bluuebunny/crossref_metadata_2025 huggingface dataset:
Nanomechanical and microrheological properties of bladder cancer cells at cellular and spheroid levels
Authors: Gnanachandran Kajangi , Kedracka-Krok Sylwia , Pabijan Joanna , Lekka Malgorzata
Published: March 2022

Cancer progression is associated with changes in cell mechanical and rheological properties that could be probed by atomic force microscopy (AFM). In this study, we applied AFM to measure elastic (by compressing the cells) and viscoelastic (by applying shear stress) properties of bladder cancers in relation to their culture morphology (in single cells, cell monolayers, and spheroids). Three different cell lines, HCV29 (non-malignant cell cancer of ureter), HT1376 (grade III bladder carcinoma), T24 (grade IV transitional cell carcinoma), were investigated. Nanoindentation measurements only differentiate between non-malignant and cancer cells, but it is difficult to distinguish between specific bladder cancers. By applying microrheological measurements, we confirm that non-malignant cells are more rigid than cancer cells but more importantly, it was possible to differentiate between two cancerous cell lines, regardless of the culture conditions. As each of them is characterized by a distinct actin filament network inside the cell, we showed that actin filaments are a key element in defining the rheological properties of spheroids originating from cells having thick actin bundles. Our results showed that HCV29 cells are more rigid than the studied cancer cells, indicating that normal cells are resistant to compressive and shear forces. Therefore, we conclude that cell mechanical and rheological properties may serve as a biophysical marker to distinguish normal and cancer cells of different malignancies.
Pinning transition in biofilm structure driven by active layer dynamics
Authors: Young Ellen , Melaugh Gavin , Allen Rosalind J
Published: March 2022

Surface-attached communities of microbes, known as biofilms, are diverse in their morphologies. Characterising distinct types of biofilm spatial structure, and understanding how they emerge, can shed light on the fundamental biological and biophysical mechanisms involved, and can improve our understanding of evolution in biofilms.
Here, we perform long-time individual-based simulations of growing biofilms. We observe distinct types of biofilm spatial structure depending on the parameters, and we classify these into three `phases' according to the behaviour of the active layer of growing cells at the biofilm interface. In the unpinned phase, the biofilm is smooth and the active layer is unbroken with no gaps. In the transiently pinned phase, short-lived gaps in the active layer arise, which can cause local parts of the biofilm interface to pin, or become stationary relative to the moving front. In the pinned phase these `pinning sites' persist, leading to fingering of the biofilm interface.
We show that pinning arises due to the dynamical behaviour of active layer gaps, and observe that the relative magnitudes of the active layer thickness and the active layer fluctuations are important in this process. We demonstrate a direct connection between biofilm pinning and interface roughness, and we show that the pinning phase transition is well described by a control parameter that combines the average and standard deviation of the active layer thickness. Taken together, our work suggests a role for active layer dynamics in controlling pinning of the biofilm interface and hence biofilm morphology.
Brain iron and mental health symptoms in youth with and without prenatal alcohol exposure
Authors: Nakhid Daphne , McMorris Carly A. , Sun Hongfu , Gibbard William B. , Tortorelli Christina , Lebel Catherine
Published: March 2022

Prenatal alcohol exposure (PAE) negatively affects brain development and increases the risk of poor mental health. We investigated if brain susceptibility, measuring iron, or volume were associated with internalizing or externalizing symptoms in youth with and without PAE. T1-weighted and quantitative susceptibility mapping (QSM) MRI scans were collected for 19 PAE and 40 unexposed participants aged 7.5-15 years. Magnetic susceptibility and volume of basal ganglia and limbic structures were extracted using FreeSurfer. Internalizing and externalizing problems were assessed using the Behavioural Assessment System for Children (BASC-2-PRS). Susceptibility in the nucleus accumbens was negatively associated with internalizing problems, while amygdala susceptibility was positively associated with internalizing problems across groups. In the PAE group, thalamus susceptibility was negatively associated with internalizing problems, and putamen susceptibility was positively associated with externalizing problems. Brain volume was not related to internalizing or externalizing symptoms. These findings highlight that brain iron is related to internalizing and externalizing symptoms differently in some brain regions for youth with and without PAE. Atypical iron levels (high or low) may indicate mental health problems across individuals, and iron in the thalamus and putamen may be particularly important for behaviour in individuals with PAE.
Application of Digital Twin and Heuristic Computer Reasoning to Workflow Management: Gastroenterology Outpatient Centers Study
Authors: Garbey Marc , Joerger Guillaume , Furr Shannon
Published: March 2022

The workflow in a large medical procedural suite is characterized by high variability of input and suboptimum throughput. Today, Electronic Health Record systems do not address the problem of workflow efficiency: there is still high frustration from medical staff who lack real-time awareness and need to act in response of events based on their personal experiences rather than anticipating. In a medical procedural suite, there are many nonlinear coupling mechanisms between individual tasks that could wrong and therefore is difficult for any individual to control the workflow in real-time or optimize it in the long run. We propose a system approach by creating a digital twin of the procedural suite that assimilates Electronic Health Record data and supports the process of making rational, data-driven, decisions to optimize the workflow on a continuous basis. In this paper, we focus on long term improvements of gastroenterology outpatient centers as a prototype example and use six months of data acquisition in two different clinical sites to validate the artificial intelligence algorithms.
Seasonality of Common Human Coronaviruses in the United States, 2014-2021
Authors: Shah Melisa M. , Winn Amber , Dahl Rebecca M. , Kniss Krista L. , Silk Benjamin J. , Killerby Marie E.
Published: March 2022

The four common human coronaviruses (HCoVs), including two alpha (HCoV-NL63 and HCoV-229E) and two beta (HCoV-HKU1 and HCoV-OC43) types, generally cause mild, upper respiratory illness. HCoVs are known to have seasonal patterns and variation in predominant types each year, but defined measures of seasonality are needed. We defined seasonality of HCoVs during July 2014 to November 2021 in the United States using a retrospective method applied to National Respiratory and Enteric Virus Surveillance System (NREVSS) data. In the six HCoV seasons prior to 2020-2021, onsets ranged from October to November, peaks from January to February, and offsets from April to June; most (>93%) HCoV detections occurred within the defined seasonal onsets and offsets. The 2020-2021 HCoV season onset was delayed by 11 weeks compared to prior seasons, likely due to COVID-19 mitigation efforts. Better defining HCoV seasonality can inform clinical preparedness and the expected patterns of emerging HCoVs.

Article Summary Line

The typical common HCoV season in the United States starts between October and November, peaks towards the end of January, and ends between April and June, but the 2020-2021 season was markedly delayed compared to prior seasons.
Identification of deleterious neutrophil states and altered granulopoiesis in sepsis
Authors: Kwok Andrew J. , Allcock Alice , Ferreira Ricardo C. , Smee Madeleine , Cano-Gamez Eddie , Burnham Katie L. , Zurke Yasemin-Xiomara ,   Oxford acute medicine/ED research, McKechnie Stuart , Monaco Claudia , Udalova Irina , Hinds Charles J. , Davenport Emma E. , Todd John A. , Knight Julian C.
Published: March 2022

Sepsis is a condition of high mortality arising from dysregulation of the host immune response. Gene expression studies have identified multiple immune endotypes but gaps remain in our understanding of the underlying biology and heterogeneity. We used single-cell multi-omics to profile 272,993 cells across 48 whole blood samples from 26 sepsis patients (9 with paired convalescent samples), 6 healthy controls and 7 post-surgery patients. We identified immature neutrophil populations specific to sepsis and demonstrated the immunosuppressive nature of sepsis neutrophils in vitro. An IL1R2+ neutrophil state was expanded in a transcriptomic sepsis endotype associated with increased early mortality (sepsis response signature 1, SRS1), together with enrichment of the response to IL-1 pathway in mature neutrophils, marking IL-1 out as a potential target for immunotherapy in SRS1 sepsis patients. We confirmed the expansion of immature neutrophils, specifically IL1R2+ neutrophils, in SRS1 in additional cohorts of patients (n = 906 RNA-sequencing samples, n = 41 CyTOF samples). Neutrophil changes persisted in convalescence, implicating disrupted granulopoiesis. Our findings establish a cellular immunological basis for transcriptomically defined sepsis endotypes and emphasise the relevance of granulopoietic dysfunction in sepsis, identifying opportunities for precision medicine approaches to the condition.
Mathematical modelling of COVID-19 transmission dynamics with vaccination: A case study in Ethiopia
Authors: Sharbayta Sileshi Sintayehu , Desta Henok Desalegn , Abdi Tadesse
Published: March 2022

Mathematical modelling is important for better understanding of disease dynamics and developing strategies to manage rapidly spreading infectious diseases. In this work, we consider a mathematical model of COVID-19 transmission with double-dose vaccination strategy to control the disease. For the analytical analysis purpose we divided the model into two, model with vaccination and without vaccination. Analytical and numerical approach is employed to investigate the results. In the analytical study of the model we have shown the local and global stability of disease-free equilibrium, existence of the endemic equilibrium and its local stability, positivity of the solution, invariant region of the solution, transcritical bifurcation of equilibrium and sensitivity analysis of the model is conducted. From these analyses, for the full model (model with vaccination) we found that the disease-free equilibrium is globally asymptotically stable forRv< 1 and is unstable forRv> 1. A locally stable endemic equilibrium exists forRv> 1, which shows the persistence of the disease if the reproduction parameter is greater than unity. The model is fitted to cumulative daily infected cases and vaccinated individuals data of Ethiopia from May 01, 2021 to January 31, 2022. The unknown parameters are estimated using the least square method with the MATLAB built-in function ‘lsqcurvefit’. The basic reproduction number,R0and controlled reproduction numberRvare calculated to beR0= 1.17 andRv= 1.15 respectively. Finally, we performed different simulations using MATLAB. From the simulation results, we found that it is important to reduce the transmission rate, infectivity factor of asymptomatic cases and, increase the vaccination coverage and quarantine rate to control the disease transmission.
Hypoxic conditions promote a proliferative, poorly differentiated, and pro-secretory phenotype in COPD lung tissue progenitor cells in vitro
Authors: Dale Tina P. , Santer Michael D. , Haris Mohammed , Zuo Wei , Forsyth Nicholas R.
Published: March 2022

Chronic obstructive pulmonary disease patients experience variable symptoms dependent on the presence of an emphysematous versus a chronic bronchitis phenotype. Both presentations can be associated with lung tissue and systemic hypoxia, at its most severe leading to Cor pulmonale. Despite this, minimal attention has been given to the effects of hypoxia at the cellular disease level.

We isolated and cultured progenitor cells from the distal lung tissue of a 64 year-old, male, emphysematous donor in ambient (21%) and hypoxic (2%) oxygen conditions. Proliferative capacity was determined on collagen coated culture plastic and growth-inactivated 3T3-J2 co-cultures. Epithelial (E-cadherin and pan-cytokeratin) and progenitor (TP63, cytokeratin 5) marker expression were examined. Expanded cells were differentiated at air-liquid interface and ciliated, mucous producing, and club cell populations identified.

Isolated cells were positive for the epithelial, pan-cytokeratin and E-cadherin, and progenitor, TP63 and cytokeratin 5, cell markers at isolation and again at passage 5. Passage 5 expanded cells in hypoxia had increased the proportion of TP63 expressing cells by 10% from 51.6 ± 1.2% to 62.6 ± 2.3% (p ≤ 0.01). Proliferative capacity was greater in 3T3J2 co-cultured cells overall and in 2% oxygen this supported the emergence of a proliferation unrestricted population with a limited differentiation capacity. Cells expanded on collagen I in either oxygen underwent differentiation having been expanded with the production of ciliated cells positive for βIV tubulin, and mucin 5ac, mucin 5b and CC10 positive secretory cells. Epithelial barrier formation was reduced significantly (p ≤ 0.0001) in hypoxia-expanded cells compared to normoxia. qRT-PCR showed higher expression of mucins in 2% expanded cells, significantly so withMUC5B(P ≤ 0.05) although mucin protein secretion was greater in 21% expanded cells.

Concomitantly these results demonstrate that hypoxia promotes a proliferative phenotype while reducing the overall differentiation capacity of the cells. Further, the retained differentiation potential becomes skewed to a more secretory phenotype demonstrating that hypoxia may be contributing to disease symptom and severity in COPD patients.
The NLRP1 and CARD8 inflammasomes detect reductive stress
Authors: Wang Qinghui , Hsiao Jeffrey , Yardeny Noah , Huang Hsin-Che , O'Mara Claire M. , Orth-He Elizabeth L. , Ball Daniel P. , Bachovchin Daniel A.
Published: March 2022

The danger signals that activate the NLRP1 and CARD8 inflammasomes have not been fully established. We recently discovered that cytosolic peptide accumulation activates these inflammasomes. In addition, we found that the oxidized form of TRX1 binds to and represses NLRP1, suggesting that NLRP1 also detects a lack of reactive oxygen species, or reductive stress. However, no agents that induce reductive stress were known to test this premise. Here, we identify and characterize several radical-trapping antioxidants, including JSH-23, that induce reductive stress. We show that these compounds accelerate the proteasome-mediated degradation of the repressive N-terminal fragments of NLRP1 and CARD8, releasing the inflammasome-forming C-terminal fragments from autoinhibition. Moreover, we found that reductive stress and peptide accumulation together trigger much more intense inflammasome activation than either signal alone. Overall, this work validates chemical probes that induce reductive stress, and establishes reductive stress alongside peptide accumulation as the key inflammasome-activating danger signals.
Distinct gene programs underpinning 'disease tolerance' and 'resistance' in influenza virus infection
Authors: Cohn Ofir , Yankovitz Gal , Peshes-Yaloz Naama , Steuerman Yael , Frishberg Amit , Brandes Rachel , Mandelboim Michal , R. Hamilton Jennifer , Hagai Tzachi , Amit Ido , G. Netea Mihai , Hacohen Nir , A. Iraqi Fuad , Bacharach Eran , Gat-Viks Irit
Published: March 2022

When challenged with an invading pathogen, the host defense response is engaged to eliminate the pathogen (resistance) and to maintain health in the presence of the pathogen (disease tolerance). However, the identification of distinct molecular programs underpinning disease tolerance and resistance remained obscure. We exploited transcriptional and physiological monitoring across 33 mouse strains, during in vivo influenza virus infection, to identify two host-defense gene programs - one is associated with hallmarks of disease tolerance and the other with hallmarks of resistance. Both programs constitute generic responses in multiple mouse and human cell types. Our study describes the organizational principles of these programs and validates Arhgdia as a regulator of disease-tolerance states in epithelial cells. We further reveal that the baseline disease-tolerance state in macrophages is associated with the pathophysiological response to injury and infection. Our framework provides a paradigm for the understanding of disease tolerance and resistance at the molecular level.
Comparison of microbial communities from diverse biological matrices using mock community as an in situ positive control
Authors: Galla Giulio , Praeg Nadine , Colla Filippo , Rzehak Theresa , Illmer Paul , Seeber Julia , Hauffe Heidi Christine
Published: March 2022

Metataxonomy has become the standard for characterizing the diversity and composition of microbial communities associated with multicellular organisms and their environment. Understanding the interactions between the microbiotas within the same ecosystem is essential for fully understanding the role of microorganisms in evolutionary and ecological processes; however, such comparative studies across diverse biological samples are rare. In particular, currently available protocols assume a uniform DNA extraction, amplification and sequencing efficiency for all sample types and taxa. The addition of a mock community (MC) to biological samples before the DNA extraction step could aid identification of technical biases, but the impact of MC on diversity estimates is unknown. Here, standardized aliquots of bovine faecal samples with high or low biomass were extracted with high or low doses of MC, characterized using standard Illumina technology for metataxonomics, and analysed with custom bioinformatic pipelines. We showed that a MC was an informative in situ positive control provided an estimate of 16S rRNA sample gene copies (which allowed a more direct measure of community size), and detected sample outliers. However, we also demonstrated that if the recommended dose of MC is added to a sample with low biomass, diversity estimates were distorted. Using our results, we recommend MC doses for a range of sample types, including rhizosphere soil, whole invertebrates, and vertebrate faecal samples.
Systematic analysis of cilia characteristics and Hedgehog signaling in five immortal cell lines
Authors: Gómez Arianna , Van De Weghe Julie Craft , Finn Malaney , Doherty Dan
Published: March 2022

Dysfunction of the primary cilium, a microtubule-based signaling organelle, leads to genetic conditions called ciliopathies. Hedgehog (Hh) signaling is mediated by the primary cilium in vertebrates and is therefore implicated in ciliopathies; however, it is not clear which immortal cell lines are the most appropriate for modeling pathway response in human disease; therefore we systematically evaluated Hh in five commercially available, immortal mammalian cell lines: ARPE-19, HEK293T, hTERT RPE-1, NIH/3T3, and SH-SY5Y. All of the cell lines ciliated adequately for our subsequent experiments, except for SH-SY5Y which were excluded from further analysis. hTERT RPE-1 and NIH/3T3 cells relocalized Hh pathway components Smoothened (SMO) and GPR161 and upregulated Hh target genes in response to pathway stimulation. In contrast, pathway stimulation did not induce target gene expression in ARPE-19 and HEK293T cells, despite SMO and GPR161 relocalization. These data indicate that human hTERT RPE-1 cells and murine NIH/3T3 cells, but not ARPE-19 and HEK293T cells, are suitable for modeling the role of Hh signaling in ciliopathies.
The effect of migration and variation on populations of Escherichia coli adapting to complex fluctuating environments
Authors: Selveshwari S , Khaire Kaustubh Chandrakant , Kadam Aditee , Dey Sutirth
Published: March 2022

Migration, a critical evolutionary force, can have contrasting effects on adaptation. It can aid as well as impede adaptation. The effects of migration on microbial adaptation have been studied primarily in simple constant environments. Very little is known about the effects of migration on adaptation to complex, fluctuating environments. In our study, we subjected replicate populations of Escherichia coli, adapting to complex and unpredictably fluctuating environments to different proportions of clonal ancestral immigrants. Contrary to the results from simple/constant environments, the presence of clonal immigrants reduced all measured proxies of fitness. However, migration from a source population with a greater variance in fitness resulted in no change in fitness w.r.t the no-migration control, except at the highest level of migration. Thus, the presence of variation in the immigrants could counter the adverse effects of migration in complex and unpredictably fluctuating environments. Our study demonstrates that the effects of migration are strongly dependent on the nature of the destination environment and the genetic makeup of immigrants. These results enhance our understanding of the influences of migrating populations, which could help better predict the consequences of migration.
Cytosolic peptide accumulation activates the NLRP1 and CARD8 inflammasomes
Authors: Orth-He Elizabeth L. , Huang Hsin-Che , Rao Sahana D. , Wang Qinghui , Chen Qifeng , O'Mara Claire M. , Chui Ashley J. , Saoi Michelle , Griswold Andrew R. , Bhattacharjee Abir , Ball Daniel P. , Cross Justin R. , Bachovchin Daniel A.
Published: March 2022

NLRP1 and CARD8 are related sensors that form inflammasomes, but the danger signals that they detect are not fully established. These proteins undergo autoproteolysis, generating repressive N-terminal (NT) and inflammatory C-terminal (CT) fragments. The proteasome-mediated degradation of the NT releases the CT from autoinhibition, but the CT is then sequestered in a complex with the full-length sensor and DPP9. Here, we show that cytosolic peptide accumulation activates these inflammasomes. We found that a diverse array of peptides accelerates NT degradation, and those with N-terminal XP sequences also destabilize the ternary complexes. Peptides interfere with many biological processes, including protein folding. We show that unrelated agents that disrupt protein folding also induce NT degradation, but do not cause inflammasome activation because DPP9 sequesters the CT fragments in the absence of XP peptides. Overall, these results indicate that NLRP1 and CARD8 detect protein misfolding that is associated with peptide accumulation.
Maximum likelihood pandemic-scale phylogenetics
Authors: De Maio Nicola , Kalaghatgi Prabhav , Turakhia Yatish , Corbett-Detig Russell , Minh Bui Quang , Goldman Nick
Published: March 2022

Phylogenetics plays a crucial role in the interpretation of genomic data1. Phylogenetic analyses of SARS-CoV-2 genomes have allowed the detailed study of the virus’s origins2, of its international3,4and local4–9spread, and of the emergence10and reproductive success11of new variants, among many applications. These analyses have been enabled by the unparalleled volumes of genome sequence data generated and employed to study and help contain the pandemic12. However, preferred model-based phylogenetic approaches including maximum likelihood and Bayesian methods, mostly based on Felsenstein’s ‘pruning’ algorithm13,14, cannot scale to the size of the datasets from the current pandemic4,15, hampering our understanding of the virus’s evolution and transmission16. We present new approaches, based on reworking Felsenstein’s algorithm, for likelihood-based phylogenetic analysis of epidemiological genomic datasets at unprecedented scales. We exploit near-certainty regarding ancestral genomes, and the similarities between closely related and densely sampled genomes, to greatly reduce computational demands for memory and time. Combined with new methods for searching amongst candidate evolutionary trees, this results in our MAPLE (‘MAximum Parsimonious Likelihood Estimation’) software giving better results than popular approaches such as FastTree 217, IQ-TREE 218, RAxML-NG19and UShER15. Our approach therefore allows complex and accurate proba-bilistic phylogenetic analyses of millions of microbial genomes, extending the reach of genomic epidemiology. Future epidemiological datasets are likely to be even larger than those currently associated with COVID-19, and other disciplines such as metagenomics and biodiversity science are also generating huge numbers of genome sequences20–22. Our methods will permit continued use of preferred likelihood-based phylogenetic analyses.
Introgression between highly divergent sea squirt genomes: an adaptive breakthrough?
Authors: Fraïsse Christelle , Le Moan Alan , Roux Camille , Dubois Guillaume , Daguin-Thiébaut Claire , Gagnaire Pierre-Alexandre , Viard Frédérique , Bierne Nicolas
Published: March 2022

Abstract

Human-mediated introductions are reshuffling species distribution on a global scale. Consequently, an increasing number of allopatric taxa are now brought into contact, promoting introgressive hybridization between incompletely isolated species and new adaptive gene transfer. The broadcast spawning marine species,Ciona robusta, has been recently introduced in the native range of its sister taxa,Ciona intestinalis, in the English Channel and North-East Atlantic. These sea squirts are highly divergent, yet hybridization has been reported by crossing experiments and genetic studies in the wild. Here, we examined the consequences of secondary contact betweenC. intestinalisandC. robustain the English Channel. We produced genomes phased by transmission to infer the history of divergence and gene flow, and analyzed introgressed genomic tracts. Demographic inference revealed a history of secondary contact with a low overall rate of introgression. Introgressed tracts were short, segregating at low frequency, and scattered throughout the genome, suggesting traces of past contacts during the last 30 ky. However, we also uncovered a hotspot of introgression on chromosome 5, characterized by several hundred kb-longC. robustahaplotypes segregating inC. intestinalis, that introgressed during contemporary times the last 75 years. Although locally more frequent than the baseline level of introgression,C. robustaalleles are not fixed, even in the core region of the introgression hotspot. Still, linkage-disequilibrium patterns and haplotype-based tests suggest this genomic region is under recent positive selection. We further detected in the hotspot an over-representation of candidate SNPs lying on a cytochrome P450 gene with a high copy number of tandem repeats in the introgressed alleles. Cytochromes P450 are a superfamily of enzymes involved in detoxifying exogenous compounds, constituting a promising avenue for functional studies. These findings support that introgression of an adaptive allele is possible between very divergent genomes and that anthropogenic hybridization can provide the raw material for adaptation of native lineages in the Anthropocene.
Validation of Reference Genes for RT-qPCR Relative Expression Analysis in Pre-Adult Stages ofTaenia solium
Authors: Castaneda-Carpio David , Maravi Jose , Gutierrez-Loli Renzo , Villar Valeria , Blume La Torre Juan , Del Aguila Segundo W. , Guerra-Giraldez Cristina
Published: March 2022

The larvae-to-adult development of the zoonotic parasitic tapewormTaenia soliuminvolves significant but often clinically overlooked events crucial in cestode biology. The early-adult stages can be studied in vitro, providing a valuable model to examine scolex evagination, strobilation, and worm development. Without a stage-specific transcriptome, postgenomic data exploration followed by single-gene relative expression analysis using RT-qPCR (reverse transcription-quantitative PCR) are effective strategies to study gene regulation during parasite development. However, achieving accurate comparisons with this approach requires the validation of an endogenous reference gene (RG).

To address this, we analyzed the expression stability of 17 candidate reference genes (RGs), representing various biological processes, in the context of the in vitro-induced early adult stages ofT. soliumlarvae (cysts). RT-qPCR of the candidate RGs was performed on different stages, defined by distinct morphology in culture, and gene expression stability was comprehensively analyzed using the RefFinder tool. Genespgk1, bact1, mapk3, tbp, rpl13, andcox1were ranked as the most stable and were used to normalize the expression ofh2bandwnt11a, which are involved in proliferation and strobilation processes in parasitic tapeworms. This study represents the first attempt to identify reliable normalization standards for transcript analysis in the genusTaenia.
Analysis of calcium dynamics for dim-light responses in rod and cone photoreceptors
Authors: Abtout Annia , Reingruber Jürgen
Published: March 2022

Rod and cone photoreceptors in the retina of vertebrate eyes are fundamental sensory neurons underlying vision. They use a sophisticated signal transduction pathway consisting of a series of biochemical processes to convert the absorption of light into an electrical current response. Several of these processes are modulated by feedback that depends on the intracellular Ca2+ concentration. In this work we use a representative phototransduction model to study how changing the Ca2+ kinetics by fast buffering affects sensitivity and dynamics of the light response in mouse rod and cone photoreceptors. We derive analytic results for dim-light stimulations that provide quantitative and conceptual insight. We show that flash responses are monophasic with low buffering, and the change in the Ca2+ concentration occurs in proportion to the current. If the amount of fast buffering is increased, the Ca2+ kinetics becomes slowed down and delayed with respect to the current, and biphasic responses emerge (damped oscillations). This shows that a biphasic response is not necessarily a manifestation of slow buffering reactions. A phase space analysis shows that the emergence of biphasic responses depends on the ratio between the effective rate μca that controls the Ca2+ kinetics, and the dark turnover rate of cyclic GMP βd. We further investigate how the light response is altered by modifying the extracellular Ca2+ concentration. In summary, we provide a comprehensive quantitative analysis that precisely links the dynamics of Ca2+ concentration to the observed current response.
Bending stiffness of Candida albicans hyphae reflects adaptive behavior of the fungal cell wall
Authors: Couttenier Elodie , Bachellier-Bassi Sophie , D'Enfert Christophe , Villard Catherine
Published: March 2022

The cell wall is a key component of fungi. It constitutes a stiff shell which counteracts internal cell turgor pressure. Its mechanical properties thus contribute to define cell mor- phology. Measurements of the elastic moduli of the fungal cell wall have been carried out in many species including Candida albicans, a major human opportunistic pathogen. They mainly relied on atomic force microscopy, and mostly considered the yeast form. We developed a parallelized pressure-actuated microfluidic device to measure the bending stiffness of hyphae. We found that the cell wall stiffness lies in the MPa range. We the used three different ways to disrupt cell wall physiology: inhibition of beta-glucan synthesis, a key component of the inner cell wall; application of an hyperosmotic shock triggering a sudden decrease of the hyphal diameter; deletion of two genes encoding GPI-modified cell wall proteins resulting in reduced cell wall thickness. The bending stiffness values were affected to different extents by these environmental stresses or genetic modifications. Overall, our results support the elastic nature of the cell wall and its ability to remodel at the scale of the entire hypha over minutes.
Premature translation of the zygotic genome activator Zelda is not sufficient to precociously activate gene expression
Authors: Larson Elizabeth D. , Komori Hideyuki , Fitzpatrick Zoe A. , Krabbenhoft Samuel D. , Lee Cheng-Yu , Harrison Melissa
Published: March 2022

Following fertilization, the unified germ cells rapidly transition to a totipotent embryo. Maternally deposited mRNAs encode the proteins necessary for this reprogramming as the zygotic genome remains transcriptionally quiescent during the initial stages of development. The transcription factors required to activate the zygotic genome are among these maternally deposited mRNAs and are robustly translated following fertilization. In Drosophila, the mRNA encoding Zelda, the major activator of the zygotic genome, is not translated until one hour after fertilization. Here we demonstrate that zelda translation is repressed following fertilization by the TRIM-NHL protein Brain tumor (BRAT). BRAT also regulates Zelda levels in the larval neuroblast lineage. In the embryo, BRAT-mediated translational repression is regulated by the Pan Gu (PNG) kinase, which is triggered by egg activation. The PNG kinase phosphorylates translational regulators, suggesting that PNG kinase activity alleviates translational repression of zelda by BRAT and coupling translation of zelda with that of other regulators of early embryonic development. Using the premature translation of zelda in embryos lacking BRAT activity, we showed that early translation of a zygotic genome activator is not sufficient to drive precocious gene expression. Instead, Zelda-target genes showed increased expression at the time they are normally activated. We propose that transition through early development requires the integration of multiple processes, including the slowing of the nuclear division cycle and activation of the zygotic genome. These processes are coordinately controlled by PNG kinase-mediated regulation of translation.
Explainable machine learning for real-time hypoglycaemia and hyperglycaemia prediction and personalised control recommendations
Authors: Duckworth Christopher , Guy Matthew J , Kumaran Anitha , O’Kane Aisling Ann , Ayobi Amid , Chapman Adriane , Marshall Paul , Boniface Michael
Published: March 2022

Background

The occurrences of acute complications arising from hypoglycaemia and hyperglycaemia peak as young adults with type 1 diabetes (T1D) take control of their own care. Continuous glucose monitoring (CGM) devices provide real-time blood glucose readings enabling users to manage their control pro-actively. Machine learning algorithms can use CGM data to make ahead-of-time risk predictions and provide insight into an individual’s longer-term control.

Methods

We introduce explainable machine learning to make predictions of hypoglycaemia (<70mg/dL) and hyperglycaemia (>270mg/dL) 60 minutes ahead-of-time. We train our models using CGM data from 153 people living with T1D in the CITY survey totalling over 28000 days of usage, which we summarise into (short-term, medium-term, and long-term) blood glucose features along with demographic information. We use machine learning explanations (SHAP) to identify which features have been most important in predicting risk per user.

Results

Machine learning models (XGBoost) show excellent performance at predicting hypoglycaemia (AUROC: 0.998) and hyperglycaemia (AUROC: 0.989) in comparison to a baseline heuristic and logistic regression model.

Conclusions

Maximising model performance for blood glucose risk prediction and management is crucial to reduce the burden of alarm-fatigue on CGM users. Machine learning enables more precise and timely predictions in comparison to baseline models. SHAP helps identify what about a CGM user’s blood glucose control has led to predictions of risk which can be used to reduce their long-term risk of complications.
Fate and state transitions during human blood vessel organoid development
Authors: Nikolova Marina T. , He Zhisong , Wimmer Reiner A. , Seimiya Makiko , Nikoloff Jonas M. , Penninger Josef M. , Camp J. Gray , Treutlein Barbara
Published: March 2022

Blood vessel organoids (BVOs) derived from human pluripotent stem cells have emerged as a novel system to understand human vascular development, model disorders, and develop regenerative therapies. However, it is unclear which molecular states constitute BVOs and how cells differentiate and self-organize within BVOs in vitro and after transplantation. Here we reconstruct BVO development over a time course using single-cell transcriptomics. We observe progenitor states that bifurcate into endothelial and mural fates, and find that BVOs do not acquire definitive arterio-venous endothelial identities in vitro. Chromatin accessibility profiling identifies gene regulatory network (GRN) features associated with endothelial and mural fate decisions, and transcriptome-coupled lineage recording reveals multipotent progenitor states within BVOs. We perform single-cell genetic perturbations within mosaic BVOs to dissect the impact of transcription factor (TF) and receptor depletion on cell differentiation, and highlight multiple TFs including MECOM and ETV2 as strong-effect regulators of human BVO development. We show that manipulation of VEGF and Notch signaling pathways alters BVO morphogenesis and endothelial GRNs, and induces arteriovenous-like state differentiation. We analyze matured BVOs after transplantation using scRNA-seq, and observe matured endothelium with clear arteriovenous specification. We also observe off-target cell fates with bone and adipocyte features, suggesting multipotent states reside within the BVOs in vitro that expand and diversify in less restrictive conditions. Finally, we map vascular disease associated genes to BVO cell states to highlight the potential of BVOs for disease modeling. Altogether, our data and analyses provide the first comprehensive cell state atlas of BVO development and illuminate both the power and limitation of BVOs for translational research.
Bipartite recruitment of PCH2 and COMET to the synaptonemal complex drives chromosome axis reconstruction leading to crossover restriction
Authors: Yang Chao , Sofroni Kostika , Hamamura Yuki , Hu Bingyan , Elbasi Hasibe Tunçay , Balboni Martina , Heese Maren , Schnittger Arp
Published: March 2022

Chromosome axis-associated HORMA domain proteins (HORMADs), e.g., ASY1 in Arabidopsis, are crucial for meiotic recombination. ASY1, as other HORMADs, is assembled on the axis at early meiosis and depleted when homologous chromosomes synapse. Puzzlingly, both processes are catalyzed by AAA+ ATPase PCH2 together with its cofactor COMET. Here, we show that the ASY1 remodeling complex is temporally and spatially differently assembled. While PCH2 and COMET appear to directly interact in the cytoplasm in early meiosis, PCH2 is recruited by the transverse filament protein ZYP1 and brought to the ASY1-bound COMET assuring the timely removal of ASY1 during chromosome synapsis. Since we found that the PCH2 homolog TRIP13 also binds to the ZYP1 homolog SYCP1 in mouse, we postulate that this mechanism is conserved among eukaryotes. Deleting the PCH2 binding site of ZYP1 led to a failure of ASY1 removal. Interestingly, the placement of one obligatory crossover per homologous chromosome pair, compromised by ZYP1 depletion, is largely restored in this engineered zyp1 allele suggesting that crossover assurance is promoted by synapsis. In contrast, the engineered zyp1 allele, similar to the zyp1 null mutant, showed elevated type I crossover numbers indicating that PCH2-mediated eviction of ASY1 from the axis restricts crossover formation.
Methodological Insights “Materiality is …”: sensemaking and sensegiving through storytelling
Authors: Bolt Rebecca , Tregidga Helen
Published: March 2022

Purpose

The purpose of this paper is to explore the role and implications of storytelling and narrative as a means of making sense of, and giving sense to, the ambiguous concept of materiality.

Design/methodology/approach

The use of stories was “discovered” through the authors' attempts to “make sense” of data from 16 interviews with participants from the financial and nonfinancial reporting and assurance contexts. The authors analyse the participants' use of stories through a sensemaking/sensegiving lens.

Findings

While participants struggle to define what materiality is, they are able to tell “stories” about materiality in action. The authors find stories are a key vehicle through which participants make sense of and give sense to materiality, for themselves and (an)other. Participants tell three types of stories in sensemaking/sensegiving processes: the lived, the adopted and the hypothetical. The authors further identify “rehearsed” and “ongoing” narratives, which take any of the three story types. The use of stories to make and give sense to materiality reveals a disconnect between the static, technical definitions of materiality currently favoured by standard setters and guidance providers, and the creative authoring processes the participants employ.

Practical implications

The authors argue for a move towards the use of stories and narratives about materiality in standard setting, specifically “materiality in action”, which the findings suggest may assist in creating shared understandings of the ambiguous concept.

Originality/value

While previous research considers what materiality means within financial and nonfinancial reporting and assurance contexts, the authors empirically analyse how people understand and make sense/give sense to materiality. The authors also contribute to the use of sensemaking/sensegiving processes within the accounting literature.
Credit default swap prediction based on generative adversarial networks
Authors: Lin Shu-Ying , Liu Duen-Ren , Huang Hsien-Pin
Published: March 2022

Purpose

Financial price forecast issues are always a concern of investors. However, the financial applications based on machine learning methods mainly focus on stock market predictions. Few studies have explored credit risk predictions. Understanding credit risk trends can help investors avoid market risks. The purpose of this study is to investigate the prediction model that can effectively predict credit default swaps (CDS).

Design/methodology/approach

A novel generative adversarial network (GAN) for CDS prediction is proposed. The authors take three features into account that are highly relevant to the future trends of CDS: historical CDS price, news and financial leverage. The main goal of this model is to improve the existing GAN-based regression model by adding finance and news feature extraction approaches. The proposed model adopts an attentional long short-term memory network and convolution network to process historical CDS data and news information, respectively. In addition to enhancing the effectiveness of the GAN model, the authors also design a data sampling strategy to alleviate the overfitting issue.

Findings

The authors conduct an experiment with a real dataset and evaluate the performance of the proposed model. The components and selected features of the model are evaluated for their ability to improve the prediction performance. The experimental results show that the proposed model performs better than other machine learning algorithms and traditional regression GAN.

Originality/value

There are very few studies on prediction models for CDS. With the proposed novel approach, the authors can improve the performance of CDS predictions. The proposed work can thereby increase the commercial value of CDS predictions to support trading decisions.
Organizational compassion, person-organization fit and discretionary behaviours in non-governmental organizations: a moderated model
Authors: Kasekende Francis , Nasiima Sentrine , Byamukama Rodgers
Published: March 2022

Purpose

The authors proposed that Organizational Compassion and Person-Organization-Fit dimensions interactively predict Discretionary Behaviours among employees in the Non-Governmental Organization (NGO) sector in Uganda.

Design/methodology/approach

The authors employ structural equation modelling to test hypotheses. The research was carried out in two studies; the second one was done six months after the first study. Two samples of respondents were drawn from NGOs operating in West Nile and Kampala regions, respectively.

Findings

Discretionary behaviours were significantly related to the cross-sectionally assessed predictors including organizational compassion and supplementary fit. Complementary fit did not significantly predict discretionary behaviours. Both supplementary fit and complementary fit moderated the association between organizational compassion and employee discretionary behaviours among both rural and urban setting placed NGOs.

Practical implications

In order to boost employee exhibition of discretionary behaviours, leaders of NGOs should always endeavour to find viable organizational compassion-supplementary fit and organizational compassion-complementary fit blend that can add value to NGOs in Uganda.

Originality/value

This is one of the few studies that have focused on testing the interaction effects of organizational compassion and person organization fit dimensions on discretionary behaviours. These results highlight both supplementary fit and complementary fit as key individual resources that promote the effects of organization compassion on discretionary behaviours among NGO workers in Uganda.
Evaluation of regional agricultural drought vulnerability based on unbiased generalized grey relational closeness degree
Authors: Zhang Dongxing , Luo Dang
Published: March 2022

Purpose

The purpose of this study is to propose an unbiased generalized grey relational closeness evaluation model to improve the accuracy of regional agricultural drought vulnerability decision-making results, as well as to provide theoretical support for reducing agricultural drought risk and losses.

Design/methodology/approach

The index weight is calculated using a rough set and deviation minimization criterion, and the relational degree between the research object and the double reference sequence is thoroughly investigated using the generalized grey relational closeness degree. Because different index rankings can correspond to different closeness degrees, the Monte Carlo method was used to calculate an unbiased estimate of the generalized grey relational closeness degree, which was used as a decision basis.

Findings

Agricultural drought vulnerability in Henan Province in 2019 was clearly spatially differentiated. The vulnerability to agricultural drought in the southern and eastern regions was generally higher than that in other regions. The evaluation results of this model are highly stable and reliable compared to those of the traditional generalized grey relational evaluation model.

Practical implications

This study proposes an evaluation model based on an unbiased generalized grey relational closeness degree, which is important to supplement the grey relational analysis method system and plays a positive role in promoting the quantitative evaluation of regional agricultural drought vulnerability.

Originality/value

The Monte Carlo method is used to calculate the unbiased estimation of the generalized grey relational closeness degree, which solves the problem of the replacement dependence of the traditional generalized grey relational degree and the one-sidedness of the evaluation results, and provides a new research idea for the evaluation of regional agricultural drought vulnerability under cross-sectional informatics.