bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Visual Dictionary of Antimicrobial Stewardship, Infection Control, and Institutional Surveillance
Authors: Keizer Julia , Luz Christian F. , Sinha Bhanu , van Gemert-Pijnen Lisette , Albers Casper , Beerlage-de Jong Nienke , Glasner Corinna 
Published: May 2021

AbstractObjectivesData and data visualization are integral parts of (clinical) decision-making in general and stewardship (antimicrobial stewardship, infection control, and institutional surveillance) in particular. However, systematic research on the use of data visualization in stewardship is lacking. This study aimed at filling this gap by creating a visual dictionary of stewardship through an assessment of data visualization in stewardship research.MethodsA random sample of 150 data visualizations from published research articles on stewardship were assessed. The visualization vocabulary (content) and design space (design elements) were combined to create a visual dictionary. Additionally, visualization errors, chart junk, and quality were assessed to identify problems in current visualizations and to provide improvement recommendations.ResultsDespite a heterogeneous use of data visualization, distinct combinations of graphical elements to reflect stewardship data were identified. In general, bar (n=54; 36.0%) and line charts (n=42; 28.1%) were preferred visualization types. Visualization problems comprised colour scheme mismatches, double y-axis, hidden data points through overlaps, and chart junk. Recommendations were derived that can help to clarify visual communication, improve colour use for grouping/stratifying, improve the display of magnitude, and match visualizations to scientific standards.ConclusionsResults of this study can be used to guide data visualization creators in designing visualizations that fit the data and visual habits of the stewardship target audience. Additionally, the results can provide the basis to further expand the visual dictionary of stewardship towards more effective visualizations that improve data insights, knowledge, and clinical decision-making.
Identifying sub-populations of cells in single cell transcriptomic data – a Bayesian mixture modelling approach to zero-inflation of counts
Authors: Wilson Tom , Vo Duong H.T. , Thorne Thomas 
Published: May 2021

AbstractIn the study of single cell RNA-seq data, a key component of the analysis is to identify sub-populations of cells in the data. A variety of approaches to this have been considered, and although many machine learning based methods have been developed, these rarely give an estimate of uncertainty in the cluster assignment. To allow for this probabilistic models have been developed, but single cell RNA-seq data exhibit a phenomenon known as dropout, whereby a large proportion of the observed read counts are zero. This poses challenges in developing probabilistic models that appropriately model the data. We develop a novel Dirichlet process mixture model which employs both a mixture at the cell level to model multiple populations of cells, and a zero-inflated negative binomial mixture of counts at the transcript level. By taking a Bayesian approach we are able to model the expression of genes within clusters, and to quantify uncertainty in cluster assignments. It is shown that this approach out-performs previous approaches that applied multinomial distributions to model single cell RNA-seq counts and negative binomial models that do not take into account zero-inflation. Applied to a publicly available data set of single cell RNA-seq counts of multiple cell types from the mouse cortex and hippocampus, we demonstrate how our approach can be used to distinguish sub-populations of cells as clusters in the data, and to identify gene sets that are indicative of membership of a sub-population. The methodology is implemented as an open source Snakemake pipeline available fromhttps://github.com/tt104/scmixture.
Protein farnesylation is upregulated in Alzheimer’s human brains and neuron-specific suppression of farnesyltransferase mitigates pathogenic processes in Alzheimer’s model mice
Authors: Jeong Angela , Cheng Shaowu , Zhong Rui , Bennett David A. , Bergö Martin O. , Li Ling 
Published: May 2021

AbstractThe pathogenic mechanisms underlying the development of Alzheimer’s disease (AD) remain elusive and to date there are no effective prevention or treatment for AD. Farnesyltransferase (FT) catalyzes a key posttranslational modification process called farnesylation, in which the isoprenoid farnesyl pyrophosphate is attached to target proteins, facilitating their membrane localization and their interactions with downstream effectors. Farnesylated proteins, including the Ras superfamily of small GTPases, are involved in regulating diverse physiological and pathological processes. Emerging evidence suggests that isoprenoids and farnesylated proteins may play an important role in the pathogenesis of AD. However, the dynamics of FT and protein farnesylation in human brains and the specific role of neuronal FT in the pathogenic progression of AD are not known. Here, using postmortem brain tissue from individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), or Alzheimer’s dementia, we found that the levels of FT and membrane-associated H-Ras, an exclusively farnesylated protein, and its downstream effector ERK were markedly increased in AD and MCI compared with NCI. To elucidate the specific role of neuronal FT in AD pathogenesis, we generated the transgenic AD model APP/PS1 mice with forebrain neuron-specific FT knockout, followed by a battery of behavioral assessments, biochemical assays, and unbiased transcriptomic analysis. Our results showed that the neuronal FT deletion mitigates memory impairment and amyloid neuropathology in APP/PS1 mice through suppressing amyloid generation and reversing the pathogenic hyperactivation of mTORC1 signaling. These findings suggest that aberrant upregulation of protein farnesylation is an early driving force in the pathogenic cascade of AD and that targeting FT or its downstream signaling pathways presents a viable therapeutic strategy against AD.
Transcriptomics of improved fruit retention by hexanal in ‘Honeycrisp’ reveals hormonal crosstalk and reduced cell-wall remodelling in the fruit-abscission zone
Authors: Sriskantharajah Karthika , Kayal Walid El , Torkamaneh Davoud , Ayyanath Murali Mohan , Saxena Praveen , Sullivan Alan J , Paliyath Gopinadhan , Subramanian Jayasankar 
Published: May 2021

AbstractApples (Malus domesticaBorkh) are prone to pre-harvest fruit drop which is more pronounced in ‘Honeycrisp’. Using a transcriptomic approach, we analyzed the molecular mechanisms of fruit retention in ‘Honeycrisp’. A total of 726 differentially expressed genes (DEGs) were identified in the abscission zone of hexanal-treated and untreated fruit (FAZ). Hexanal down-regulated the genes involved in ethylene biosynthesis, such as S-adenosylmethionine synthase (SAM2) and 1-aminocyclopropane-1carboxylic acid oxidases (ACO3,ACO4andACO4-like). Genes related to ABA biosynthesis (FDPSandCLE25) were also down-regulated. On the contrary, gibberellic acid (GA) biosynthesis genes, gibberellin 20 oxidase1-like (GA20OX-like) and ent-kaurene oxidase (KO) were up-regulated. Further, hexanal down-regulated the expression of genes related to cell-wall remodelling enzymes such as polygalacturonase (PG1), glucanases (endo-β-1,4-glucanase; EG) and expansins (EXPA1-like, EXPA6, EXPA8, EXPA10-like, EXPA16-like). Hexanal also reduced ethylene, and abscisic acid (ABA) production at commercial harvest stage. Hexanal reduced ethylene production in fruits and thus reduced the sensitivity of FAZ cells to ethylene and ABA. Simultaneously, hexanal maintained the cell-wall integrity of FAZ cells by regulating genes involved in cell-wall modifications. Our findings show that fruit abscission is delayed by hexanal, by down regulating ABA through an ethylene-dependent mechanism.HighlightHexanal, a naturally occurring plant compound, increased fruit retention in apples by decreasing ethylene and ABA production and maintaining the cell-wall integrity in the fruit abscission zone.
4’-Fluorouridine is a broad-spectrum orally efficacious antiviral blocking respiratory syncytial virus and SARS-CoV-2 replication
Authors: Sourimant Julien , Lieber Carolin M , Aggarwal Megha , Cox Robert M , Wolf Josef D , Yoon Jeong-Joong , Toots Mart , Ye Chengin , Sticher Zachary , Kolykhalov Alexander A , Martinez-Sobrido Luis , Bluemling Gregory R , Natchus Michael G , Painter George R , Plemper Richard K 
Published: May 2021

AbstractThe COVID-19 pandemic has underscored the critical need for broad-spectrum therapeutics against respiratory viruses. Respiratory syncytial virus (RSV) is a major threat to pediatric patients and the elderly. We describe 4’-fluorouridine (4’-FlU, EIDD-2749), a ribonucleoside analog that inhibits RSV, related RNA viruses, and SARS-CoV-2 with high selectivity index in cells and well-differentiated human airway epithelia. Polymerase inhibition inin vitroRdRP assays established for RSV and SARS-CoV-2 revealed transcriptional pauses at positionsiori+3/4 post-incorporation. Once-daily oral treatment was highly efficacious at 5 mg/kg in RSV-infected mice or 20 mg/kg in ferrets infected with SARS-CoV-2 WA1/2020 or variant-of-concern (VoC) isolate CA/2020, initiated 24 or 12 hours after infection, respectively. These properties define 4’-FlU as a broad-spectrum candidate for the treatment of RSV, SARS-CoV-2 and related RNA virus infections.One-Sentence Summary4’-Fluorouridine is an orally available ribonucleoside analog that efficiently treats RSV and SARS-CoV-2 infectionsin vivo.
Sub-lethal radiation-induced senescence impairs resolution programs and drives cardiovascular inflammation
Authors: Sadhu Sudeshna , Decker Christa , Sansbury Brian E. , Marinello Michael , Seyfried Allison , Howard Jennifer , Mori Masayuki , Hosseini Zeinab , Arunachalam Thilaka , Finn Aloke V. , Lamar John M. , Jourd’heuil David , Guo Liang , MacNamara Katherine C. , Spite Matthew , Fredman Gabrielle 
Published: May 2021

AbstractRadiation is associated with tissue damage and increased risk of atherosclerosis but there are currently no treatments and a very limited mechanistic understanding of how radiation impacts tissue repair mechanisms. We uncovered that radiation significantly delayed temporal resolution programs that was associated with decreased efferocytosis in vivo. Resolvin D1 (RvD1), a known pro-resolving ligand, promoted swift resolution and restored efferocytosis in sub-lethally irradiated mice. Irradiated macrophages exhibited several features of senescence, including increased expression of p16INK4A and p21, heightened levels of SA-β-gal, COX-2, and oxidative stress (OS) in vitro, and when transferred to mice exacerbated inflammation in vivo. Mechanistically, heightened OS in senescent macrophages led to impairment in their ability to carry out efficient efferocytosis and treatment with RvD1 reduced OS and improved efferocytosis. Sub-lethally irradiated Ldlr-/- mice exhibited increased plaque necrosis and p16INK4A cells compared with non-irradiated controls and treatment with RvD1 significantly reduced these endpoints. Removal of p16INK4A hematopoietic cells during advanced atherosclerosis with p16-3MR mice reduced plaque necrosis and increased production of key intraplaque resolving mediators. Our results demonstrate that sub-lethal radiation drives macrophage senescence and efferocytosis defects and suggest that RvD1 may be a new therapeutic strategy to limit radiation-induced tissue damage.
Structures of the human cholecystokinin receptors in complex with agonists and antagonists
Authors: Zhang Xuefeng , He Chenglin , Wang Mu , Zhou Qingtong , Yang Dehua , Zhu Ya , Feng Wenbo , Zhang Hui , Dai Antao , Chu Xiaojing , Wang Jia , Yang Zhenlin , Jiang Yi , Sensfuss Ulrich , Tan Qiuxiang , Han Shuo , Reedtz-Runge Steffen , Xu Eric H. , Zhao Suwen , Wang Ming-Wei , Wu Beili , Zhao Qiang 
Published: May 2021

SummaryCholecystokinin receptors, CCKAR and CCKBR, are important neuro-intestinal peptide hormone receptors and play a vital role in food intake and appetite regulation. Here we report three crystal structures of the human CCKAR in complex with different ligands, including one peptide agonist and two small-molecule antagonists, as well as two cryo-electron microscopy structures of CCKBR–gastrin in complex with Gi2 and Gq, respectively. These structures reveal the recognition pattern of different ligand types and the molecular basis of peptide selectivity in the cholecystokinin receptor family. By comparing receptor structures in different conformational states, a stepwise activation process of cholecystokinin receptors is proposed. Combined with pharmacological data, our results provide atomic details for differential ligand recognition and receptor activation mechanisms. These insights will facilitate the discovery of potential therapeutics targeting cholecystokinin receptors.
TLR2 on CD4+ and CD8+ T cells promotes late control of Mycobacterium tuberculosis infection
Authors: Reba Scott M. , Li Qing , Onwuzulike Sophia , Nagy Nancy , Parker Kyle , Umphred-Wilson Katharine , Shukla Supriya , Harding Clifford V. , Boom W. Henry , Rojas Roxana E. 
Published: May 2021

AbstractAlthough a role for TLR2 on T cells has been indicated in prior studies, in vivo stimulation of TLR2 on T cells by Mtb and its impact on Mtb infection has not been tested. Furthermore, it is not known if the enhanced susceptibility to Mtb of Tlr2 gene knockout (ko) mice is due to its role in macrophages, on T cells or both. To address TLR2 on T cells, we generated Tlr2fl/flxCd4cre/cre mice, which lack expression of TLR2 on both CD4 and CD8 T cells, to study the in vivo role of TLR2 on T cells after aerosol infection with virulent Mtb. Deletion of TLR2 in CD4+ and CD8+ T cells reduces their ability to be co-stimulated by TLR2 ligands for cytokine production. These include both pro-(IFN-γ, TNF-α) and anti-inflammatory cytokines (IL-10). Deletion of TLR2 in T cells did not affect early control but did result in decreased late control of Mtb in the lungs of infected mice. This suggests that T cell co-stimulation by mycobacterial TLR2 ligands in vivo is important for control of infection during the chronic phase of Mtb infection in the lung.
A 2SIR-VD Model for Optimizing Geographical COVID-19 Vaccine Distribution in the Philippines
Authors: Almajose Allan Paolo L. , White Angus , Diego Chelsea , Lazaro Red , Austriaco Nicanor 
Published: May 2021

ABSTRACTCOVID-19 is a novel respiratory disease first identified in Wuhan, China, that is caused by the novel coronavirus, SARS-CoV-2. It has triggered a global pandemic of historic proportions. The government of the Philippines began its national vaccine drive on March 1, 2021, with the goal of vaccinating seventy million of its citizens by the end of the calendar year. To determine the optimum geographical distribution strategy in the Philippines for the limited supply of vaccines that is currently available, we developed and adapted a basic SIR model that allows us to understand the evolution of a pandemic when public health authorities are vaccinating two susceptible populations within a country with different vaccine rates. Our analysis with our 2SIR-VD model revealed that prioritizing vaccine deployment to the National Capital Region (NCR) of the Philippines minimized the number of COVID-19 cases in the country. We therefore recommend deploying 90% of the available vaccine supply to the NCR to mitigate viral transmission there. The remaining 10% would allow the rest of the archipelago to vaccinate all of their senior citizens, thus shielding this vulnerable population against severe disease and death from COVID-19.
The Rysto immune receptor recognizes a broadly conserved feature of potyviral coat proteins
Authors: Grech-Baran Marta , Witek Kamil , Poznański Jarosław , Grupa-Urbańska Anna , Malinowski Tadeusz , Lichocka Małgorzata , Jones Jonathan DG , Hennig Jacek 
Published: May 2021

AbstractPotyviruses are the largest group of plant RNA viruses, causing significant losses in many crops. Among them, potato virus Y (PVY) is particularly important, and enhances the severity of infections by other viruses. The Rysto gene confers PVY resistance and encodes a TIR-NLR intracellular immune receptors that recognizes PVY coat protein (CP). To define a minimal CP fragment sensed by Rysto, we created a series of truncated CP variants and expressed these CP derivatives in Rysto transgenic plants. Deletions that affect the 149 amino acid CP core region lose the ability to trigger Rysto-dependent defence activation. Furthermore, point mutations in the amino acid residues Ser126, Arg157, and Asp201 of the highly conserved RNA-binding pocket of potyviral CP, reduce or abolish Rysto-dependent responses, demonstrating that appropriate folding of the CP core is required for Rysto-mediated recognition. Consistent with these data, we found Rysto recognises CPs of various viruses that share a similar core region, but not those lacking it. Finally, we demonstrated that Rysto provides immunity to plum pox virus and turnip mosaic virus, demonstrating its wide range of applications in disease-resistant crop engineering. In parallel, we showed that CP triggered Rysto activation is SAG101- but not PAD4- or SA-level dependent. Our findings shed new light on how R proteins can detect viruses by sensing highly conserved structural patterns.
Alum:CpG adjuvant enables SARS-CoV-2 RBD-induced protection in aged mice and synergistic activation of human elder type 1 immunity
Authors: Nanishi Etsuro , Borriello Francesco , O’Meara Timothy R. , McGrath Marisa E. , Saito Yoshine , Haupt Robert E. , Seo Hyuk-Soo , van Haren Simon D. , Brook Byron , Chen Jing , Diray-Arce Joann , Doss-Gollin Simon , Leon Maria De , Chew Katherine , Menon Manisha , Song Kijun , Xu Andrew Z. , Caradonna Timothy M. , Feldman Jared , Hauser Blake M. , Schmidt Aaron G. , Sherman Amy C. , Baden Lindsey R. , Ernst Robert K. , Dillen Carly , Weston Stuart M. , Johnson Robert M. , Hammond Holly L. , Mayer Romana , Burke Allen , Bottazzi Maria E. , Hotez Peter J. , Strych Ulrich , Chang Aiquan , Yu Jingyou , Barouch Dan H. , Dhe-Paganon Sirano , Zanoni Ivan , Ozonoff Al , Frieman Matthew B. , Levy Ofer , Dowling David J. 
Published: May 2021

ABSTRACTGlobal deployment of vaccines that can provide protection across several age groups is still urgently needed to end the COVID-19 pandemic especially for low- and middle-income countries. While vaccines against SARS-CoV-2 based on mRNA and adenoviral-vector technologies have been rapidly developed, additional practical and scalable SARS-CoV-2 vaccines are needed to meet global demand. In this context, protein subunit vaccines formulated with appropriate adjuvants represent a promising approach to address this urgent need. Receptor-binding domain (RBD) is a key target of neutralizing antibodies (Abs) but is poorly immunogenic. We therefore compared pattern recognition receptor (PRR) agonists, including those activating STING, TLR3, TLR4 and TLR9, alone or formulated with aluminum hydroxide (AH), and benchmarked them to AS01B and AS03-like emulsion-based adjuvants for their potential to enhance RBD immunogenicity in young and aged mice. We found that the AH and CpG adjuvant formulation (AH:CpG) demonstrated the highest enhancement of anti-RBD neutralizing Ab titers in both age groups (∼80-fold over AH), and protected aged mice from the SARS-CoV-2 challenge. Notably, AH:CpG-adjuvanted RBD vaccine elicited neutralizing Abs against both wild-type SARS-CoV-2 and B.1.351 variant at serum concentrations comparable to those induced by the authorized mRNA BNT162b2 vaccine. AH:CpG induced similar cytokine and chemokine gene enrichment patterns in the draining lymph nodes of both young adult and aged mice and synergistically enhanced cytokine and chemokine production in human young adult and elderly mononuclear cells. These data support further development of AH:CpG-adjuvanted RBD as an affordable vaccine that may be effective across multiple age groups.One Sentence SummaryAlum and CpG enhance SARS-CoV-2 RBD protective immunity, variant neutralization in aged mice and Th1-polarizing cytokine production by human elder leukocytes.
Bioluminescent Synthetic Cells Communicate with Natural Cells and Self-Activate Light-Responsive Proteins
Authors: Adir Omer , Abel Ravit , Albalak Mia R. , Weiss Lucien E. , Chen Gal , Gruber Amit , Staufer Oskar , Shklover Jeny , Shainsky-Roitman Janna , Platzman Ilia , Gepstein Lior , Shechtman Yoav , Horwitz Benjamin A. , Schroeder Avi 
Published: May 2021

AbstractDevelopment of regulated cellular processes and signaling methods in synthetic cells is essential for their integration with living materials. Light is an attractive tool to achieve this, but the limited penetration depth into tissue of visible light restricts its usability for in-vivo applications. Here, we describe the synthesis and application of blue-light-generating synthetic cells using bioluminescence, dismissing the need for an external light source. First, the lipid membrane and internal composition of light-producing synthetic cells were optimized to enable high-intensity emission. Next, we show these cells’ capacity for triggering bioprocesses in natural cells by initiating asexual sporulation of dark-grown mycelial cells of the fungus Trichoderma atroviride in a quorum-sensing like mechanism. Finally, we demonstrate regulated transcription and membrane recruitment in synthetic cells using bioluminescent self-activating fusion proteins. These functionalities pave the way for deploying synthetic cells as embeddable microscale light sources that are capable of activating engineered processes inside tissues.
Where are the beachmasters? Unexpectedly weak polygyny among southern elephant seals on a South Shetland Island
Authors: Nichols H.J. , Fuchs B. , Paijmans A.J , Lewis G. , Bonin C.A. , Goebel M.E. , Hoffman J.I. 
Published: May 2021

ABSTRACTIntraspecific variation in animal mating systems can have important implications for ecological, evolutionary and demographic processes in wild populations. For example, patterns of mating can impact social structure, dispersal, effective population size and inbreeding. However, few species have been studied in sufficient detail to elucidate mating system plasticity and its dependence on ecological and demographic factors. Southern elephant seals (Mirounga leonina) have long been regarded as a textbook example of a polygynous mating system, with dominant ‘beachmaster’ males controlling harems of up to several hundred females. However, behavioural and genetic studies have uncovered appreciable geographic variation in the strength of polygyny among elephant seal populations. We therefore used molecular parentage analysis to investigate patterns of parentage in a small satellite colony of elephant seals at the South Shetland Islands. We hypothesised that dominant males would be able to successfully monopolise the relatively small numbers of females present in the colony, leading to relatively high levels of polygyny. A total of 424 individuals (comprising 33 adult males, 101 adult females and 290 pups) sampled over eight years were genotyped at 20 microsatellites and reproductive success was analysed by genetically assigning parents. Paternity could only be assigned to 31 out of 290 pups (10.7%), despite our panel of genetic markers being highly informative and the genotyping error rate being very low. The strength of inferred polygyny was weak in comparison to previous genetic studies of the same species, with the most successful male fathering only seven pups over the entire course of the study. Our results show that, even in a species long regarded as a model for extreme polygyny, male reproductive skew can vary substantially among populations.