bluuebunny/crossref_metadata_2025 huggingface dataset:
Short-term elevations in glucocorticoids do not alter telomere lengths: A systematic review and meta-analysis of non-primate vertebrate studies
Authors: Zane Lauren , Ensminger David C. , Vázquez-Medina José Pablo
Published: May 2021

Background

The neuroendocrine stress response allows vertebrates to cope with stressors via the activation of the Hypothalamic-Pituitary-Adrenal (HPA) axis, which ultimately results in the secretion of glucocorticoids (CORT). Glucocorticoids have pleiotropic effects on behavior and physiology, and might influence telomere length dynamics. During a stress event, CORT mobilizes energy towards survival mechanisms rather than to telomere maintenance. Additionally, reactive oxidative species produced in response to increased CORT levels can damage telomeres, also leading to telomere shortening. In our systematic review and meta-analysis, we tested whether CORT levels impact telomere length and if this relationship differs among time frame, life history stage, or stressor type. We hypothesized that elevated CORT levels are linked to a decrease in telomere length.

Methods

To test this hypothesis, we conducted a literature search for studies investigating the relationship between telomere length and CORT levels in non-human vertebrates using four search engines: Web of Science, Google Scholar, Pubmed and Scopus, last searched on September 27th, 2020. This review identified 31 studies examining the relationship between CORT and telomere length. We pooled the data using Fisher’s Z for 15 of these studies. All quantitative studies underwent a risk of bias assessment. This systematic review study was registered in the Open Science Framework Registry (https://osf.io/rqve6).

Results

The pooled effect size from fifteen studies and 1066 study organisms shows no relationship between CORT and telomere length ((Fisher’s Z= 0.1042, 95% CI = 0.0235; 0.1836). While these results support some previous findings, other studies have found a direct relationship between CORT and telomere dynamics, suggesting underlying mechanisms or concepts that are not currently taken into account in our analysis. The risk of bias assessment revealed an overall low risk of bias with occasional instances of bias from missing outcome data or bias in the reported result.

Conclusion

We highlight the need for more targeted experiments to understand how conditions, such as experimental timeframes, stressor(s), and stressor magnitudes can drive a relationship between the neuroendocrine stress response and telomere length.
GeneTonic: an R/Bioconductor package for streamlining the interpretation of RNA-seq data
Authors: Marini Federico , Ludt Annekathrin , Linke Jan , Strauch Konstantin
Published: May 2021

Background

The interpretation of results from transcriptome profiling experiments via RNA sequencing (RNA-seq) can be a complex task, where the essential information is distributed among different tabular and list formats - normalized expression values, results from differential expression analysis, and results from functional enrichment analyses. A number of tools and databases are widely used for the purpose of identification of relevant functional patterns, yet often their contextualization within the data and results at hand is not straightforward, especially if these analytic components are not combined together efficiently.

Results

We developed the GeneTonic software package, which serves as a comprehensive toolkit for streamlining the interpretation of functional enrichment analyses, by fully leveraging the information of expression values in a differential expression context. GeneTonic is implemented in R and Shiny, leveraging packages that enable HTML-based interactive visualizations for executing drilldown tasks seamlessly, viewing the data at a level of increased detail. GeneTonic is integrated with the core classes of existing Bioconductor workflows, and can accept the output of many widely used tools for pathway analysis, making this approach applicable to a wide range of use cases. Users can effectively navigate interlinked components (otherwise available as flat text or spreadsheet tables), bookmark features of interest during the exploration sessions, and obtain at the end a tailored HTML report, thus combining the benefits of both interactivity and reproducibility.

Conclusion

GeneTonic is distributed as an R package in the Bioconductor project (https://bioconductor.org/packages/GeneTonic/) under the MIT license. Offering both bird’s-eye views of the components of transcriptome data analysis and the detailed inspection of single genes, individual signatures, and their relationships, GeneTonic aims at simplifying the process of interpretation of complex and compelling RNA-seq datasets for many researchers with different expertise profiles.
Targeting of Protein Kinase CK2 in Acute Myeloid Leukemia Cells Using the Clinical-Grade Synthetic-Peptide CIGB-300
Authors: Rosales Mauro , Pérez George V. , Ramón Ailyn C. , Cruz Yiliam , Rodríguez-Ulloa Arielis , Besada Vladimir , Ramos Yassel , Vázquez-Blomquist Dania , Caballero Evelin , Aguilar Daylen , González Luis J. , Zettl Katharina , Wiśniewski Jacek R. , Ke Yang , Perera Yasser , Perea Silvio E.
Published: May 2021

Protein kinase CK2 has emerged as an attractive therapeutic target in acute myeloid leukemia (AML), advent that becomes particularly relevant since the treatment of this hematological neoplasia remains challenging. Here we explored for the first time the effect of the clinical-grade peptide-based CK2 inhibitor CIGB-300 on AML cells proliferation and viability. CIGB-300 internalization and subcellular distribution were also studied, and the role of B23/nucleophosmin 1 (NPM1), a major target for the peptide in solid tumors, was addressed by knock-down in model cell lines. Finally, pull-down experiments and phosphoproteomic analysis were performed to study CIGB-interacting proteins and identify the array of CK2 substrates differentially modulated after treatment with the peptide. Importantly, CIGB-300 elicited a potent anti-proliferative and proapoptotic effect in AML cells, with more than 80% of peptide transduced cells within three minutes. Unlike solid tumor cells, NPM1 did not appear to be a major target for CIGB-300 in AML cells. However, in vivo pull-down experiments and phosphoproteomic analysis evidenced that CIGB-300 targeted the CK2α catalytic subunit, different ribosomal proteins, and inhibited the phosphorylation of a common CK2 substrates array among both AML backgrounds. Remarkably, our results not only provide cellular and molecular insights unveiling the complexity of the CIGB-300 anti-leukemic effect in AML cells, but also reinforce the rationale behind the pharmacologic blockade of protein kinase CK2 for AML targeted therapy.
Single-dose AAV-based vaccine induces a high level of neutralizing antibodies against SARS-CoV-2 in rhesus macaques
Authors: Tong Dali , Zhang Mei , Yang Yunru , Xia Han , Tong Haiyang , Zhang Huajun , Zeng Weihong , Liu Muziying , Wu Yan , Ma Huan , Hu Xue , Liu Weiyong , Cai Yuan , Yao Yanfeng , Yao Yichuan , Liu Kunpeng , Shan Shifang , Li Yajuan , Gao Ge , Guo Weiwei , Peng Yun , Chen Shaohong , Rao Juhong , Zhao Jiaxuan , Min Juan , Zhu Qingjun , Zheng Yanmin , Liu Lianxin , Shan Chao , Zhong Kai , Qiu Zilong , Jin Tengchuan , Chiu Sandra , Yuan Zhiming , Xue Tian
Published: May 2021

Coronavirus disease 2019 (COVID-19), which is triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, continues to threaten global public health. Developing a vaccine that only requires single immunization but provides long-term protection for the prevention and control of COVID-19 is important. Here, we developed an adeno-associated virus (AAV)-based vaccine expressing a stable receptor-binding domain (SRBD) protein. The vaccine requires only a single shot but provides effective neutralizing antibodies (NAbs) over 598 days in rhesus macaques (Macaca mulatta). Importantly, our results showed that the NAbs were kept in high level and long lasting against authentic wild-type SARS-CoV-2, Beta, Delta and Omicron variants using plaque reduction neutralization test. Of note, although we detected pre-existing AAV2/9 antibodies before immunization, the vaccine still induced high and effective NAbs against COVID-19 in rhesus macaques. AAV-SRBD immune serum also efficiently inhibited the binding of ACE2 with RBD in the SARS-CoV-2 B.1.1.7 (Alpha), B.1.351 (Beta), P.1/P.2 (Gamma), B.1.617.2 (Delta), B.1.617.1/3(Kappa), and C.37 (Lambda) variants. Thus, these data suggest that the vaccine has great potential to prevent the spread of SARS-CoV-2.
Ankrd26 is critical for cell differentiation and cancer-linked mutations affect its key properties
Authors: Hofbrucker-MacKenzie Sarah A. , Englisch A. Sofie , Izadi Maryam , Metzner Klara , Kessels Michael M. , Qualmann Britta
Published: May 2021

Derailed signaling originating from the plasma membrane is associated with many types of cancer. Different human cancers and thrombocytopenia are linked toANKRD26mutations. We unveil that Ankrd26 is a plasma membrane-localized protein forming nanoclusters and that Ankrd26 is critical for retinoic acid/BDNF-induced neuroblastoma differentiation. An N-terminal amphipathic structure lacking in an AML-associated Ankrd26 mutant is indispensable for membrane binding and bending by partial membrane insertion and renders Ankrd26 inactive in both gain-of-function and loss-of- function/rescue studies addressing cellular differentiation. In a papillary thyroid carcinoma-linked mutant, truncated Ankrd26 is fused with the kinase domain of the protooncogene RET. Our data show that the Ankrd26 part of this fusion mutant mediates anchoring of the RET kinase domain to the plasma membrane and self-association by the coiled coil domain of Ankrd26. Ankrd26-RET fusion led to massively increased ERK1/2 activity and RET autophosphorylation at both Y905 and Y1015, i.e. caused aberrant RET signaling. Our results highlight the importance and molecular details of Ankrd26-mediated organizational platforms for cellular differentiation and signaling pathways from the plasma membrane, which, if derailed, lead to cancer-associated pathomechanisms involving the unveiled Ankrd26 properties.
Metformin Is Associated with Favorable Outcomes in Patients with COVID-19 and Type 2 Diabetes Mellitus
Authors: Ma Zhiyuan , Patel Nishit , Vemparala Pranathi , Krishnamurthy Mahesh
Published: May 2021

Aim

Coronavirus disease 2019 (COVID-19) is a new pandemic the entire world is facing since December of 2019. In this retrospective study, we aim to address whether metformin use offers a low mortality on patients with COVID-19 and pre-existing type 2 diabetes mellitus (T2DM).

Materials and Methods

A cohort of 1356 hospitalized patients with COVID-19 and pre-existing T2DM was analyzed by multivariate regression. Covariates that potentially confound the association were further adjusted using propensity score matching or inverse probability of treatment weighting. A meta-analysis of the present study along with 5 published studies with metformin use prior to admission in patients with COVID-19 and T2DM was carried out.

Results

We found that metformin therapy prior to admission in patients with COVID-19 and T2DM was significantly associated with less primary outcome events including in-hospital mortality and hospice care enrollment with an odds ratio (OR) of 0.25 (95% CI, 0.06-0.74) and less in-hospital length of stay, compared to non-metformin group. There were no statistical differences between the metformin group and non-metformin group for all three inflammatory markers (ferritin, CRP, and IL-6) on admission or peak levels during hospitalization. Furthermore, meta-analysis demonstrated that metformin use was significantly correlated with reduced mortality with an OR of 0.73 (95% CI, 0.65-0.82) in the fixed effect model and 0.58 (95% CI, 0.42-0.80) for the random effect model.

Conclusions

Our results provide supporting evidence that metformin may confer increased survival in patients with COVID-19 and T2DM treated with Metformin prior to hospitalization.
Association of Microalbuminuria with High HbA1C levels in Melanesian Adults with Diabetes of at-least 1 Year Duration
Authors: Billy Ian , Aglua Izzard
Published: May 2021

Background

Evidence suggest a potential relationship between high or variable HbA1C levels and presence or rate of change of microalbuminuria. Disruption of the vascular endothelial glycocalyx has been linked to chronic hyperglycemia and microalbuminuria, suggesting a possible shared pathophysiological mechanism.

Aim

To 1) explore potential association between microalbuminuria and high HbA1C levels in Melanesian adults with diabetes mellitus, and 2) asses predictive value of a high HbA1C reading as an indicator of the presence or progression of microalbuminuria.

Method

A cross-sectional study on 190 patients with either type 1 or 2 diabetes of at least 1-year duration done at a provincial hospital in Papua New Guinea in 2017.

Result

A significant [P=0.0221], though weak [R2=0.028 <0.70], correlation between UACR and HbA1C [95% statistical confidence] was observed in univariate regression, which was marginally significant [P=0.056] after controlling for weight, systolic hypertension, duration of diabetes, gender and age in multivariate regression.

Conclusion

A significant [p=0.022], though weak, correlation between UACR and HbA1C levels was observed, which may support usefulness of HbA1C as a predictor for microalbuminuria and diabetic kidney disease. In settings without microalbuminuria testing, high HbA1c levels can be used as a proxy to indicate presence or progression of microalbuminuria, thus prompting timely interventions to prevent further progression of diabetic nephropathy.
Growth and eGFP-production of CHO-K1 suspension cells cultivated from single-cell to lab-scale
Authors: Schmitz Julian , Hertel Oliver , Yermakov Boris , Noll Thomas , Grünberger Alexander
Published: May 2021

Scaling down bioproduction processes became a major driving force for more accelerated and efficient process development over the last decades. Especially expensive and time-consuming processes like the production of biopharmaceuticals with mammalian cell lines benefit clearly from miniaturisation, due to higher parallelisation and increased insights while at the same time decreasing experimental time and costs. Lately, novel microfluidic methods have been developed, especially microfluidic single-cell cultivation (MSCC) devices proofed to be valuable to miniaturise the cultivation of mammalian cells. So far growth characteristics of microfluidic cultivated cell lines were not systematically compared to larger cultivation scales, however validation of a miniaturisation tool against initial cultivation scales is mandatory to proof its applicability for bioprocess development. Here, we systematically investigate growth, morphology, and eGFP-production of CHO-K1 cells in different cultivation scales including microfluidic chip (230 nL), shake flask (60 mL), and lab-scale bioreactor (1.5 L). Our study shows a high comparability regarding growth rates, cellular diameters, and eGFP production which proofs the feasibility of MSCC as miniaturised cultivation tool for mammalian cell culture. In addition, we demonstrate that MSCC allows insights into cellular heterogeneity and single-cell dynamics concerning growth and production behaviour which, when occurring in bioproduction processes, might severely affect process robustness. Eventually, by providing insights into cellular heterogeneity, MSCC has the potential to be applied as a novel and powerful tool in the context of cell line development and bioprocesses implementation.
Differential interferon-α subtype immune signatures suppress SARS-CoV-2 infection
Authors: Schuhenn J. , Meister T.L. , Todt D. , Bracht T. , Schork K. , Billaud J.-N. , Elsner C. , Heinen N , Karakoese Z. , Haid S. , Kumar S. , Brunotte L. , Eisenacher M. , Chen J. , Yuan Z , Pietschmann T. , Wiegmann B. , Beckert H. , Taube C. , Le-Trilling VTK. , Trilling M. , Krawczyk A. , Ludwig S. , Sitek B. , Steinmann E. , Dittmer U. , Sutter K. , Pfaender S.
Published: May 2021

Type I interferons (IFN-I) exert pleiotropic biological effects during viral infections, balancing virus control versus immune-mediated pathologies and have been successfully employed for the treatment of viral diseases. Humans express twelve IFN-alpha (α) subtypes, which activate downstream signalling cascades and result in distinct patterns of immune responses and differential antiviral responses. Inborn errors in type I IFN immunity and the presence of anti-IFN autoantibodies account for very severe courses of COVID-19, therefore, early administration of type I IFNs may be protective against life-threatening disease. Here we comprehensively analysed the antiviral activity of all IFNα subtypes against SARS-CoV-2 to identify the underlying immune signatures and explore their therapeutic potential. Prophylaxis of primary human airway epithelial cells (hAEC) with different IFNα subtypes during SARS-CoV-2 infection uncovered distinct functional classes with high, intermediate and low antiviral IFNs. In particular IFNα5 showed superior antiviral activity against SARS-CoV-2 infection. Dose-dependency studies further displayed additive effects upon co-administered with the broad antiviral drug remdesivir in cell culture. Transcriptomics of IFN-treated hAEC revealed different transcriptional signatures, uncovering distinct, intersecting and prototypical genes of individual IFNα subtypes. Global proteomic analyses systematically assessed the abundance of specific antiviral key effector molecules which are involved in type I IFN signalling pathways, negative regulation of viral processes and immune effector processes for the potent antiviral IFNα5. Taken together, our data provide a systemic, multi-modular definition of antiviral host responses mediated by defined type I IFNs. This knowledge shall support the development of novel therapeutic approaches against SARS-CoV-2.
Development of a Bayesian network for probabilistic risk assessment of pesticides
Authors: Mentzel Sophie , Grung Merete , Tollefsen Knut Erik , Stenrød Marianne , Petersen Karina , Moe S. Jannicke
Published: May 2021

Conventional environmental risk assessment of chemicals is based on a calculated risk quotient, representing the ratio of exposure to effects of the chemical, in combination with assessment factors to account for uncertainty. Probabilistic risk assessment approaches can offer more transparency, by using probability distributions for exposure and/or effects to account for variability and uncertainty. In this study, a probabilistic approach using Bayesian network (BN) modelling is explored as an alternative to traditional risk calculation. BNs can serve as meta-models that link information from several sources and offer a transparent way of incorporating the required characterization of uncertainty for environmental risk assessment. To this end, a BN has been developed and parameterised for the pesticides azoxystrobin, metribuzin, and imidacloprid. We illustrate the development from deterministic (traditional) risk calculation, via intermediate versions, to fully probabilistic risk characterisation using azoxystrobin as an example. We also demonstrate seasonal risk calculation for the three pesticides.
The gatekeeper of Yersinia type III secretion is under RNA thermometer control
Authors: Pienkoß Stephan , Javadi Soheila , Chaoprasid Paweena , Nolte Thomas , Twittenhoff Christian , Dersch Petra , Narberhaus Franz
Published: May 2021

Many bacterial pathogens use a type III secretion system (T3SS) as molecular syringe to inject effector proteins into the host cell. In the foodborne pathogen Yersinia pseudotuberculosis, delivery of the secreted effector protein cocktail through the T3SS depends on YopN, a molecular gatekeeper that controls access to the secretion channel from the bacterial cytoplasm. Here, we show that several checkpoints adjust yopN expression to virulence conditions. A dominant cue is the host body temperature. A temperature of 37 °C is known to induce the RNA thermometer (RNAT)-dependent synthesis of LcrF, a transcription factor that activates expression of the entire T3SS regulon. Here, we uncovered a second layer of temperature control. We show that another RNAT silences translation of the yopN mRNA at low environmental temperatures. The long and short 5’-untranslated region of both cellular yopN isoforms fold into a similar secondary structure that blocks ribosome binding. The hairpin structure with an internal loop melts at 37 °C and thereby permits formation of the translation initiation complex as shown by mutational analysis, in vitro structure probing and toeprinting methods. Importantly, we demonstrate the physiological relevance of the RNAT in the faithful control of type III secretion by using a point-mutated thermostable RNAT variant with a trapped SD sequence. Abrogated YopN production in this strain led to unrestricted effector protein secretion into the medium, bacterial growth arrest and delayed translocation into eukaryotic host cells. Cumulatively, our results show that substrate delivery by the Yersinia T3SS is under hierarchical surveillance of two RNATs.

Author summary

Temperature serves as reliable external cue for pathogenic bacteria to recognize the entry into or exit from a warm-blooded host. At the molecular level, a temperature of 37 °C induces various virulence-related processes that manipulate host cell physiology. Here, we demonstrate the temperature-dependent synthesis of the secretion regulator YopN in the foodborne pathogen Yersinia pseudotuberculosis, a close relative of Yersinia pestis. YopN blocks secretion of effector proteins through the type III secretion system unless host cell contact is established. Temperature-specific regulation relies on an RNA structure in the 5’-untranslated region of the yopN mRNA, referred to as RNA thermometer, which allows ribosome binding and thus translation initiation only at an infection-relevant temperature of 37 °C. A mutated variant of the thermosensor resulting in a closed conformation prevented synthesis of the molecular gatekeeper YopN and led to permanent secretion and defective translocation of virulence factors into host cells. We suggest that the RNA thermometer plays a critical role in adjusting the optimal cellular concentration of a surveillance factor that maintains the controlled translocation of virulence factors.
Fluorescence signatures of SARS-CoV-2 spike S1 proteins and an human ACE-2: excitation-emission maps and fluorescence lifetimes
Authors: Grzesiak Jonas , Fellner Lea , Grünewald Karin , Kölbl Christoph , Walter Arne , Horlacher Reinhold , Duschek Frank
Published: May 2021

Significance

Fast and reliable detection of infectious SARS-CoV-2 virus loads is an important issue. Fluorescence spectroscopy is a sensitive tool to do so in clean environments. This presumes a comprehensive knowledge of fluorescence data.

Aim

This work aims at providing fully featured information on wavelength and time-dependent data of the fluorescence of the SARS-CoV-2 spike protein S1 subunit, its receptor binding domain (RBD) and the human angiotensinconverting enzyme 2 (hACE2), especially with respect to possible optical detection schemes.

Approach

Spectrally resolved excitation-emission maps of the involved proteins and measurements of fluorescence lifetimes were recorded for excitations from 220 to 295 nm. The fluorescence decay times were extracted by using a bi-exponential kinetic approach. The binding process in the SARS-CoV-2 RBD was likewise examined for spectroscopic changes.

Results

Distinct spectral features for each protein are pointed out in relevant spectra extracted from the excitation emission maps. We also identify minor spectroscopic changes under the binding process. The decay times in the bi-exponential model are found to be (2.0± 0.1) ns and (8.0 ±1.0) ns.

Conclusions

Specific material data serve as important background information for the design of optical detection and testing methods for SARS-CoV-2 loaded media.
Predictive and motivational factors influencing anticipatory contrast: A comparison of contextual and gustatory predictors in food restricted and free-fed rats
Authors: Hayes Jessica , Garau Celia , Chiacchierini Giulia , Urcelay Gonzalo P. , McCutcheon James E. , Apergis-Schoute John
Published: May 2021

In anticipation of palatable food, rats can learn to restrict consumption of a less rewarding food type resulting in a binge on the preferred food when it is made available. This construct is known as anticipatory negative contrast (ANC) and can help elucidate the processes that underlie binge-like behavior as well as self-control in rodent motivation models. In the current investigation we aimed to shed light on the ability of distinct predictors of a preferred food choice to generate contrast effects and the motivational processes that underlie this behavior. Using a novel set of rewarding solutions, we directly compared contextual and gustatory ANC predictors in both food restricted and free-fed Sprague-Dawley rats. Our results indicate that, despite being food restricted, rats are selective in their eating behavior and show strong contextually-driven ANC and do so after fewer training sessions than free-fed animals. These differences mirrored changes in palatability for the less preferred solution across the different sessions as measured by lick microstructure analysis. Moreover, in contrast to previous research, gustatory cues in both food restricted and free-fed rats were sufficient for ANC to develop although this flavor-driven ANC did not relate to a corresponding change in lick patterning. These differences in the lick microstructure between context- and flavor-driven ANC indicate that the motivational processes underlying ANC generated by the two predictor types are distinct.
A CRISPR/Cas9 genetically engineered organoid biobank reveals essential host factors for coronaviruses
Authors: Beumer Joep , Geurts Maarten H. , Lamers Mart M. , Puschhof Jens , Zhang Jingshu , van der Vaart Jelte , Mykytyn Anna Z. , Breugem Tim I. , Riesebosch Samra , Schipper Debby , van den Doel Petra B. , Lau Wim de , Pleguezuelos-Manzano Cayetano , Busslinger Georg , Haagmans Bart L. , Clevers Hans
Published: May 2021

Rapid identification of host genes essential for virus replication may expedite the generation of therapeutic interventions. Genetic screens are often performed in transformed cell lines that poorly represent viral target cells in vivo, leading to discoveries that may not be translated to the clinic. Intestinal organoids (IOs) are increasingly used to model human disease and are amenable to genetic engineering. To discern which host factors are reliable anti-coronavirus therapeutic targets, we generate mutant clonal IOs for 19 host genes previously implicated in coronavirus biology. We verify ACE2 and DPP4 as entry receptors for SARS-CoV/SARS-CoV-2 and MERS-CoV respectively. SARS-CoV-2 replication in IOs does not require the endosomal Cathepsin B/L proteases, but specifically depends on the cell surface protease TMPRSS2. Other TMPRSS family members were not essential. The newly emerging coronavirus variant B.1.1.7, as well as SARS-CoV and MERS-CoV similarly depended on TMPRSS2. These findings underscore the relevance of non-transformed human models for coronavirus research, identify TMPRSS2 as an attractive pan-coronavirus therapeutic target, and demonstrate that an organoid knockout biobank is a valuable tool to investigate the biology of current and future emerging coronaviruses.
Identifying cancer pathway dysregulations using differential causal effects
Authors: Jablonski Kim Philipp , Pirkl Martin , Ćevid Domagoj , Bühlmann Peter , Beerenwinkel Niko
Published: May 2021

Signaling pathways control cellular behavior. Dysregulated pathways, for example due to mutations that cause genes and proteins to be expressed abnormally, can lead to diseases, such as cancer. We introduce a novel computational approach, called Differential Causal Effects (dce), which compares normal to cancerous cells using the statistical framework of causality. The method allows to detect individual edges in a signaling pathway that are dysregulated in cancer cells, while accounting for confounding. Hence, artificial signals from, for example, batch effects have less influence on the result and dce has a higher chance to detect the biological signals. We show that dce outperforms competing methods on synthetic data sets and on CRISPR knockout screens. In an exploratory analysis on breast cancer data from TCGA, we recover known and discover new genes involved in breast cancer progression.
Cochlear nucleus small cells use olivocochlear collaterals to encode sounds in noise
Authors: Hockley Adam , Wu Calvin , Shore Susan E
Published: May 2021

Understanding communication signals, especially in noisy environments, is crucial to social interactions. Yet, as we age, acoustic signals can be disrupted by cochlear damage and the subsequent auditory nerve fiber degeneration. The most vulnerable—medium and high-threshold—auditory nerve fibers innervate various cell types in the cochlear nucleus, among which, the small cells are unique in receiving this input exclusively. Furthermore, small cells project to medial olivocochlear (MOC) neurons, which in turn send branched collaterals back into the SCC. Here, we use single-unit recordings to characterise small cell firing characteristics and demonstrate superior intensity coding in this cell class. We show converse effects when activating/blocking the MOC system, demonstrating that small-cell unique coding properties are facilitated by direct cholinergic input from the MOC system. Small cells also maintain tone-level coding in the presence of background noise. Finally, small cells precisely code low-frequency modulation more accurately than other ventral CN (VCN) cell types, demonstrating accurate envelope coding that may be important for vocalisation processing. These results highlight the small cell–olivocochlear circuit as a key player in signal processing in noisy environments, which may be selectively degraded in aging or after noise insult.
Acute SARS-CoV-2 infection is associated with an expansion of bacteria pathogens in the nose including Pseudomonas Aeruginosa
Authors: Rhoades Nicholas S. , Pinski Amanda , Monsibais Alisha N. , Jankeel Allen , Doratt Brianna M. , Cinco Isaac R. , Ibraim Izabela , Messaoudi Ilhem
Published: May 2021

Much of the research conducted on SARS-CoV-2 and COVID-19 has focused on the systemic host response, especially that generated by severely ill patients. Very few studies have investigated the impact of acute SARS-CoV-2 within the nasopharynx, the site of initial infection and viral replication. In this study we profiled changes in the nasal microbial communities as well as in host transcriptional profile during acute SARS-CoV-2 infection using 16S amplicon sequencing and RNA sequencing. These analyses were coupled to viral genome sequencing. Our microbiome analysis revealed that the nasal microbiome of COVID patients was unique and was marked by an expansion of bacterial pathogens. Some of these microbes (i.e. Acinetobacter) were shared with COVID negative health care providers from the same medical center but absent in COVID negative outpatients seeking care at the same institutions suggesting acquisition of nosocomial respiratory pathogens. Specifically, we report a distinct increase in the prevalence and abundance of the pathogen Pseudomonas aeruginosa in COVID patients that correlated with viral RNA load. These data suggest that the inflammatory environment caused by SARS-CoV-2 infection and potentially exposure to the hospital environment leads to an expansion of bacterial pathogens in the nasal cavity that could contribute to increased incidence of secondary bacterial infections. Additionally, we observed a robust host transcriptional response in the nasal epithelia of COVID patients, indicative of an antiviral innate immune repones and neuronal damage. Finally, analysis of viral genomes did not reveal an association between viral loads and viral sequences.
Novel entropy-based metrics for predicting choice behavior based on local response to reward
Authors: Trepka Ethan , Spitmaan Mehran , Bari Bilal A. , Costa Vincent D. , Cohen Jeremiah Y. , Soltani Alireza
Published: May 2021

For decades, behavioral scientists have used the matching law to quantify how animals distribute their choices between multiple options in response to reinforcement they receive. More recently, many reinforcement learning (RL) models have been developed to explain choice by integrating reward feedback over time. Despite reasonable success of RL models in capturing choice on a trial-by-trial basis, these models cannot capture variability in matching. To address this, we developed novel metrics based on information theory and applied them to choice data from dynamic learning tasks in mice and monkeys. We found that a single entropy-based metric can explain 50% and 41% of variance in matching in mice and monkeys, respectively. We then used limitations of existing RL models in capturing entropy-based metrics to construct a more accurate model of choice. Together, our novel entropy-based metrics provide a powerful, model-free tool to predict adaptive choice behavior and reveal underlying neural mechanisms.
Illusory tactile movement crosses arms and legs and is coded in external space
Authors: Martel Marie , Fuchs Xaver , Trojan Jörg , Gockel Valerie , Habets Boukje , Heed Tobias
Published: May 2021

Humans often misjudge where on the body a touch occurred. Theoretical accounts have ascribed such misperceptions to local interactions in peripheral and primary somatosensory neurons, positing that spatial-perceptual mechanisms adhere to limb boundaries and skin layout. Yet, perception often reflects integration of sensory signals with prior experience. On their trajectories, objects often touch multiple limbs; therefore, body-environment interactions should manifest in perceptual mechanisms that reflect external space.

Here, we demonstrate that humans perceived the cutaneous rabbit illusion – the percept of multiple identical stimuli as hopping across the skin – along the Euclidian trajectory between stimuli on two body parts and regularly mislocalized stimuli from one limb to the other. A Bayesian model based on Euclidian, as opposed to anatomical, distance faithfully reproduced key aspects of participants’ localization behavior.

Our results suggest that prior experience of touch in space critically shapes tactile spatial perception and illusions beyond anatomical organization.
RNA silencing by CRISPR in plants does not require Cas13
Authors: Sharma VK , Marla S , Zheng WG , Mishra D , Huang J , Zhang W , Morris GP , Cook DE
Published: May 2021

RNA-targeting CRISPR-Cas can provide potential advantages over DNA editing, such as avoiding pleiotropic effects of genome editing, providing precise spatiotemporal regulation and expanded function including anti-viral immunity. Here, we report the use of CRISPR-Cas13 in plants to reduce both viral and endogenous RNA. Unexpectedly, we discovered that crRNA designed to guide Cas13 could, in the absence of the Cas13 protein, cause substantial reduction in RNA levels as well. We demonstrate Cas13-independent guide-induced gene silencing (GIGS) in three plant species, including stable transgenic Arabidopsis. We determined that GIGS utilizes endogenous RNAi machinery despite the fact that crRNA are unlike canonical triggers of RNAi such as miRNA, hairpins or long double-stranded RNA. These results suggest that GIGS offers a novel and flexible approach to RNA reduction with potential benefits over existing technologies for crop improvement. Our results demonstrate that GIGS is active across a range of plant species, evidence similar to recent findings in an insect system, which suggests that GIGS is potentially active across many eukaryotes.
catena-Poly[[bis(1H-indole-5-carboxylato-κ2
O,O′)zinc(II)]-μ-4,4′-azobipyridine-κ2
N
1:N
1′]
Authors: Sathya Udhayasuriyan , Nirmal Ram Jeyaraman Selvaraj , Gomathi Sundaramoorthy , Jegan Jennifer Samson , Abdul Razak Ibrahim
Published: May 2021

The asymmetric unit of the title coordination polymer [Zn(C9H6NO2)2(C10H8N4)]
n
, consists of one ZnII cation, one bidentate 1H-indole-5-carboxylate (I5C) anion and half of a 4,4′-azobipyridine (Abpy) neutral ligand. In the coordination polyhedron, the ZnII ion adopts a distorted octahedral geometry. The coordination polymer is stabilized by a combination of N—H...O and C—H...π interactions, which leads to the formation of wave-like two-dimensional coordination polymeric layers.
Study on fire resistance of a prefabricated reinforced concrete frame structure
Authors: Li Shufeng , Jiaolei Zhang , Zhao Di , Deng Le
Published: May 2021

Purpose

This study aims to further study the fire resistance of prefabricated concrete beam-column joints with end-plate connection. This paper aims to analyze the fire resistance of this joint in prefabricated reinforced concrete frame structure (PRCS).

Design/methodology/approach

First, the accuracy of the model is verified by using the test data. Based on this, a refined finite element model of PRCS structure with two stories and two spans is established. The influence of four working conditions with different fire floors (positions) and different axial compression ratios on the deformation, failure and fire resistance of PRCS structure are analyzed.

Findings

The results show that under the four working conditions, the fire resistance of the PRCS structure under Condition 1 and Condition 2 is smaller. It shows that the beam deformation develops slowly in PRCS structure under four kinds of fire positions, and the large displacement emerges 60 min later, which is poles apart from that of prefabricated beam column members. With the increase of the fire time, the material is damaged and deteriorated, which leads to the eccentricity of the axial load, so that the column top appears large lateral displacement. Under the Conditions 1 and 3, the lateral displacement of the column gradually decreases as the axial compression ratio rises.

Originality/value

It is found that there is a distinct lack of researching on the fire resistance of prefabricated joints, and the existed research studies are limited to the fire resistance of members. Thus, it is necessary to strengthen the first floor and side column design of prefabricated frame structure.
The impacts of ambidextrous innovation on organizational obsolescence in turbulent environments
Authors: Chen Shuting , Yu Dengke
Published: May 2021

Purpose

The authors aim to measure the effects of ambidextrous innovation and its mix strategy on organizational obsolescence with the moderating roles of environmental turbulence.

Design/methodology/approach

Hierarchical regression analysis was used to test the hypotheses on the basis of the survey data of 198 firm employees in China.

Findings

Both exploratory and exploitative innovations significantly restrain organizational obsolescence. The complementary strategy of ambidextrous innovation is negatively correlated to organizational obsolescence, but the impact of balanced strategy is not significant. Environmental turbulence negatively moderates the relationship between exploratory innovation and organizational obsolescence, whereas it cannot moderate the effect of exploitative innovation.

Originality/value

The empirical and conceptual findings have important implications for organizations countering obsolescence through the construction of a mix strategy of ambidextrous innovation. This study enriches and extends obsolescence theory by introducing the joint mechanism of ambidextrous innovation and environmental turbulence.
Option informativeness before earnings announcements and under real activity manipulation
Authors: Gao Xiang , Gu Jiahao , Zhang Yingchao
Published: May 2021

Purpose

This paper aims to investigate whether single-name options trading prior to earnings announcements is more informative when there exist real activity manipulations.

Design/methodology/approach

Using 5,419 earnings announcements during 2004–2018 made by 208 public US companies with relatively high options volumes ranked by the CBOE, the authors uncover two regularities using predictive regressions for stock return.

Findings

First, the total options volume up to twenty days pre-announcement is significantly higher than that in other periods only for earnings management firms; moreover, after detailing options characteristics, the authors find these intensive pre-announcement trading to be concentrated in transactions of in-the-money call and long-term maturity put options. Second, an increase in the single-name call minus put options volume can positively predict the underlying stock’s next-day excess return much better in real earnings management firms, with a larger magnitude of effect in periods right before regular earnings announcement dates.

Originality/value

This paper makes a marginal and novel contribution by showing that real earnings management can serve as a proxy for the potential profit from informed trading in options as the return predictability of options volume becomes stronger for firms that have the manipulation motive and indeed perform manipulative actions.
Clinical analysis of generalized pustular psoriasis in Chinese patients: A retrospective study of 110 patients
Authors: Zheng Jianfeng , Chen Wenjuan , Gao Yunlu , Chen Fujuan , Yu Ning , Ding Yangfeng , Liu Na
Published: May 2021

Generalized pustular psoriasis is an immune‐mediated dermatologic condition characterized by widespread, sterile, subcorneal pustules. However, limited information exists regarding the clinical course of generalized pustular psoriasis. This study aimed to examine the precipitating factors, clinical manifestations, laboratory data, relapse patterns, and prognosis of generalized pustular psoriasis at our hospital and to improve the diagnosis and treatment. A retrospective analysis was conducted for generalized pustular psoriasis in our department from 2014 to 2019. In total, 110 patients were included in our study (mean age 46.5 years). The female:male ratio was 1:2.7. Ninety‐four (85.5%) had a psoriasis vulgaris history, 12 (10.9%) had a psoriatic arthritis history, five (4.5%) had an erythrodermic psoriasis history, and 16 (14.5%) had a family history of psoriasis. Eleven (10.0%) cases were triggered by infections and 17 (15.5%) were caused by the sudden discontinuation of systemic drugs. During hospitalization, the proportion of patients with hyperlipidemia was higher after acitretin treatment than before acitretin treatment (P < 0.05). The proportion of patients with abnormal liver function was higher after methotrexate treatment than before methotrexate treatment (P > 0.05). The onset age of generalized pustular psoriasis was younger in patients without prior psoriasis (P < 0.05). The mean time to pustular clearance was shorter in patients with prior psoriasis than in those without prior psoriasis (P > 0.05). Moreover, among patients with fever, skin lesion clearance rates were highest in the biological agent group (81.8%). However, among patients without fever, skin lesion clearance rates were highest in the acitretin group (86.7%). No patients presented serious complications or died. Our study presents the detailed clinical course of generalized pustular psoriasis in Chinese patients. These results will help to better understand and treat generalized pustular psoriasis.
Wider crown shyness between broad‐leaved tree species than between coniferous tree species in a mixed forest of Castanopsis cuspidata and Chamaecyparis obtusa
Authors: Onoda Yusuke , Bando Reo
Published: May 2021

Persistent openings (gaps) between adjacent crowns at similar heights can be found in tall forests. Such openings are called “crown shyness” and are formed through the collision of tree crowns during high winds. While crown shyness has been studied in plantations, much less studied in natural forests despite its importance for light acquisition, competition, and coexistence. In this study, we focused on a mixed forest in Japan, and examined a hypothesis that broad‐leaved tree species, which often have top‐wide crowns, have wider crown shyness than coniferous tree species, which often have narrow cone‐shape crowns, because top‐wide crowns may be more exposed to wind and more likely to collide with their neighbors. Crown shyness, which was measured by drone imagery, was clearly found between individuals of the broad‐leaved tree species Castanopsis cuspidata but not between the coniferous tree species Chamaecyparis obtusa. This interspecific difference may be associated with differences in crown shape; Castanopsis had wider (1.57‐fold) and shallower (0.64‐fold) crowns than Chamaecyparis. Within Castanopsis, the size of crown shyness tended to negatively correlated with stem diameter and positively correlated with stem slenderness. Our study showed that the difference in crown shape among species is one of the key factors in determining the size of crown shyness. Top‐wide crowns of broad‐leaved trees compared to conifers may have a competitive advantage in light interception, but it may come at the cost of crown collisions with adjacent crowns and resulting in persistent openings at the canopy layer.
White Suits and Kangaroo Kills: Making Men's Careers in American Nursing
Authors: Elder Rachel
Published: May 2021

This article explores nursing as an emerging career path for men in interwar America. As women reached historic concentrations within the profession, it examines how early gradutes of the Pennsylvania Hospital School of Nursing for Men created a distinct form of gendered professionalism that allowed them to enter an otherwise female‐dominated field. Drawing on school records and oral histories, it argues that men's training simultaneously integrated the feminised aspects of caring labour while upholding strict codes of masculinity that also excluded gay men and men of colour. In contrast to the few existing studies of men in traditionally female fields throughout the twentieth century, this case thus more closely resembles histories of women in male‐dominated professions, in which participants calibrated their presentations of gender to appease both gender and professional norms.
Using two‐holed needles for both arterial and venous accesses to the arteriovenous fistula to improve flow during hemodialysis
Authors: Yilmaz Ustun , Unal Aysun , Gul Semih , Demirtas Gulay , Inci Ayca , Sahinturk Yasin
Published: May 2021

This prospective study compared methods using both arterial and venous needles with back eyes with those using only arterial needle with back eye for arteriovenous fistula cannulation. Sixty‐one patients receiving hemodialysis (HD) via an arteriovenous fistula were evaluated. All patients underwent arteriovenous fistula puncture using only arterial needle with back eye in first 3 months and both arterial and venous needles with back eyes in following 3 months. Arterial and venous pressures, blood flow velocities, total blood volume cleared, and Kt/V values were compared. Mean blood flow velocity, arterial pressure, Kt/V, and cleared total blood volume values were higher and venous pressure was lower in patients who underwent cannulation using both needles with back eyes than in those with only the arterial needle with back eye. For arteriovenous fistula cannulation, using both arterial and venous needles with back eyes provides adequate HD more successfully.