently under clinical development that shows both in vitro and in vivo activity against a number of filamentous fungi including Aspergillus fumigatus. In this study we screened A. fumigatus isolates for intrinsic olorofim-resistant A. fumigatus and evaluated the ability of A. fumigatus to acquire an olorofim-resistant phenotype. No intrinsic resistance was found in 975 clinical A. fumigatus isolates. However, we found that isolates with increased olorofim MICs (> 8 mg/L) could be selected using a high number of conidia and olorofim exposure under laboratory conditions. Assessment of the frequency of acquired olorofim resistance development of A. fumigatus was shown to be higher than for voriconazole but lower than for itraconazole. Sequencing the PyrE gene of isogenic isolates with olorofim MICs of >8 mg/L identified various amino acid substitutions with a hotspot at locus G119. Olorofim was shown to have reduced affinity to mutated target protein dihydroorotate dehydrogenase (DHODH) and the effect of these mutations were proven by introducing the mutations directly in A. fumigatus. We then investigated whether G119 mutations were associated with a fitness cost in A. fumigatus. These experiments showed a small but significant reduction in growth rate for strains with a G119V substitution, while strains with a G119C substitution did not exhibit a reduction in growth rate. These in vitro findings were confirmed in an in vivo pathogenicity model.ImportanceOlorofim represents an important new treatment option for patients with difficult to treat invasive fungal infections, including triazole-resistant A. fumigatus infection. Our study provides insights into one resistance mechanism and the potential dynamics of olorofim resistance, which will help to prevent and manage resistance selection. Such insights are critical to antifungal stewardship and to safeguard its prolonged use in clinical practice.
NMR metabolomics of symbioses between bacterial vaginosis associated bacteria
Authors: Horrocks Victoria , Hind Charlotte K. , Wand Matthew E. , Chan Joel , Hopkins Jade C. , Houston Georgina L. , Tribe Rachel M. , Sutton J. Mark , Mason A. James 
Published: November 2021

ABSTRACTBacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome, characterised by low levels of lacto-bacilli and overgrowth of a diverse group of bacteria, and associated with higher risk of a variety of infections, surgical complications, cancer and spontaneous preterm birth (PTB). Despite the lack of a consistently applicable aetiology, Prevotella spp. are often associated with both BV and PTB and P. bivia has known symbiotic relationships with both Peptostreptococcus anaerobius and Gardnerella vaginalis. Higher risk of PTB can also be predicted by a composite of metabolites linked to bacterial metabolism but their specific bacterial source remains poorly understood. Here we characterise diversity of metabolic strategies among BV associated bacteria and lactobacilli and the symbiotic metabolic relationships between P. bivia and its partners and show how these influence the availability of metabolites associated with BV/PTB and/or pro- or anti-inflammatory immune responses. We confirm a commensal relationship between Pe. anaerobius and P. bivia, refining its mechanism; P. bivia supplies tyrosine, phenylalanine, methionine, uracil and proline, the last of which leads to a substantial increase in overall acetate production. In contrast, our data indicate the relationship between P. bivia and G. vaginalis strains, with sequence variant G2, is mutualistic with outcome dependent on the metabolic strategy of the G. vaginalis strain. Seven G. vaginalis strains could be separated according to whether they performed mixed acid fermentation (MAF) or bifid shunt (BS). In co-culture, P. bivia supplies all G. vaginalis strains with uracil and received substantial amounts of asparagine in return. Acetate production, which is lower in BS strains, then matched that of MAF strains while production of aspartate increased for the latter. Taken together, our data show how knowledge of inter- and intra-species metabolic diversity and the effects of symbiosis may refine our understanding of the mechanism and approach to risk prediction in BV and/or PTB.
Predicting SARS-CoV-2 epitope-specific TCR recognition using pre-trained protein embeddings
Authors: Han Youngmahn , Lee Aeri 
Published: November 2021

AbstractThe COVID-19 pandemic is ongoing because of the high transmission rate and the emergence of SARS-CoV-2 variants. The P272L mutation in SARS-Cov-2 S-protein is known to be highly relevant to the viral escape associated with the second pandemic wave in Europe. Epitope-specific T-cell receptor (TCR) recognition is a key factor in determining the T-cell immunogenicity of a SARS-CoV-2 epitope. Although several data-driven methods for predicting epitope-specific TCR recognition have been proposed, they remain challenging owing to the enormous diversity of TCRs and the lack of available training data. Self-supervised transfer learning has recently been demonstrated to be powerful for extracting useful information from unlabeled protein sequences and increasing the predictive performance of the fine-tuned models in downstream tasks.Here, we present a predictive model based on Bidirectional Encoder Representations from Transformers (BERT), employing self-supervised transfer learning, to predict SARS-CoV-2 T-cell epitope-specific TCR recognition. The fine-tuned model showed notably high predictive performance for independent evaluation using the SARS-CoV-2 epitope-specific TCR CDR3β sequence datasets. In particular, we found the proline at position 4 corresponding to the P272L mutation in the SARS-CoV-2 S-protein269-277 epitope (YLQPRTFLL) may contribute substantially to TCR recognition of the epitope through interpreting the output attention weights of our model.We anticipate that our findings will provide new directions for constructing a reliable data-driven model to predict the immunogenic T-cell epitopes using limited training data and help accelerate the development of an effective vaccine in response to SARS-CoV-2 variants.
An assessment of the evidence for antibacterial activity of stinging nettle (Urtica dioica) extracts
Authors: Harrison Freya , Furner-Pardoe Jessica , Connelly Erin 
Published: November 2021

AbstractStinging nettles (Urtica spp.) have been used in a diverse range of traditional and historical medicines from around the world for the treatment of skin diseases, wounds, urinary disorders, respiratory diseases, bone and joint pain, anaemia and other circulatory problems, as well as in cosmetic preparations for skin and haircare. As part of an interdisciplinary exploration of nettle-based remedies, we performed a systematic review of published evidence for the antimicrobial activity of Urtica spp. extracts against bacteria and fungi that commonly cause skin, soft tissue and respiratory infections. We focussed on studies in which minimum inhibitory concentration (MIC) assays of U. dioica were conducted on the common bacterial opportunistic pathogens Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus. No studies used fresh leaves (all were dried prior to use), and no studies prepared nettles in weak acid (corresponding to vinegar) or in fats/oils, which are common combinations in historical and traditional preparations. We addressed this gap by conducting new antibacterial tests of extracts of fresh U. dioica leaves prepared in vinegar, butter or olive oil against P. aeruginosa and S. aureus. Our systematic review and additional experimental data leads us to conclude that there is no strong evidence for nettles containing molecules with clinically useful antimicrobial activity. It seems most likely that the utility of nettles in traditional topical preparations for wounds may simply be as a “safe” absorbent medium for keeping antibacterial (vinegar) or emollient (oils) ingredients at the treatment site.Data SummaryAll data relating to the systematic review are supplied in the Datasets and Supplementary tables contained in the Supporting Data file.