bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of multidrug-resistant coagulase-positive staphylococci in canine and feline dermatological patients over a 10-year period: a retrospective study
Authors: Burke Mikaela , Santoro Domenico
Published: February 2023

Coagulase-positive staphylococci (CPS) are common cutaneous pathogens often requiring multiple courses of antibiotics, which may facilitate selection for methicillin-resistant (MR) and/or multidrug-resistant (MDR) strains. To determine the prevalence of canine and feline MR/MDR CPS associated with skin diseases, medical records were retrospectively searched from April 2010 to April 2020. Pets with at least one positive culture for CPS were selected. Age, sex, antimicrobial sensitivity, previous history of antimicrobial/immunomodulatory medications and methicillin resistance/multidrug resistance status were recorded.

Staphylococcus pseudintermedius

(SP) (575/748) and

Staphylococcus schleiferi

(SS) (159/748) in dogs, and

Staphylococcus aureus

(12/22) in cats, were the most common CPS isolated. Three hundred and twenty-three out of 575 isolates were MR-SP (56.2 %), 304/575 were MDR-SP (52.8 %), 100/159 were MR-SS (62.9 %) and 71/159 were MDR-SS (44.6 %). A trend analysis showed a significant increase of resistance to oxacillin and chloramphenicol for

S. pseudintermedius

(r=0.86, 0.8; P=0.0007, 0.0034, respectively). Major risk factors for MDR-SP included oxacillin resistance (OR: 3; 95 % CI: 1.4–6.5; P=0.0044), positivity for PBP2a (OR: 2.3; 95 % CI: 1–5; P=0.031) and use of antibiotics in the previous year (OR: 2.8; 95 % CI: 1.3–5.8; P=0.0071). Oxacillin resistance was identified as a major risk factor for MDR-SS (OR: 8.8; 95 % CI: 3.6–21.1; P<0.0001). These results confirmed the widespread presence of MR/MDR CPS in referred dermatological patients. Judicious antibiotic use, surveillance for MR/MDR infections and consideration of alternative therapies are crucial in mitigating the development of resistant strains.
Quantifying the impact of interventions againstPlasmodium vivaxmalaria: a model for country-specific use
Authors: Champagne C. , Gerhards M. , Lana J. , Menach A. Le , Pothin E.
Published: February 2023

In order to evaluate the impact of various intervention strategies onPlasmodium vivaxdynamics, we introduce a simple mathematical model that can be easily adapted to country-specific data. The model includes case management, vector control, mass drug administration and reactive case detection interventions and is implemented in both deterministic and stochastic frameworks. It is available as an R package to enable users to calibrate and simulate it with their own data. By simulating and comparing the impact of various intervention combinations on malaria risk and burden, this model can a useful tool for strategic planning, implementation and resource mobilization.
Dual-systems models of the genetic architecture of impulsive personality traits: Neurogenetic evidence of distinct but related factors
Authors: Miller Alex P. , Gizer Ian R.
Published: February 2023

Background

Dual-systems models provide a parsimonious framework for understanding the interplay between cortical and subcortical brain regions relevant to impulsive personality traits (IPTs) and their associations with psychiatric disorders. Despite recent developments in multivariate analysis of genome-wide association studies (GWAS), molecular genetic investigations of these models have not been conducted.

Methods

Using extant IPT GWAS, we conducted confirmatory genomic structural equation models (GenomicSEM) to empirically evaluate dual-systems models of the genetic architecture of IPTs. Genetic correlations between results of multivariate GWAS of dual-systems factors and GWAS of relevant cortical and subcortical neuroimaging phenotypes (regional/structural volume, cortical surface area, cortical thickness) were calculated and compared.

Results

Evaluation of GenomicSEM model fit indices for dual-systems models suggested that these models highlight important sources of shared and unique genetic variance between top-down and bottom-up constructs. Specifically, a dual-systems genomic model consisting of sensation seeking and lack of self-control factors demonstrated distinct but related sources of genetic influences (rg=.60). Genetic correlation analyses provided evidence of differential associations between dual-systems factors and cortical neuroimaging phenotypes (e.g., lack of self-control negatively associated with cortical thickness, sensation seeking positively associated with cortical surface area). However, no significant associations were observed for subcortical phenotypes inconsistent with hypothesized functional localization of dual-systems constructs.

Conclusions

Dual-systems models of the genetic architecture of IPTs tested here demonstrate evidence of shared and unique genetic influences and associations with relevant neuroimaging phenotypes. These findings emphasize potential advantages in utilizing dual-systems models to study genetic influences for IPTs and transdiagnostic associations with psychiatric disorders.
Quantifying the rate and magnitude of the Omicron outbreak in China after sudden exit from ‘zero-COVID’ restrictions
Authors: Goldberg Emma E. , Lin Qianying , Romero-Severson Ethan O. , Ke Ruian
Published: February 2023

In late 2022, China transitioned from a strict ‘zero-COVID’ policy to rapidly abandoning nearly all interventions and data reporting. This raised great concern about the presumably-rapid but undisclosed spread of the SARS-CoV-2 Omicron variant in a very large population of very low pre-existing immunity. A quantitative understanding of the epidemic dynamics of COVID-19 during this period is urgently needed. Here, by modeling a combination of case count and survey data, we show that Omicron spread extremely fast, at a rate of 0.42/day (95% CrI: [0.35, 0.51]/day) after the full exit from zero-COVID policies on Dec. 7, 2022. Consequently, we estimate that the vast majority of the population (97%, 95% CrI [95%, 99%]) was infected during December, with the nation-wide epidemic peaking on Dec. 23. Overall, our results highlight the extremely high transmissibility of the variant and the importance of proper design of intervention exit strategies to avoid large infection waves.
Integrative single-cell characterization of frugivory adaptations in the bat kidney and pancreas
Authors: Gordon Wei E. , Baek Seungbyn , Nguyen Hai P. , Kuo Yien-Ming , Bradley Rachael , Galazyuk Alex , Lee Insuk , Ingala Melissa R. , Simmons Nancy B. , Schountz Tony , Cooper Lisa Noelle , Georgakopoulos-Soares Ilias , Hemberg Martin , Ahituv Nadav
Published: February 2023

Frugivory evolved multiple times in mammals, including bats. However, the cellular and molecular components driving it remain largely unknown. Here, we used integrative single-cell sequencing on insectivorous and frugivorous bat kidneys and pancreases and identified key cell population, gene expression and regulatory element differences associated with frugivorous adaptation that also relate to human disease, particularly diabetes. We found an increase in collecting duct cells and differentially active genes and regulatory elements involved in fluid and electrolyte balance in the frugivore kidney. In the frugivorous pancreas, we observed an increase in endocrine and a decrease in exocrine cells and differences in genes and regulatory elements involved in insulin regulation. Combined, our work provides novel insights into frugivorous adaptation that also could be leveraged for therapeutic purposes.
Extra-islet expression of islet antigen boosts T-cell exhaustion to prevent autoimmune diabetes
Authors: Selck Claudia , Jhala Gaurang , De George David , Kwong Chun-Ting J. , Christensen Marie K. , Pappas Evan , Liu Xin , Ge Tingting , Trivedi Prerak , Kallies Axel , Thomas Helen E. , Kay Thomas W.H. , Krishnamurthy Balasubramanian
Published: February 2023

Persistent antigen exposure results in the differentiation of functionally impaired, also termed exhausted, T cells which are maintained by a distinct population of precursors of exhausted T (TPEX) cells. T cell exhaustion is well studied in the context of chronic viral infections and cancer, but it is unclear if and how antigen-driven T cell exhaustion controls progression of autoimmune diabetes and whether this process can be harnessed to prevent diabetes. Using non-obese diabetic (NOD) mice, we show that some CD8+ T cells specific for the islet antigen, islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) displayed terminal exhaustion characteristics within pancreatic islets but were maintained in the TPEXcell state in peripheral lymphoid organs. To examine the impact of antigen on T cell exhaustion in diabetes, we generated transgenic NOD mice with inducible IGRP expression in peripheral antigen presenting cells. Antigen exposure in the extra-islet environment induced severely exhausted IGRP-specific T cells with reduced ability to produce IFNγ, which protected these mice from diabetes. Our data demonstrate that T cell exhaustion induced by delivery of antigen can be harnessed to prevent autoimmune diabetes.
Impacts of invasive fishes on ghost frog tadpoles
Authors: van Blerk Daniel , Melotto Andrea , Pegg Josie , Measey John
Published: February 2023

Global amphibian populations are declining, and invasive fish are known to impact many threatened species. South Africa has both a biodiverse amphibian fauna and a rich history of invasive fish introductions with high establishment success. Studies have identified some preliminary evidence for negative impacts of invasive salmonids on two ghost frog species (Anura: Heleophrynidae). This study aims to investigate whether these negative impacts previously reported are reflected across a broader scale. Tadpoles of two species,Heleophryne regisandH. purcelliwere sampled in the presence and absence of invasive fish at 112 sites across 26 streams in the Western Cape province of South Africa. A generalised linear mixed model showed invasive fish to have the most significant negative effect explaining tadpole abundance. Mean tadpole abundance decreases by 18 times in the presence of invasive fish. Environmental variables with significant effects on tadpole abundance include pH, oxygen saturation, temperature, stream depth and non-native riparian vegetation type. We can define an environmental niche of ghost frog tadpoles which does not differ between species. We conclude that invasive fish have significant negative impacts on ghost frog tadpole abundance, but the effect of the environment should not be overlooked in amphibian conservation planning and invasive species management decisions. This study supports the removal of invasive fish and alien vegetation to improve the conservation of ghost frogs.
An expanded 2-pyridinecarboxaldehyde (2PCA)-based chemoproteomics toolbox for probing protease specificity
Authors: Bridge Haley N. , Frazier Clara L. , Weeks Amy M.
Published: February 2023

Proteomic profiling of protease-generated N termini, or N terminomics, provides key insights into protease function and specificity. However, current N terminomics technologies have sequence limitations or require specialized synthetic reagents for N-terminal peptide isolation. Here, we introduce an expanded N terminomics toolbox that is based on 2-pyridinecarboxaldehyde (2PCA) reagents. These tools enable efficient enrichment of protein N termini by combining selective N-terminal biotinylation using 2PCA reagents with chemically cleavable linkers for N-terminal peptide recovery. By incorporating a commercially available alkyne-modified 2PCA in combination with Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), our strategy eliminates the need for chemical synthesis of N-terminal probes. Using these reagents, we developed PICS2 (Proteomic Identification ofCleavageSites with2PCA reagents) to profile the specificity of subtilisin/kexin-type proprotein convertases (PCSKs). We also implemented CHOPPER (Chemical enrichmentOfProtease substrates withPurchasable,ElutableReagents) for global sequencing of apoptotic proteolytic cleavage sites. Based on their broad applicability and ease of implementation, PICS2 and CHOPPER are useful tools that will advance our understanding of protease biology.
Znf598-mediated Rps10/eS10 ubiquitination contributes to the ribosome ubiquitination dynamics during zebrafish development
Authors: Ugajin Nozomi , Imami Koshi , Takada Hiraku , Ishihama Yasushi , Chiba Shinobu , Mishima Yuichiro
Published: February 2023

Ribosome is a translational apparatus that comprises about 80 ribosomal proteins and four rRNAs. Recent studies reported that ribosome ubiquitination is crucial for translational regulation and ribosome-associated quality control (RQC). However, little is known about the dynamics of ribosome ubiquitination under complex biological processes of multicellular organisms. To explore ribosome ubiquitination during animal development, we generated a zebrafish strain that expresses a FLAG-tagged ribosomal protein Rpl36/eL36 from its endogenous locus. We examined ribosome ubiquitination during zebrafish development by combining affinity purification of ribosomes fromrpl36-FLAG zebrafish embryos with immunoblotting analysis. Our findings showed that ubiquitination of ribosomal proteins dynamically changed as development proceeded. We also showed that during zebrafish development, the ribosome was ubiquitinated by Znf598, an E3 ubiquitin ligase that activates RQC. Ribosomal protein Rps10/eS10 was found to be a key ubiquitinated protein during development. Furthermore, we showed that Rps10/eS10 ubiquitination-site mutations reduced the overall ubiquitination pattern of ribosome. These results demonstrate the complexity and dynamics of ribosome ubiquitination during zebrafish development.
Vampyroteuthis pseudoinfernalissp. nov.: the second extant widespread deep sea squid species of Vampyromorpha (Cephalopoda: Coleoidea)
Authors: Qiu Dajun , Liu Bilin , Guo Yupei , Lakmini Wijesooriya A.S.W. , Tan Yehui , Li Gang , Ke Zhixin , Li Kaizhi , Huang Liangmin
Published: February 2023

The vampire squid,Vampyroteuthis infernalisChun, 1903, is currently the only extant species in the family Vampyroteuthidae Chun, 1903. However, specimens from the Gulf of Guinea, Africa, and California suggested the possibility of additional taxa. Here, we report the second species ofVampyroteuthis, collected from the South China Sea, China, which differs fromV. infernalisby the tail shape, the lower beak, and the phylogenetic analysis of mitochondrial COI and nuclear large subunit ribosomal DNA (LSU) sequences:V. infernalispresent by the lacking of the tail, photophores located approximately one-third of the points between the fins and end, and the lower beak with a broad, short wing;V. pseudoinfernalisQiu, Liu & Huang,sp. nov.present by an acuate tail, a pair of photophores located at the midpoints between the fins and tail, and a lower beak with a broad, elongate wing.
Macrophage epigenetic memories of early life injury drive neonatal nociceptive priming
Authors: Dourson Adam J. , Fadaka Adewale O. , Warshak Anna M. , Paranjpe Aditi , Weinhaus Benjamin , Queme Luis F. , Hofmann Megan C. , Evans Heather M. , Donmez Omer A. , Forney Carmy , Weirauch Matthew T. , Kottyan Leah C. , Lucas Daniel , Deepe George S. , Jankowski Michael P.
Published: February 2023

The developing peripheral nervous and immune systems are functionally distinct from adults. These systems are vulnerable to early life injury, which influences outcomes related to nociception following subsequent injury later in life (i.e., “neonatal nociceptive priming”). The underpinnings of this phenomenon are largely unknown, although previous work indicates that macrophages are epigenetically trained by inflammation and injury. We found that macrophages are both necessary and partially sufficient to drive neonatal nociceptive priming possibly due to a long-lasting epigenetic remodeling. The p75 neurotrophic factor receptor (NTR) was an important effector in regulating neonatal nociceptive priming through modulation of the inflammatory profile of rodent and human macrophages. This “pain memory” was long lasting in females and could be transferred to a naïve host to alter sex-specific pain-related behaviors. This study reveals a novel mechanism by which acute, neonatal post-surgical pain drives a peripheral immune-related predisposition to persistent pain following a subsequent injury.

Graphical Abstract
DNA Polymerases in Precise and Predictable CRISPR/Cas9-mediated Chromosomal Rearrangements
Authors: Mehryar Mohammadreza M. , Shi Xin , Li Jingwei , Wu Qiang
Published: February 2023

Recent studies have shown that Cas9-mediated CRISPR gene editing outcomes at junctions of chromosomal rearrangements are precise and predictable; however, the underlying mechanisms are poorly understood due to lack of suitable assay system and analysis tool. Here we developed a customized computer program to take account of staggered Cas9 cleavage and to rapidly process large volumes of junctional sequencing reads from chromosomal rearrangements, including DNA-fragment inversions, duplications, and deletions. We also established a sensitive assay system usingHPRT1andDCKas reporters for cell growth during DNA-fragment editing by Cas9 with dual sgRNAs and found prominent large resections at junctions of chromosomal rearrangements. In addition, we found that knockdown ofPolQ(encoding Polθ) results in increased large resections but decreased small deletions. We also found that the mechanisms for generating small deletions of 1bp and >1bp during DNA-fragment editing are different with regards to their opposite dependencies on Polθ and Polλ. Specifically, Polθ suppresses 1bp deletions but promotes >1bp deletions, whereas Polλ promotes 1bp deletions but suppresses >1bp deletions. Finally, we found that Polλ is the main DNA polymerase responsible for fill-in of the 5’ overhangs of staggered Cas9 cleavage ends. These findings contribute to our understanding of the molecular mechanisms of CRISPR/Cas9-mediated DNA-fragment editing and have important implications for controllable, precise, and predictable gene editing.
Intracellular replication ofPseudomonas aeruginosain epithelial cells requires suppression of the caspase-4 inflammasome
Authors: Kroken Abby R , Klein Keith A , Mitchell Patrick S , Nieto Vincent , Jedel Eric J , Evans David J , Fleiszig Suzanne M J
Published: February 2023

Pathogenesis ofPseudomonas aeruginosainfections can include bacterial survival inside epithelial cells. Previously, we showed this involves multiple roles played by the type three-secretion system (T3SS), and specifically the effector ExoS. This includes ExoS-dependent inhibition of a lytic host cell response that subsequently enables intracellular replication. Here, we studied the underlying cell death response to intracellularP. aeruginosa, comparing wild-type to T3SS mutants varying in capacity to induce cell death and that localize to different intracellular compartments. Results showed that corneal epithelial cell death induced by intracellularP. aeruginosalacking the T3SS, which remains in vacuoles, correlated with activation of NF-κB as measured by p65 relocalization and TNFα transcription and secretion. Deletion of caspase-4 through CRISPR-Cas9 mutagenesis delayed cell death caused by these intracellular T3SS mutants. Caspase-4 deletion also countered more rapid cell death caused by T3SS effector-null mutants still expressing the TSSS apparatus that traffic to the host cell cytoplasm, and in doing so rescued intracellular replication normally dependent on ExoS. While HeLa cells lacked a lytic death response to T3SS mutants, it was found to be enabled by interferon gamma treatment. Together, these results show that epithelial cells can activate the noncanonical inflammasome pathway to limit proliferation of intracellularP. aeruginosa, not fully dependent on bacterially-driven vacuole escape. Since ExoS inhibits the lytic response, the data implicate targeting of caspase-4, an intracellular pattern recognition receptor, as another contributor to the role of ExoS in the intracellular lifestyle ofP. aeruginosa.

Importance

Pseudomonas aeruginosacan exhibit an intracellular lifestyle within epithelial cells in vivo and in vitro. The type three secretion system (T3SS) effector ExoS contributes via multiple mechanisms, including extending the life of invaded host cells. Here, we aimed to understand the underlying cell death inhibited by ExoS whenP. aeruginosais intracellular. Results showed that intracellularP. aeruginosalacking T3SS effectors could elicit rapid cell lysis via the non-canonical inflammasome pathway. Caspase-4 contributed to cell lysis even when the intracellular bacteria lacked the entire T33S and were consequently unable to escape vacuoles, representing a naturally occurring subpopulation during wildtype infection. Together, the data show the caspase-4 inflammasome as an epithelial cell defense against intracellularP. aeruginosa, and implicate its targeting as another mechanism by which ExoS preserves the host cell replicative niche.
Non-specificity fingerprints for clinical stage antibodies in solution
Authors: Herling Therese W. , Invernizzi Gaetano , Ausserwöger Hannes , Bjelke Jais Rose , Egebjerg Thomas , Lund Søren , Lorenzen Nikolai , Knowles Tuomas P. J.
Published: February 2023

Monoclonal antibodies (mAbs) have successfully been developed for the treatment of a wide range of diseases. The clinical success of mAbs, does not solely rely on optimal potency and safety, but also require good biophysical properties to ensure high developability potential. In particular, non-specific interactions are a key developability measure to monitor during discovery. Despite an increased focus on the detection of non-specific interactions, their physicochemical origins remain poorly understood. Here, we employ solution-based microfluidic technologies to characterise a set of clinical stage mAbs and their interactions with commonly used non-specificity ligands to generate non-specificity fingerprints, providing quantitative data on the underlying physical chemistry. Furthermore, the solution-based analysis enables us to evaluate the contribution of avidity in non-specific binding by mAbs. Based on our findings, we propose a quantitative solution-based non-specificity score, which can be exploited in the development of biological therapeutics and more widely in protein engineering.
simCAS: an embedding-based method for simulating single-cell chromatin accessibility sequencing data
Authors: Li Chen , Chen Xiaoyang , Chen Shengquan , Jiang Rui , Zhang Xuegong
Published: February 2023

Single-cell chromatin accessibility sequencing (scCAS) technology provides an epigenomic perspective to characterize gene regulatory mechanisms at single-cell resolution. With an increasing number of computational methods proposed for analyzing scCAS data, a powerful simulation framework is desirable for evaluation and validation of these methods. However, existing simulators generate synthetic data by sampling reads from real data or mimicking existing cell states, which is inadequate to provide credible ground-truth labels for method evaluation. We present simCAS, an embedding-based simulator, for generating high-fidelity scCAS data from both cell-wise and peak-wise embeddings. We demonstrate simCAS outperforms existing simulators in resembling real data and show that simCAS can generate cells of different states with user-defined cell populations and differentiation trajectories. Additionally, simCAS can simulate data from different batches and encode user-specified interactions of chromatin regions in the synthetic data, which provides ground-truth labels more than cell states. We systematically demonstrate that simCAS facilitates the benchmarking of four core tasks in downstream analysis: cell clustering, trajectory inference, data integration, andcis-regulatory interaction inference. We anticipate simCAS will be a reliable and flexible simulator for evaluating the ongoing computational methods applied on scCAS data.

Availability

simCAS is freely available athttps://github.com/Chen-Li-17/simCAS.
Biphasic responses in cell signalling: A unified approach
Authors: Ramesh Vaidhiswaran , Krishnan J.
Published: February 2023

Biphasic responses are encountered at all levels in biological systems. At the cellular level, biphasic dose-responses are widely encountered in cell signalling and post-translational modification systems and represent safeguards against over-activation or overexpression of species. In this paper we provide a unified theoretical synthesis of biphasic responses in cell signalling systems, by assessing signalling systems ranging from basic biochemical building blocks to canonical network structures to well-characterized exemplars on one hand, and examining different types of doses on the other. By using analytical and computational approaches applied to a range of systems across levels (described by broadly employed models) we reveal (i) design principles enabling the presence of biphasic responses, including in almost all instances, an explicit characterization of the parameter space (ii) structural factors which preclude the possibility of biphasic responses (iii) different combinations of the presence or absence of enzyme-biphasic and substrate-biphasic responses, representing safeguards against overactivation and overexpression respectively (iv) the possibility of broadly robust biphasic responses (v) the complete alteration of signalling behaviour in a network due to biphasic interactions between species (biphasic regulation) (vi) the propensity of different co-existing biphasic responses in the Erk signalling network. These results both individually and in totality have a number of important consequences for systems and synthetic biology.
Conflicts are parametrically encoded: initial evidence for a cognitive space view to reconcile the debate of domain-general and domain-specific cognitive control
Authors: Yang Guochun , Wu Haiyan , Li Qi , Liu Xun , Fu Zhongzheng , Jiang Jiefeng
Published: February 2023

Cognitive control resolves conflicts between task-relevant and -irrelevant information to enable goal-directed behavior. As conflicts can arise from different sources (e.g., sensory input, internal representations), how a limited set of cognitive control processes can effectively address diverse conflicts remains a major challenge. Based on the cognitive space theory, different conflicts can be parameterized and represented as distinct points in a (low-dimensional) cognitive space, which can then be resolved by a limited set of cognitive control processes working along the dimensions. It leads to a hypothesis that conflicts similar in their sources are also represented similarly in the cognitive space. We designed a task with five types of conflicts that could be conceptually parameterized. Both human performance and fMRI activity patterns in the right dorsolateral prefrontal (dlPFC) support that different types of conflicts are organized based on their similarity, thus suggesting cognitive space as a principle for representing conflicts.
Working memory signals in early visual cortex do not depend on visual imagery
Authors: Weber Simon , Christophel Thomas , Görgen Kai , Soch Joram , Haynes John-Dylan
Published: February 2023

It has been suggested that visual images are memorized across brief periods of time by vividly imagining them as if they still were there. In line with this, the contents of both working memory and visual imagery are known to be encoded already in early visual cortex. If these signals in early visual areas were indeed to reflect a combined imagery and memory code, one would predict them to be weaker for individuals with reduced visual imagery vividness. Here, we systematically investigated this question in two groups of participants. Strong and weak imagers were asked to remember images across brief delay periods. We were able to reliably reconstruct the memorized stimuli from early visual cortex during the delay. Importantly, in contrast to the prediction, the quality of reconstruction was equally accurate for both strong and weak imagers. The decodable information also closely reflected behavioral precision in both groups, suggesting it could contribute to behavioral performance, even in the extreme case of completely aphantasic individuals. Our data thus suggest that working memory signals in early visual cortex can be present even in the (near) absence of phenomenal imagery.
Mutation and selection induce correlations between selection coefficients and mutation rates
Authors: Gitschlag Bryan L. , Cano Alejandro V. , Payne Joshua L. , McCandlish David M. , Stoltzfus Arlin
Published: February 2023

The joint distribution of selection coefficients and mutation rates is a key determinant of the genetic architecture of molecular adaptation. Three different distributions are of immediate interest: (1) thenominaldistribution of possible changes, prior to mutation or selection, (2) thede novodistribution of realized mutations, and (3) thefixeddistribution of selectively established mutations. Here, we formally characterize the relationships between these joint distributions under the strong selection, weak mutation (SSWM) regime. Thede novodistribution is enriched relative to the nominal distribution for the highest rate mutations, and the fixed distribution is further enriched for the most highly beneficial mutations. Whereas mutation rates and selection coefficients are often assumed to be uncorrelated, we show that even with no correlation in the nominal distribution, the resultingde novoand fixed distributions can have correlations with any combination of signs. Nonetheless, we suggest that natural systems with a finite number of beneficial mutations will frequently have the kind of nominal distribution that induces negative correlations in the fixed distribution. We apply our mathematical framework, along with population simulations, to explore joint distributions of selection coefficients and mutation rates from deep mutational scanning and cancer informatics. Finally, we consider the evolutionary implications of these joint distributions together with two additional joint distributions relevant to parallelism and the rate of adaptation.
Multi-Omics Data of Perturbation Studies are Determined by Memory Effects from Subculture
Authors: Bortel Patricia , Hagn Gerhard , Skos Lukas , Bileck Andrea , Paulitschke Verena , Paulitschke Philipp , Gleiter Lion , Mohr Thomas , Gerner Christopher , Meier-Menches Samuel M.
Published: February 2023

Mass spectrometry-based omics technologies are increasingly used to map drug effects to biological pathways by identifying significant molecular events. Significance is influenced by the effect size and the variation of each molecular parameter. While the former is largely determined by the biological system, the latter can be tuned by the experimental workflow. Here, we unequivocally show that memory effects originating from subculture of colon carcinoma cells before treating with arsenic trioxide exacerbate the variation of multiple omics levels, including eicosadomics, proteomics and phosphoproteomics, without necessarily impacting on effect size. Real-time monitoring of individual samples enables control over subculture homogeneity and improves the median variation >2-fold across omics levels. This considerably facilitated mode of action deconvolution and resulted in a bilevel perturbation network of 321 causal conjectures. Controlling memory effects from subculture revealed key signaling cascades and transcriptional regulatory events that extend the molecular understanding of arsenic trioxide in solid tumors.
Hemoxygenase-1 as a key mediator of acute radiation pneumonitis revealed in a human lung alveolus-on-a-chip
Authors: Dasgupta Queeny , Jiang Amanda , Hall Sean , Mannix Robert , Wen Amy M. , Ingber Donald E.
Published: February 2023

Exposure to gamma radiation either due to environmental disasters or cancer radiotherapy can result in development of acute radiation syndrome (ARS), characterized by pneumonitis and lung fibrosis. We leveraged a microfluidic organ-on-a-chip lined by human lung alveolar epithelium interfaced with pulmonary endothelium to model acute radiation-induced lung injuryin vitro. Both lung epithelium and endothelium exhibited DNA damage, cellular hypertrophy, upregulation of inflammatory cytokines, and loss of barrier function within 6 h of radiation exposure, although greater damage was observed in the endothelium. Transcriptomic analysis revealed increased expression of the cytoprotective gene, hemoxygenase-1 (HMOX-1) and gene network analysis identified it as a central mediator of radiation-induced injury. Pharmacological stimulation of HMOX-1 activity also significantly reduced acute radiation-induced lung injury, although it enhanced damage at later times. Thus, this human lung chip offers a new platform to study ARS and these results suggest that HMOX-1 may be mechanistically involved in this injury response.
Fixation Before Dissociation Using a Deep Eutectic Solvent PreservesIn VivoStates and Phospho-Signaling in Single-Cell Sequencing
Authors: Fortmann Seth D. , Frey Blake F. , Hanumanthu Vidya Sagar , Liu Shanrun , Goldsborough Andrew , Kilchrist Kameron V. , Ferrell P. Brent , Weaver Casey T. , Grant Maria B. , Welner Robert S.
Published: February 2023

Single-cell RNA-sequencing (scRNA-seq) presents an opportunity to deconstruct cellular networks but is limited by the loss of biological information, includingin vivocellular states and phospho-signaling. Herein, we present fixation before dissociation using a deep eutectic solvent (DES), which preserves multiple domains ofin vivobiological data, including morphology, RNA, proteins, and post-translational modifications. In scRNA-seq of viable versus DES bone marrow, dissociation induced global stress responses, immune and stromal cell activation, and loss of highly sensitive cell populations, which were prevented with DES. Further, we introduce a validated and flexible method for performing intracellular CITE-seq in DES-fixed cells. Leveraging this approach during Th17 T cell stimulation allowed the simultaneous quantification of transcriptomes and four phosphorylated proteins, leading to the identification of a hyperactivated state in p-ERK/p-FOS double positive cells, which we experimentally validated. We anticipate that DES-based fixatives will allow the accurate reconstruction ofin vivocellular networks and uncover cooperativity amongst intracellular pathways.
Viral attachment blocking chimera composed of DNA origami and nanobody inhibits Pseudorabies Virus infectionin vitro
Authors: Pradhan Swechchha , Swanson Carter , Leff Chloe , Tengganu Isadonna , Bergeman Melissa H. , Hogue Ian B. , Hariadi Rizal F.
Published: February 2023

Antivirals are indispensable tools that can be targeted at viral domains directly or indirectly at cellular domains to obstruct viral infections and reduce pathogenicity. Despite their transformative use in healthcare, antivirals have been clinically approved to treat only 10 of the more than 200 known pathogenic human viruses. Additionally, many virus functions are intimately coupled with host cellular processes, which present challenges in antiviral development due to the limited number of clear targets per virus, necessitating an extensive insight into these molecular processes. Compounding this challenge, many viral pathogens have evolved to evade effective antivirals. We hypothesize that a Viral Attachment Blocking Chimera (VirABloC) composed of a viral binder and a bulky scaffold that sterically blocks interactions between a viral particle and a host cell may be suitable for the development of antivirals agnostic to the extravirion epitope that is being bound. We test this hypothesis by modifying a nanobody that specifically recognizes a non-essential epitope presented on the extra virion surface of Pseudorabies virus strain 486 with a 3-dimensional wireframe DNA origami structure ∼100 nm in diameter. The nanobody switches from having no inhibitory properties (tested up to 50 µM) to 4.2 ± 0.9 nM IC50when conjugated with the DNA origami scaffold. Mechanistic studies support that inhibition is mediated by the non-covalent attachment of the DNA origami scaffold to the virus particle, which obstructs the attachment of the viruses onto host cells. These results support the potential of VirABloC as a generalizable approach to developing antivirals.
Carbonylbis{6,6′-[(3,3′-di-tert-butyl-5,5′-dimethoxy-1,1′-biphenyl-2,2′-diyl)bis(oxy)]bis(dibenzo[d,f][1,3,2]-dioxaphosphepine)}hydridorhodium(I) toluene-d
8 2.25-solvate
Authors: Leidecker Benedict N. , Spannenberg Anke , Franke Robert , Börner Armin , Kubis Christoph
Published: February 2023

The crystal-structure determination of the title compound, [RhH(C46H44O8P2)2(CO)]·2.25C7D8, is reported. The bisphosphite ligand, C46H44O8P2, is well known as Biphephos. One specific characteristic of this hydrido rhodium(I) monocarbonyl complex is that one bisphosphite ligand is coordinated in the expected bidentate mode and the other is coordinated in a monodentate mode. Thus, one phosphite moiety remains non-coordinating. All three coordinating phosphorus atoms occupy the equatorial positions in the trigonal–bipyramidal environment around the rhodium atom. The crystals of the hydrido rhodium(I) monocarbonyl complex contains deuterated solvent molecules (toluene-d
8). Most of them are included in the model, but the contributions of about 0.84 toluene per unit cell were removed from the diffraction data, using the SQUEEZE procedure in PLATON [Spek (2015). Acta Cryst. C71, 9–18].
Diisopropyl 2-[(4-nitrobenzoyl)amino]propanedioate
Authors: Deleon Cristi P. , Ramirez Anthony D. , Gonzalez Diana , Ghosh Arghya , Kürti László , Yousufuddin Muhammed
Published: February 2023

The title compound, C16H20N2O7, crystallizes in the space group C2 with two molecules in the asymmetric unit. The crystal packing shows O...π interactions between the two molecules.
Would consumers help achieve sustainable development in the Qinghai–Tibet Plateau with a forage–livestock balance certification label?
Authors: Zhang Yan , Jin Shaosheng , Lin Wen
Published: February 2023

Purpose

The contradiction and conflict between grassland conservation and economic development are prominent in the Qinghai–Tibet Plateau (QTP) with its fragile environment and ecosystem. How to promote sustainable grazing in the plateau without hurting the economic welfare of local residents is a key challenge facing the Chinese government. This study explores the potential of market-based grassland conservation policies by evaluating consumer preferences and valuations for forage–livestock balance certification labeled yak products.

Design/methodology/approach

This study adopts a choice experiment with four attributes of yak meat, including forage–livestock balance certification, feeding type, age at slaughter and price. A sample size of 2,999 respondents from Beijing, Shanghai, Wuhan, Guangzhou and Chengdu was collected by a professional online survey company.

Findings

The result reveals that urban Chinese consumers are willing to pay highest price premiums for forage–livestock balance certified yak meat, followed by grass-fed claim labeled meat. Consumers on average place negative valuations for grain-fed claims, meat from yak slaughtered above 2 and 4 years old. Heterogeneous analysis indicates that individuals who are female, younger, married, and better educated, and with above median income, Tibet travel or yak consumption experience, are more receptive to the forage–livestock balance certification.

Originality/value

It is the first study to explore demand-driven mechanisms for grassland conservation by focusing on consumer valuation for the forage–livestock balance certification.
Agility and digitalization: why strategic agility is a success factor for mastering digitalization – evidence from Industry 4.0 implementations across a supply chain
Authors: Pfaff Yuko Melanie
Published: February 2023

Purpose

This paper addresses the emergence of strategic agility as adaptive capability to face the need to adapt to a constantly changing environment. Special emphasis is paid to governance mechanisms as a microfoundation of dynamic capabilities, investigating the dynamics and outcome in regards to the digitalization of supply chains and its socio-economic relations of its members.

Design/methodology/approach

A multiple-case study method is applied to explain the impact of a digitalization initiative in the form of an I4.0 implementation in a supply chain context. Building on qualitative in-depth interviews of experts in managerial positions, 16 cases from the manufacturing industry involving an I4.0 implementation across the supply chain were analyzed. Based on a conceptual design science approach, the CIMO logic (context, intervention, mechanisms and outcome) framework is used to investigate the interplay between agility as a dynamic capability and governance mechanisms.

Findings

The studied cases demonstrate an intensification of synergistic combinations of inter-firm resources to manage digitalization across the supply chain (SC). With the implementation of I4.0, competitive advantage along the SC takes higher priority over the competitive advantage in the individual or dyadic perspective. Strategic agility as a dynamic capability to cope with and adapt to the changing environment is hereby crucial emphasizing relational SC governance (SCG) as essential as a microfoundation to adjust the structure and management of SCs. Relationships, which allow competitive advantage as a SC balance out traditional power mechanisms within the SC hierarchy. Trust, collaboration and flexibility, aligned with common incentives in generating competitive advantages enable the SCs to mitigate uncertainty and risk while preventing opportunistic behavior.

Practical implications

The study offers SCM managers in-depth insights into strategic agility and how to address the recent challenge of digitalization successfully. Identifying crucial dynamics within SCG mechanisms based on first-hand use cases, practical success factors for implementing I4.0 to optimize effectiveness and efficiency can be derived how to structure and manage future SCs.

Originality/value

This paper contributes to the first insights examining the implications of digitalization and the role of strategic agility as a capability to adapt. Investigating the microfoundation of governance within this capability, this research provides insights on the socio-economic level, while discussing specific mechanisms how relationships of SCs evolve proposing relevant insights for future research.
Distance is no longer a barrier to healthcare services: current state and future trends of telehealth research
Authors: Sahoo Saumyaranjan , Sahoo Junali , Kumar Satish , Lim Weng Marc , Ameen Nisreen
Published: February 2023

Purpose

Taking a business lens of telehealth, this article aims to review and provide a state-of-the-art overview of telehealth research.

Design/methodology/approach

This research conducts a systematic literature review using the scientific procedures and rationales for systematic literature reviews (SPAR-4-SLR) protocol and a collection of bibliometric analytical techniques (i.e. performance analysis, keyword co-occurrence, keyword clustering and content analysis).

Findings

Using performance analysis, this article unpacks the publication trend and the top contributing journals, authors, institutions and regions of telehealth research. Using keyword co-occurrence and keyword clustering, this article reveals 10 major themes underpinning the intellectual structure of telehealth research: design and development of personal health record systems, health information technology (HIT) for public health management, perceived service quality among mobile health (m-health) users, paradoxes of virtual care versus in-person visits, Internet of things (IoT) in healthcare, guidelines for e-health practices and services, telemonitoring of life-threatening diseases, change management strategy for telehealth adoption, knowledge management of innovations in telehealth and technology management of telemedicine services. The article proposes directions for future research that can enrich our understanding of telehealth services.

Originality/value

This article offers a seminal state-of-the-art overview of the performance and intellectual structure of telehealth research from a business perspective.
Impact of customer-centric approach and customer dissatisfying cost on supply chain profit under price competition
Authors: Jena Sarat Kumar
Published: February 2023

Purpose

The purpose of this study is to provide a unique competitive advantage to businesses in providing a wide range of products to prospective customers. To the best of the author’s knowledge, there is no study to discuss the impact of customer-centric retailing on total supply chain profit under price competition between organized and unorganized retailers.

Design/methodology/approach

This paper considers a supply chain comprising of organized and unorganized retailers and a single manufacturer. This paper proposes three mathematical models considering a customer-centric approach in a competitive environment. Stackelberg game is used to examine how members of the chain interact, and Nash equilibrium was used to find optimal strategies for players under different customer-centric approaches.

Findings

The results show that the total supply chain profit is higher when both organized and unorganized retailers use a customer-centric approach independently instead of collaborating process. The result, in addition, establishes that when the dissatisfying cost exceeds a certain threshold (1.5), the total profit is higher for the organized customer-centric effort model compared to the other two models.

Originality/value

The main contribution of the study is to examine the effect of customer-centric retailing, considering dissatisfying costs on supply chains profit and individual decision-making under price competition between organized retailers and unorganized retailers. The authors developed different mathematical models in the different customer-centric approach.