bluuebunny/crossref_metadata_2025 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

Objectives

Data 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.

Methods

A 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.

Results

Despite 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.

Conclusions

Results 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.
Maternal separation affects fronto-cortical activity in rat pups during dam-pup interactions and behavioral transitions
Authors: Ranger Manon , Behring Tatyana B. , Kaidbey Jasmine H. , Anwar Muhammad , Lipshutz Allie B. , Mollicone Isabelle , Hassan Gehad , Fasano Kathryn , Hinz Nicole K. , Ludwig Robert J. , Myers Michael M. , Welch Martha G. , Dumitriu Dani
Published: May 2021

Early-life stress is known to impair neurodevelopment. Prior work from our group showed that prolonged physical and emotional separation necessitated by the medical needs of preterm infants (born <37 weeks) is associated with lower electroencephalogram (EEG) power in frontal areas, and that trend can be reversed by an intervention that enhances the physical and emotional contact between preterm infant and mother. Here we sought to model the changes in preterm infant frontal EEG power in a rodent model. We examined effects of daily maternal separation (MS) on frontal cortex electrophysiological (electrocorticography [EcoG]) activity in neonatal rats. We also explored the effects of dam-pup behavioral interactions on EcoG activity. From postnatal days (P) 2-10, rat pups were separated daily from their dam and isolated from their littermates for 3 hours. Control rats were normally reared. On P10, pups were implanted with telemetry devices and an electrode placed on the left frontal dura. EcoG activity was recorded during daily sessions over the next four days while pups remained in the home cage, as well as in response to a pup-dam isolation-reunion paradigm at P12. EcoG power was computed in 1 Hz frequency bins between 1-100 Hz. Dam and pup behavioral interactions during recording sessions were coded and synchronized to EcoG data. MS pups showed lower EcoG power during dam-pup interactions. These data parallel human and provide evidence of lower fronto-cortical activity as an early marker of early-life stress and possible mechanism for long-term effects of maternal separation on neurobehavioral development.
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

In 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

The 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

Apples (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.

Highlight

Hexanal, 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

The 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 Summary

4’-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

Radiation 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

Cholecystokinin 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

Although 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

COVID-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

Potyviruses 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

Global 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 Summary

Alum 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

Development 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

Intraspecific 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.
Modular evolution of secretion systems and virulence plasmids in a bacterial species complex
Authors: Chou Lin , Lin Yu-Chen , Haryono Mindia , Santos Mary Nia M. , Cho Shu-Ting , Weisberg Alexandra J. , Wu Chih-Feng , Chang Jeff H. , Lai Erh-Min , Kuo Chih-Horng
Published: May 2021

Background

Many bacterial taxa are species complexes and uncertainties regarding the organization of their genetic diversity challenge research efforts. We utilizedAgrobacterium tumefaciens, a taxon known for its phytopathogenicity and applications in transformation, as a study system and devised strategies for investigating genome diversity and evolution of species complexes.

Results

We utilized 35 genome assemblies to achieve a comprehensive and balanced sampling ofA. tumefaciens. Our confident inference of gene content and core-genome phylogeny supported a quantitative guideline for delineating 12 species and allowed for robust investigations of genes critical in fitness and ecology. For the type VI secretion system (T6SS) involved in interbacterial competition and thought to be conserved, we detected multiple losses and one horizontal gene transfer. For the tumor-inducing plasmids (pTi) and pTi-encoded type IV secretion system (T4SS) that are essential for agrobacterial phytopathogenicity, we uncovered novel diversity and hypothesized their involvement in shaping this species complex. Intriguingly, for both T6SS and T4SS, genes encoding structural components are highly conserved, whereas extensive diversity exists for genes encoding effectors and other proteins.

Conclusions

We demonstrated that the combination of a phylogeny-guided sampling scheme and an emphasis on high-quality assemblies provides a cost-effective approach for robust analysis in evolutionary genomics. Our strategies for multi-level investigations at scales that range from whole-genomes to intragenic domains and phylogenetic depths of between- and within-species are applicable to other bacteria. Finally, modularity observed in the molecular evolution of genes and domains is useful for inferring functional constraints and informing experimental works.
A memristor-based neuromodulation device for real-time monitoring and adaptive control ofin vitroneuronal populations
Authors: Dias Catarina , Castro Domingos , Aroso Miguel , Ventura João , Aguiar Paulo
Published: May 2021

Neurons are specialized cells in information transmission and information processing. Following this, many neurologic disorders are directly linked not to cellular viability/homeostasis issues but rather to specific anomalies in electrical activity dynamics. Acknowledging this fact, therapeutic strategies based on direct modulation of neuronal electrical activity have been producing remarkable results, with successful examples ranging from cochlear implants to deep brain stimulation. Development on these implantable devices are hindered, however, by important challenges: power requirements, size factor, signal transduction, and adaptability/computational capabilities. Memristors, nanoscale electronic components able to emulate natural synapses, provide unique properties to address these constraints and their use in neuroprosthetic devices is being actively explored. Here we demonstrate for the first time the use of memristive devices in a clinically relevant setting where communication between two neuronal populations is conditioned to specific activity patterns in the source population. In our approach, the memristor device performs a simple pattern detection computation and acts as a synapstor capable of reversible short-term plasticity. Usingin vitrohippocampal neuronal cultures, we show real-time adaptive control with a high degree of reproducibility using our monitor-compute-actuate paradigm. We envision very similar systems being used for automatic detection and suppression of seizures in epileptic patients.
The adenosine 2a receptor and TIM3 directly inhibit killing of tumor cells by cytotoxic T lymphocytes through interference with cytoskeletal polarization
Authors: Edmunds Grace L. , Wong Carissa C.W. , Ambler Rachel , Milodowski Emily , Alamir Hanin , Cross Stephen J. , Galea Gabriella , Wülfing Christoph , Morgan David J.
Published: May 2021

Tumors generate an immune-suppressive environment that prevents effective killing of tumor cells by CD8+ cytotoxic T cells (CTL). It remains largely unclear upon which cell type and at which stage of the anti-tumor response mediators of suppression act. We have combined an in vivo tumor model with a matching in vitro reconstruction of the tumor microenvironment based on tumor spheroids to identify suppressors of anti-tumor immunity that directly act on interaction between CTL and tumor cells and to determine mechanisms of action. An adenosine 2a receptor antagonist, as enhanced by blockade of TIM3, slowed tumor growth in vivo. Engagement of the adenosine 2a receptor and TIM3 reduced tumor cell killing in spheroids, impaired CTL cytoskeletal polarization ex vivo and in vitro and inhibited CTL infiltration into tumors and spheroids. With this focus on CTL killing, blocking A2aR and TIM3 complements therapies that enhance T cell priming, e.g. anti-PD1 and anti-CTLA-4.
FIND-IT: Ultrafast mining of genome diversity
Authors: Knudsen Søren , Wendt Toni , Dockter Christoph , Thomsen Hanne C. , Rasmussen Magnus , Jørgensen Morten Egevang , Lu Qiongxian , Voss Cynthia , Murozuka Emiko , Østerberg Jeppe Thulin , Harholt Jesper , Braumann Ilka , Cuesta-Seijo Jose A. , Bodevin Sabrina , Petersen Lise T. , Carciofi Massimiliano , Pedas Pai Rosager , Husum Jeppe Opstrup , Simmelsgaard Nielsen Martin Toft , Nielsen Kasper , Jensen Mikkel K. , Møller Lillian A. , Gojkovic Zoran , Striebeck Alexander , Lengeler Klaus , Fennessy Ross T. , Katz Michael , Garcia Sanchez Rosa , Solodovnikova Natalia , Förster Jochen , Olsen Ole , Møller Birger Lindberg , Fincher Geoffrey B. , Skadhauge Birgitte
Published: May 2021

Novel crop improvement methodologies, including the exploitation of natural genetic variation, are urgently required to feed our rapidly growing human population in the context of global climate change. Here we describe a ‘Fast Identification of Nucleotide variants by DigITal PCR’ (FIND-IT) method for the rapid identification of pre-targeted genetic variants or rare alleles in large genomic populations. Libraries of 500,000 individuals can be screened and desired variants isolated within two weeks. FIND-IT is widely applicable for mining valuable diversity in any genomic population, including elite breeding and wild germplasm collections. The method provides single nucleotide resolution that has been validated by identifying and isolating knockout lines, non-synonymous codon changes and variants of miRNA and transcription factor binding sites in the agronomically important crop barley. In contrast to existing methods, FIND-IT does not require transformation, cloning or enzymatic steps, and is exempt from GMO regulations. Thus, FIND-IT can be applied immediately to elite crop cultivars and can be tailored to minimize or eliminate time-consuming backcrossing requirements.
Altered hippocampal transcriptome dynamics following sleep deprivation
Authors: Gaine Marie E. , Bahl Ethan , Chatterjee Snehajyoti , Michaelson Jacob. J. , Abel Ted , Lyons Lisa C.
Published: May 2021

Widespread sleep deprivation is a continuing public health problem in the United States and worldwide affecting adolescents and adults. Acute sleep deprivation results in decrements in spatial memory and cognitive impairments. The hippocampus is vulnerable to acute sleep deprivation with changes in gene expression, cell signaling, and protein synthesis. Sleep deprivation also has long lasting effects on memory and performance that persist after recovery sleep, as seen in behavioral studies from invertebrates to humans. Although previous research has shown that acute sleep deprivation impacts gene expression, the extent to which sleep deprivation affects gene regulation remains unknown. Using an unbiased deep RNA sequencing approach, we investigated the effects of acute sleep deprivation on gene expression in the hippocampus. We identified 1,146 genes that were significantly dysregulated following sleep deprivation with 507 genes upregulated and 639 genes downregulated, including protein coding genes and long non-coding RNAs not previously identified as impacted by sleep deprivation. Notably, genes significantly upregulated after sleep deprivation were associated with RNA splicing and the nucleus. In contrast, downregulated genes were associated with cell adhesion, dendritic localization, the synapse, and postsynaptic membrane. These results clearly demonstrate that sleep deprivation differentially regulates gene expression on multiple transcriptomic levels to impact hippocampal function.

Graphical Abstract
A novel gene-by-environment quantitative trait locus on mouse chromosome 15 underlies susceptibility to acute ozone-induced lung injury
Authors: Tovar Adelaide , Smith Gregory J. , Thomas Joseph M. , McFadden Kathryn M. , Kelada Samir N. P.
Published: May 2021

Respiratory toxicity caused by the common urban air pollutant ozone (O3) varies considerably within the human population and across inbred mouse strains, suggestive of gene-environment interactions (GxE). Though previous studies genetic mapping studies using classical inbred strains have identified several and quantitative trait locus (QTL) and candidate genes underlying responses to O3 exposure, precise mechanisms of susceptibility remain incompletely described. We sought to expand our understanding of the genetic architecture of O3 responsiveness using the Collaborative Cross (CC) recombinant inbred mouse panel, which contains more genetic diversity than previous inbred strain panels. We evaluated hallmark O3-induced respiratory phenotypes in 56 CC strains after exposure to filtered air or 2 ppm O3, and performed focused genetic analysis of variation in lung injury as measured by the total bronchoalveolar lavage protein concentration. Because animals were exposed in sex- and batch-matched pairs, we defined a protein response phenotype as the difference in lavage protein between the O3- and FA-exposed animal within a pair. The protein response phenotype was heritable, and QTL mapping revealed two novel loci on Chromosomes 10 (peak: 26.2 Mb; 80% CI: 24.6-43.6 Mb) and 15 (peak: 47.1 Mb; 80% CI: 40.2-54.9 Mb), the latter surpassing the 95% significance threshold. At the Chr. 15 locus, C57BL/6J and CAST/EiJ founder haplotypes were associated with higher protein responses compared to all other CC founder strain haplotypes. Using additional statistical analysis and high-density SNP data, we delimited the Chr. 15 QTL to a ∼2 Mb region containing 21 genes (10 protein coding). Using a weight of evidence approach that incorporated candidate variant analysis, functional annotations, and publicly available lung gene expression data, we nominated three candidate genes (Oxr1, Rspo2, and Angpt1). In summary, we have shown that O3-induced lung injury is modulated by genetic variation and demonstrated the value of the CC for uncovering and dissecting gene-environment interactions.
Maladaptive avoidance learning in the orbitofrontal cortex in adolescents with major depression
Authors: Willinger David , Karipidis Iliana I. , Neuer Selina , Emery Sophie , Rauch Carolina , Häberling Isabelle , Berger Gregor , Walitza Susanne , Brem Silvia
Published: May 2021

Background

Understanding the mechanisms in the brain’s incentive network that give rise to symptoms of major depressive disorder (MDD) during adolescence provides new perspectives to address MDD in early stages of development. This functional magnetic resonance imaging study determines whether instrumental vigor and brain responses to appetitive and aversive monetary incentives are altered in adolescent MDD and associated with symptom severity.

Methods

Adolescents with moderate to severe MDD (n=30, age=16.1 [1.4]), and healthy controls (n=33, age=16.2 [1.9]) matched for age, sex, and IQ performed a monetary incentive delay task. During outcome presentation, prediction error signals were used to study the response and coupling of the incentive network during learning of cue-outcome associations. A computational reinforcement model was used to assess adaptation of response vigor. Brain responses and effective connectivity to model-derived prediction errors were assessed and related to depression severity and anhedonia levels.

Results

Participants with MDD behaved according to a more simplistic learning model and exhibited slower learning. Effective connectivity analysis of fMRI data revealed that impaired loss error processing in the orbitofrontal cortex was associated with aberrant gain-control. Anhedonia scores correlated with loss-related error signals in the posterior insula and habenula.

Conclusions

Adolescent MDD is selectively related to impaired processing of error signals during loss, but not reward, in the orbitofrontal cortex. Aberrant evaluation of loss outcomes might reflect an early mechanism of how negative bias and helplessness manifest in the brain. This approach sheds light on pathomechanisms in MDD and may improve early diagnosis and treatment selection.
Melanin Concentrating Hormone- and sleep-dependent synaptic downscaling is impaired in Alzheimer’s Disease
Authors: Calafate Sara , Özturan Gökhan , Thrupp Nicky , Vanderlinden Jeroen , Chen Wei-Ting , Fiers Mark , Lu Ashley , Creemers Eline , Craessaerts Katleen , Vandenbempt Joris , van Boekholdt Luuk , Poovathingal Suresh , Davie Kristofer , Thal Dietmar Rudolf , Wierda Keimpe , De Strooper Bart , de Wit Joris
Published: May 2021

In Alzheimer’s disease (AD), pathophysiological changes in the hippocampus cause deficits in episodic memory formation, leading to cognitive impairment 1,2. Neuronal hyperactivity is observed early in AD 3,4. Here, we find that homeostatic mechanisms transiently counteract increased neuronal activity in the hippocampal CA1 region of the AppNL-G-F humanized knock-in mouse model for AD 5, but ultimately fail to maintain neuronal activity at set-point. Spatial transcriptomic analysis in CA1 during the homeostatic response identifies the Melanin-Concentrating Hormone (MCH)-encoding gene. MCH is expressed in sleep-active lateral hypothalamic neurons that project to CA1 and modulate memory 6. We show that MCH regulates synaptic plasticity genes and synaptic downscaling in hippocampal neurons. Furthermore, MCH-neuron activity is impaired in AppNL-G-F mice, disrupting sleep-dependent homeostatic plasticity and stability of neuronal activity in CA1. Finally, we find perturbed MCH-axon morphology in CA1 early in AppNL-G-F mice and in AD patients. Our work identifies dysregulation of the MCH-system as a key player in aberrant neuronal activity in the early stages of AD.
Significance of Oct-4 transcription factor as a pivotal therapeutic target for CD44+/24- mammary tumour initiating cells; aiming at the root of the recurrence
Authors: Sen Utsav , Shanavas Shanooja , Gowda Apoorva , Nihad Muhammad , Rachamalla Hari Krishnareddy , Banerjee Rajkumar , Shenoy P Sudheer , Bose Bipasha
Published: May 2021

Breast cancer (BC) remains one of the deadliest and frequently diagnosed metastatic cancers worldwide. Cancer stem cells (CSCs) are the cell population within the tumour niche, having an epithelial to mesenchymal (EMT) transition phenotype, high self-renewal, vigorous metastatic capacity, drug resistance, and tumour relapse. Identification of targets for induction of apoptosis is essential to provide novel therapeutic approaches in BC. Our earlier studies showed that Vitamin C induces apoptotic cell death by losing redox balance in TNBC CSCs. In this study, we have attempted to identify previously unrecognized CSC survival factors that can be used as druggable targets for bCSCs apoptosis regulators isolated from the TNBC line, MDA MB 468. After a thorough literature review, Oct-4 was identified as the most promising marker for its unique abundance in cancer and absence in normal cells and the contribution of Oct-4 to the sustenance of cancer cells. We then validated a very high expression of Oct-4 in the MDA MB 468 bCSCs population using flow-cytometry. The loss of Oct-4 was carried out using siRNA-mediated knockdown in the bCSCs, followed by assessing for cellular apoptosis. Our results indicated that Oct-4 knockdown induced cell death, changes in cellular morphology, inhibited mammosphere formation, and positive for Annexin-V expression, thereby indicating the role of Oct-4 in bCSC survival. Moreover, our findings also suggest the direct interaction between Oct-4 and Vitamin C using in silico docking. This data, hence, contributes towards novel information about Oct-4 highlighting this molecule as a novel survival factor in bCSCs.
Crystal structure and Hirshfeld surface analysis of 2-(2-oxo-3-phenyl-1,2,3,8a-tetrahydroquinoxalin-1-yl)ethyl acetate
Authors: Abad Nadeem , El Ghayati Lhoussaine , Kalonji Mubengayi Camille , Essassi El Mokhtar , Kaya Savaş , Mague Joel T. , Ramli Youssef
Published: May 2021

In the title molecule, C18H16N2O3, the dihydroquinoxaline moiety, with the exception of the N atom is essentially planar with the inner part of the methylpropanoate group (CH2—CH2—O) nearly perpendicular to it. In the crystal, inversion dimers formed by C—H...O hydrogen bonds are connected into oblique stacks by π-stacking and C—H...π(ring) interactions.
The disruption of blockchain in auditing – a systematic literature review and an agenda for future research
Authors: Lombardi Rosa , de Villiers Charl , Moscariello Nicola , Pizzo Michele
Published: May 2021

Purpose

This paper presents a systematic literature review, including content and bibliometric analyses, of the impact of blockchain technology (BT) in auditing, to identify trends, research areas and construct an agenda for future research.

Design/methodology/approach

The authors include studies from 2010 to 2020 in their structured literature review (SLR), using accounting journals on the Scopus database, which yielded 40 articles with blockchain and auditing at its core.

Findings

One of the contributions of the authors’ analyses is to group the prior research, and therefore also the agenda for future research, into three main research areas: (1) Blockchain as a tool for auditing professionals to improve business information systems to save time and prevent fraud; (2) Smart contracts enabling Audit 4.0 efficiency, reporting, disclosure and transparency; (3) Cryptocurrency and initial coin offerings (ICOs) as a springboard for corporate governance and new venture financing. The authors’ findings have several important implications for practice and theory.

Practical implications

The results of this study emphasise that (1) the disruption of blockchain in auditing is in a nascent phase and there is a need for compelling empirical studies and potential for the involvement of practitioners; (2) there may be a need to reconsider audit procedures especially suited for digitalisation and BT adoption; (3) standards, guidelines and training are required to pivot towards and confront the challenge BT will represent for auditing; and (4) there are two sides to the BT coin for auditing, enthusiasm about the potential and risk upon implementation. These practical implications can also be seen as a template for future research in a quest to align theory and practice.

Originality/value

The authors’ SLR facilitates the identification of research areas and implications, forming a useful baseline for practitioners, professionals and academics, as they draft the state of the art on the disruption of blockchain in auditing, highlighting how BT is changing auditing activities and traditions.
Agency costs, board structure and institutional investors: case of India
Authors: Chaudhary Pankaj
Published: May 2021

Purpose

The author examines the role of board structure and institutional investors in dealing with the agency issues for the Indian firms by taking the data of NSE-500 nonfinancial firms for the period 2010–2019.

Design/methodology/approach

The author applies dynamic panel data methodology to deal with endogeneity concerns prevalent in corporate finance variables.

Findings

The agency view is consistent with the board size in the context of India. The author observed that the board size has a harmful effect on agency cost. A larger board size may create a coordination problem, or CEO may find it easy to thrust his or her decisions on board. The author also noticed that firms should have sizeable institutional ownership, particularly pressure-insensitive investors, in equity as they can reduce agency-related issues.

Originality/value

This study focuses on one of the largest emerging economies, i.e. India.