bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of Culture Top transport systems for assessing the bacterial diversity of microbiota by culturomics as compared to a routine transport system
Authors: Cassir Nadim , Belkacemi Souad , Ballouche Mehdi , Khelaifia Saber , La Scola Bernard
Published: October 2021

In recent years, metagenomics and then culturomics, which consists of the multiplication of media and culture conditions and the rapid identification of all bacterial colonies, have generated renewed interest in the human microbiota, and diseases associated with modifications in its composition in particular. The sample transport media included in diverse swab transport systems and the storage conditions are among the factors that influence the results of the culturomics. In this study, we compared the results of culturomics from paired skin, oral and rectal swabs from intensive care unit (ICU) patients using Culture Top sample transport medium as compared to our routine one. From 152 clinical samples, we were able to isolate and identify 45 600 colonies, belonging to 338 different bacterial species. The transport system Culture Top identified 282 different bacterial species, while 244 were identified by our routine system. Of these, 188 different bacterial species were commonly identified using both transport systems, while 94 (27.8 %) and 56 (16.5 %) were only identified using Culture Top and our routine system, respectively (P<0.001), but there was no significant difference in bacterial diversity at the genus or phylum level, or in terms of their type of respiration and cell wall. In conclusion, the Culture Top transport system appears to be complementary to our routine system, although it seems slightly superior in terms of isolated bacterial species.
Carbapenem-resistant Klebsiella pneumoniae colonization and infection is associated with lower overall survival in a cohort of haematopoietic stem-cell transplantation patients: mechanism of resistance and virulence by whole-genome sequencing
Authors: Higashino Hermes Ryoiti , Marchi Ana Paula , Ruedas Martins Roberta Cristina , Bubach Carvalho Laina , Vieira Perdigão Neto Lauro , Farrel Côrtes Marina , Nivaldo de Oliveira Fernando , Tarsia Duarte Edson Luiz , Guimaraes Thais , Rossi Flavia , Ferreira Aliana M. , Rocha Vanderson , Costa Silvia Figueiredo
Published: October 2021

Carbapenem-resistant

Klebsiella pneumoniae

(CRK) infections are a growing concern in immunocompromised patients. The aim of the present study was to evaluate the impact of CRK colonization and infection in overall mortality for haematopoietic stem-cell transplant (HSCT) patients. We also aimed to investigate resistance and virulence profiles of CRK isolates and assess their epidemiological and genetic relatedness. Patients in the HSCT unit were screened for colonization with CRK with weekly rectal swab or stool cultures and placed under contact precautions. We defined CRK colonization as positive culture from a swab or stool sample grown in MacConkey agar with meropenem at 1 µg ml−1. Demographic and clinical data were retrieved from the patients’ charts and electronic records. According to resistance mechanisms and pulsed field gel electrophoresis profile, isolates were selected based on whole-genome sequencing (WGS) using MiSeq Illumina. Outcomes were defined as overall mortality (death up to D+100), and infection-related death (within 14 days of infection). We report a retrospective cohort of 569 haematopoietic stem-cell transplant patients with 105 (18.4 %) CRK colonizations and 30 (5.3 %) infections. blaKPC was the most frequent carbapenemase in our cohort with three isolates co-harbouring blaKPC and blaNDM. We found no difference in virulence profiles from the CRK isolates. There were also no significant differences in virulence profiles among colonization and infection isolates regarding genes encoding for type 1 and 3 fimbriae, siderophores, lipopolysaccharide and colibactin. In clonality analysis by PFGE and WGS, isolates were polyclonal and ST340 was the most prevalent. Overall survival at D+100 was 75.4 % in in CRK-colonized (P=0.02) and 35.7 % in infected patients and significantly lower than non-colonized patients (85.8 %; P<0.001). We found a higher overall mortality associated with colonization and infection; KPC was the main resistance mechanism for carbapenems. The polyclonal distribution of isolates and findings of CRK infection in patients not previously colonized suggest the need to reinforce antibiotic stewardship.
Emergence of novel strains of Shigella flexneri associated with sexual transmission in adult men in England, 2019–2020
Authors: Dallman Timothy J , Charles Hannah , Prochazka Mateo , Sinka Katy , Hughes Gwenda , Godbole Gauri , Jenkins Claire
Published: October 2021

National surveillance of shigellosis in England revealed an increase in sexually transmitted

Shigella flexneri

in adult males in 2019 that persisted throughout 2020. We observed a resurgence of azithromycin-resistant

S. flexneri

serotype 3a, and the emergence of two novel multidrug-resistant clades of

S. flexneri

2a and

S. flexneri

1b.
Reward Dysfunction in General and Specific Psychopathology in Children and Adults
Authors: Saxena Ankita , Hartman Catharina A. , Blatt Steven D. , Fremont Wanda P. , Glatt Stephen J. , Faraone Stephen V. , Zhang-James Yanli
Published: October 2021

Background

Reward dysfunction has been implicated in many psychiatric disorders such as attention-deficit/hyperactivity disorders, depression, and substance use disorders. However, psychiatric comorbidities are common, and the specificity of reward dysfunction to individual psychopathologies is unknown. The objective of this study was to evaluate the association between reward functioning and specific or general psychopathologies.

Methods

1044 adults and their 1215 children (ages 6-12) completed various measures of the Positive Valence System domain from the Research Domain Criteria (RDoC), which included the Delayed and Probability Discounting Tasks, Energy Expenditure for Reward Task, and Iowa Gambling Task. Children also completed the Experienced Pleasure Scale for children, while adults completed the Temporal Experience of Pleasure Scale and the Behavioral Activation System tasks. Psychopathology was assessed using the Child Behavior Checklist (CBCL) for children and the Adult Self Report (ASR) for parents.

Results

One general factor identified via principal factors factor analysis explained the majority of variance in psychopathology in both groups. Reward measures in both adults and children were significantly associated with general psychopathology as well as most specific psychopathologies. Some associations between reward and psychopathology did not hold following removal of general psychopathology; nonetheless, certain reward constructs were uniquely associated with specific disorder problems but not general psychopathology.

Conclusion

Disorder problem specific associations with reward functioning can be identified after removal of comorbidity. General propensity toward psychopathology is significantly but not uniquely correlated with reward dysfunction. Altogether, this may have broader implications for future study of the role of reward in disease pathogenesis.
Combining Tumor Segmentation Masks with PET/CT Images and Clinical Data in a Deep Learning Framework for Improved Prognostic Prediction in Head and Neck Squamous Cell Carcinoma
Authors: Wahid Kareem A. , He Renjie , Dede Cem , Mohamed Abdallah , Abdelaal Moamen Abobakr , van Dijk Lisanne V. , Fuller Clifton D. , Naser Mohamed A.
Published: October 2021

PET/CT images provide a rich data source for clinical prediction models in head and neck squamous cell carcinoma (HNSCC). Deep learning models often use images in an end-to-end fashion with clinical data or no additional input for predictions. However, in the context of HNSCC, the tumor region of interest may be an informative prior in the generation of improved prediction performance. In this study, we utilize a deep learning framework based on a DenseNet architecture to combine PET images, CT images, primary tumor segmentation masks, and clinical data as separate channels to predict progression-free survival (PFS) in days for HNSCC patients. Through internal validation (10-fold cross-validation) based on a large set of training data provided by the 2021 HECKTOR Challenge, we achieve a mean C-index of 0.855 ± 0.060 and 0.650 ± 0.074 when observed events are and are not included in the C-index calculation, respectively. Ensemble approaches applied to cross-validation folds yield C-index values up to 0.698 in the independent test set (external validation). Importantly, the value of the added segmentation mask is underscored in both internal and external validation by an improvement of the C-index when compared to models that do not utilize the segmentation mask. These promising results highlight the utility of including segmentation masks as additional input channels in deep learning pipelines for clinical outcome prediction in HNSCC.
Psychometric Properties of the ASEBA Child Behaviour Checklist and Youth Self-Report in Sub-Saharan Africa: A Systematic Review
Authors: Zieff Michal R. , Fourie Claire , Hoogenhout Michelle , Donald Kirsten A.
Published: October 2021

Objective

Behavioural screening tools may be used to identify at-risk children in resource-limited settings in sub-Saharan Africa. The ASEBA forms (Child Behaviour Checklist and Youth Self-Report) are frequently translated and adapted for use in sub-Saharan African populations, but little is known about their measurement properties in these contexts.

Methods

We conducted a systematic review of all published journal articles that used the ASEBA forms with sub-Saharan African samples. We evaluated the reported psychometric properties, as well as the methodological quality of the psychometric evaluations, using COSMIN (COnsensus-based Standards for the selection of health Measurement INstruments) guidelines.

Results

Fifty-eight studies reported measurement properties of the ASEBA forms. Most studies came from Southern (n = 29, 50%) or East African (n = 25, 43%) countries. Forty-nine studies (84%) used translated versions of the tool, but details regarding the translation process, if available, were often sparse. Most studies (n = 47, 81%) only reported internal consistency (using coefficient alpha) for one or more subscales. The methodological quality of the psychometric evaluations ranged from ‘very good’ to ‘inadequate’ across all measurement properties, except for internal consistency.

Conclusion

There is limited good quality psychometric evidence available for the ASEBA forms in sub-Saharan Africa. We recommend (i) implementing a standardised procedure for conducting and reporting translation processes, and (ii) conducting more comprehensive psychometric evaluations of the translated versions of the tools.
Factors affecting use of speech testing in adult audiology
Authors: Parmar Bhavisha J , Rajasingam Saima L , Bizley Jennifer K , Vickers Deborah A
Published: October 2021

Objective

To investigate the factors affecting the use speech testing in adult audiology services

Design

A mixed-methods cross-sectional questionnaire study

Study Sample

A UK sample (n=306) of hearing healthcare professionals (HHPs) from the public (64%) and private sector (36%) completed the survey

Results

In the UK, speech testing practice varied significantly between health sector. Speech testing was carried out during the audiology assessment by 68% of private sector HHPs and 5% of those from the public sector. During the hearing aid intervention stage speech testing was carried out by 40% and 8% of HHPs from the private and public sector, respectively. Recognised benefits of speech testing included: 1) providing patients with relatable assessment information, 2) guiding hearing aid fitting, 3) supporting a diagnostic test battery. A lack of clinical time was a key barrier to uptake.

Conclusion

Use of speech testing varies in adult audiology. Results from the present study found the percentage of UK HHPs making use of speech tests was low compared to other countries. HHPs recognised different benefits of speech testing in audiology practice but the barriers limiting uptake were often driven by factors derived from decision makers rather than clinical rationale. Privately funded HHPs used speech tests more frequently than those working in the public sector where time and resources are under greater pressure and governed by guidance that does not include a recommendation for speech testing. Therefore, the inclusion of speech testing in national clinical guidelines could increase the consistency of use.
Mitoxantrone modulates a glycosaminoglycan-spike complex to inhibit SARS-CoV-2 infection
Authors: Zhang Qi , Radvak Peter , Lee Juhyung , Xu Yue , Cao-Dao Vivian , Xu Miao , Zheng Wei , Chen Catherine Z. , Xie Hang , Ye Yihong
Published: October 2021

Spike-mediated entry of SARS-CoV-2 into human airway epithelial cells is an attractive therapeutic target for COVID-19. In addition to protein receptors, the SARS-CoV-2 spike (S) protein also interacts with heparan sulfate, a negatively charged glycosaminoglycan (GAG) attached to certain membrane proteins on the cell surface. This interaction facilitates the engagement of spike with a downstream receptor to promote viral entry. Here, we show that Mitoxantrone, an FDA-approved topoisomerase inhibitor, targets a spike-GAG complex to compromise the fusogenic function of spike in viral entry. As a single agent, Mitoxantrone inhibits the infection of an authentic SARS-CoV-2 strain in a cell-based model and in human lung EpiAirway 3D tissues. Gene expression profiling supports the plasma membrane as a major target of Mitoxantrone but also underscores an undesired activity targeting nucleosome dynamics. We propose that Mitoxantrone analogs bearing similar GAG-binding activities but with reduced affinity for DNA topoisomerase may offer an alternative therapy to overcome breakthrough infections in the post-vaccine era.
Boosting of SARS-CoV-2 immunity in nonhuman primates using an oral rhabdoviral vaccine
Authors: Peng Kah-Whye , Carey Timothy , Lech Patrycja , Vandergaast Rianna , Muñoz-Alía Miguel Á. , Packiriswamy Nandakumar , Gnanadurai Clement , Krotova Karina , Tesfay Mulu , Ziegler Christopher , Haselton Michelle , Sevola Kara , Lathrum Chase , Reiter Samantha , Narjari Riya , Balakrishnan Baskar , Suksanpaisan Lukkana , Sakuma Toshie , Recker Jordan , Zhang Lianwen , Waniger Scott , Russell Luke , Petro Christopher D. , Kyratsous Christos A. , Baum Alina , Janecek Jody L. , Lee Rachael M. , Ramachandran Sabarinathan , Graham Melanie L. , Russell Stephen J.
Published: October 2021

An orally active vaccine capable of boosting SARS-CoV-2 immune responses in previously infected or vaccinated individuals would help efforts to achieve and sustain herd immunity. Unlike mRNA-loaded lipid nanoparticles and recombinant replication-defective adenoviruses, replicating vesicular stomatitis viruses with SARS-CoV-2 spike glycoproteins (VSV-SARS2) were poorly immunogenic after intramuscular administration in clinical trials. Here, by G protein trans-complementation, we generated VSV-SARS2(+G) virions with expanded target cell tropism. Compared to parental VSV-SARS2, G-supplemented viruses were orally active in virus-naive and vaccine-primed cynomolgus macaques, powerfully boosting SARS-CoV-2 neutralizing antibody titers. Clinical testing of this oral VSV-SARS2(+G) vaccine is planned.
A method for quantifyingPhytophthoraoospore viability using fluorescent dyes and automated image analysis
Authors: Fairhurst Michael J. , Vink Jochem N.A. , Deslippe Julie R. , Gerth Monica L.
Published: October 2021

Phytophthoraare eukaryotic microbes that cause disease in a wide range of agriculturally and ecologically important plants. During thePhytophthoradisease cycle, thick-walled oospores can be produced via sexual reproduction. These resting spores can survive in the soil for several years in the absence of a host plant, thus providing a long-term inoculum for disease. The ability to quantitatively evaluate oospore viability is an important part of many phytopathology studies. Here, we tested six fluorescent viability dyes for their ability to differentially stainPhytophthora agathidicidaoospores: SYTO 9, FUN-1, fluorescein diacetate (FDA), 5-carboxyfluorescein diacetate (CFDA), propidium iodide, and TOTO-3 iodide. Each dye was first tested individually with untreated or heat-treated oospores as proxies for viable and non-viable oospores, respectively. SYTO9, FUN-1, CFDA and propidium iodide stained untreated and heat-treated oospores indiscriminately. In contrast, FDA (a green-fluorescent viable cell stain) and TOTO-3 (a red-fluorescent non-viable cell stain) differentially stained untreated or heat-treated oospores with no cross-fluorescence. We then tested the efficacy of dual viability staining and in conjunction with a pipeline for automated image analysis. To validate the method, untreated and heat-treated oospores were mixed at specific ratios, dual-stained, and analyzed using the pipeline. Linear regression of the resulting data showed a clear correlation between the expected and measured oospore ratios (dy/dx=0.95,R2=0.88). Overall, the combination of dual-fluorescence staining and automated image analysis provides a high-throughput method for quantitatively assessing oospore viability and therefore can facilitate further studies on this key part of thePhytophthoradisease cycle.
Aerosolization of Mycobacterium tuberculosis by tidal breathing
Authors: Dinkele Ryan , Gessner Sophia , McKerry Andrea , Leonard Bryan , Leukes Juane , Seldon Ronnett , Warner Digby F. , Wood Robin
Published: October 2021

Rationale

Interrupting tuberculosis (TB) transmission requires an improved understanding of how – and when – the causative organism, Mycobacterium tuberculosis (Mtb), is aerosolized. Although Cough is commonly assumed to be the dominant source of Mtb aerosols, recent evidence of Cough-independent Mtb release implies the contribution of alternative mechanisms.

Objective

To compare the aerosolization of Mtb and particulate matter from GeneXpert-positive patients during three separate respiratory manoeuvres: Tidal Breathing (TiBr), Forced Vital Capacity (FVC), and Cough.

Methodology

Bioaerosol sampling and Mtb detection were combined with real-time assessments of CO2 production and particle counts from 39 confirmed TB patients.

Measurements and Main Results

TiBr and FVC produced comparable numbers of particles, with Cough producing >4-fold more. For all manoeuvres, the proportions of particles detected across size categories from 0.5 – 5 μm were similar, with minor differences observed only in particles between 1.5 – 2 μm (p = 0.014) and >5 μm (p = 0.020). Viable Mtb bacilli were detected in 66%, 70%, and 65% of TiBr, FVC, and Cough samples, respectively. Notably, while Cough produced 3-fold more Mtb than TiBr, the relative infrequency of coughing compared to breathing implies that TiBr likely contributes >90% of the daily aerosolised Mtb across a range of Cough frequencies.

Conclusions

Our results suggest that, while Cough increases particle aerosolization compared to TiBr, this is not associated with increased Mtb aerosolization. Instead, TiBr produces more Mtb per particle than Cough. Assuming the number of viable Mtb organisms detected provides a proxy measure of patient infectiousness, these observations imply a significant contribution of TiBr to TB transmission.
Alone Again: Altered Activation in the Observation Execution System during Synchronization in High Loneliness Individuals
Authors: Saporta Nira , Scheele Dirk , Lieberz Jana , Nevat Michael , Kanterman Alisa , Hurlemann René , Shamay-Tsoory Simone G.
Published: October 2021

1

Abstract

Lonely people evaluate social exchanges negatively and display difficulties in interactions. Interpersonal synchronization is crucial for achieving positive interactions, promoting affinity, closeness, and satisfaction. However, little is known about lonely individuals’ ability to synchronize and about their brain activity while synchronizing. Following the screening of 303 participants we recruited 32 low and 32 high loneliness participants. They were scanned while engaged in movement synchronization, using a novel dyadic interaction paradigm. Results showed that high loneliness individuals exhibited a reduced ability to adapt their movement to their partner’s movement. Intriguingly, during movement adaptation periods, high loneliness individuals showed increased activation in the observation-execution (OE) system, specifically in the inferior frontal gyrus and the inferior parietal lobule. They did not show increased activation in the dorsomedial prefrontal cortex, which in the context of synchronization was suggested to be related to gap-monitoring. Based on these findings, we propose a model according to which lonely people may require stronger activation of their OE system for alignment, to compensate for some deficiency in their synchronization ability. Despite this hyper-activation, they still suffer from reduced synchronization capacity. Consequently, synchronization may be a relevant intervention area for the amelioration of chronic loneliness.
Strip1 regulates retinal ganglion cell survival by suppressing Jun-mediated apoptosis to promote retinal neural circuit formation
Authors: Ahmed Mai , Kojima Yutaka , Masai Ichiro
Published: October 2021

In the vertebrate retina, an interplay between retinal ganglion cells (RGCs), amacrine, and bipolar cells establishes a synaptic layer called the inner plexiform layer (IPL). This circuit conveys signals from photoreceptors to visual centers in the brain. However, the molecular mechanisms involved in its development remain poorly understood. Striatin-interacting protein 1 (Strip1) is a core component of the STRIPAK complex, and it has shown emerging roles in embryonic morphogenesis. Here, we uncover the importance of Strip1 in inner retina development. Using zebrafish, we show that loss of Strip1 causes defects in IPL formation. Instrip1mutants, RGCs undergo dramatic cell death shortly after birth. Amacrine and bipolar cells subsequently invade the degenerating RGC layer, leading to a disorganized IPL. Mechanistically, zebrafish Strip1 interacts with its STRIPAK partner, Striatin3, and both show overlapping functions in RGC survival. Furthermore, loss of Strip1 or Striatin 3, leads to activation of the pro-apoptotic marker, Jun, within RGCs, and Jun knockdown rescues RGC survival instrip1mutants. In addition to its function in RGC maintenance, Strip1 is required for RGC dendritic patterning, which likely contributes to proper IPL formation. Taken together, we propose that a series of Strip1-mediated regulatory events coordinates inner retinal circuit formation by maintaining RGCs during development, which ensures proper positioning and neurite patterning of inner retinal neurons.
Bees can be trained to identify SARS-CoV-2 infected samples
Authors: Kontos Evangelos , Samimi Aria , Hakze-van der Honing Renate W. , Priem Jan , Avarguès-Weber Aurore , Haverkamp Alexander , Dicke Marcel , Gonzales Jose L , van der Poel Wim H.M.
Published: October 2021

The COVID-19 pandemic has illustrated the need for the development of fast and reliable testing methods for novel, zoonotic, viral diseases in both humans and animals. Pathologies lead to detectable changes in the Volatile Organic Compound (VOC) profile of animals, which can be monitored, thus allowing the development of a rapid VOC-based test. In the current study, we successfully trained honeybees (Apis mellifera) to identify SARS-CoV-2 infected minks (Neovison vison) thanks to Pavlovian conditioning protocols. The bees can be quickly conditioned to respond specifically to infected mink’s odours and could therefore be part of a wider SARS-CoV-2 diagnostic system. We tested two different training protocols to evaluate their performance in terms of learning rate, accuracy and memory retention. We designed a non-invasive rapid test in which multiple bees are tested in parallel on the same samples. This provided reliable results regarding a subject’s health status. Using the data from the training experiments, we simulated a diagnostic evaluation trial to predict the potential efficacy of our diagnostic test, which yielded a diagnostic sensitivity of 92% and specificity of 86%. We suggest that a honeybee-based diagnostics can offer a reliable and rapid test that provides a readily available, low-input addition to the currently available testing methods. A honeybee-based diagnostic test might be particularly relevant for remote and developing communities that lack the resources and infrastructure required for mainstream testing methods.
Quantifying full-length circular RNAs in cancer
Authors: Yu Ken Hung-On , Shi Christina Huan , Wang Bo , Chow Savio Ho-Chit , Chung Grace Tin-Yun , Lung Raymond Wai-Ming , Tan Ke-En , Lim Yat-Yuen , Tsang Anna Chi-Man , Lo Kwok-Wai , Yip Kevin Y.
Published: October 2021

Circular RNAs (circRNAs) are abundantly expressed in cancer. Their resistance to exonucleases enables them to have potentially stable interactions with different types of biomolecules. Alternative splicing can create different circRNA isoforms that have different sequences and unequal interaction potentials. The study of circRNA function thus requires knowledge of complete circRNA sequences. Here we describe psirc, a method that can identify full-length circRNA isoforms and quantify their expression levels from RNA sequencing data. We confirm the effectiveness and computational efficiency of psirc using both simulated and actual experimental data. Applying psirc on transcriptome profiles from nasopharyngeal carcinoma and normal nasopharynx samples, we discover and validate circRNA isoforms differentially expressed between the two groups. Compared with the assumed circular isoforms derived from linear transcript annotations, some of the alternatively spliced circular isoforms have 100 times higher expression and contain substantially fewer microRNA response elements, showing the importance of quantifying full-length circRNA isoforms.
Cellular abundance shapes function in piRNA-guided genome defense
Authors: Genzor Pavol , Konstantinidou Parthena , Stoyko Daniel , Manzourolajdad Amirhossein , Marlin Andrews Celine , Elchert Alexandra R. , Stathopoulos Constantinos , Haase Astrid D.
Published: October 2021

Defense against genome invaders universally relies on RNA-guided immunity. Prokaryotic CRISPR-Cas and eukaryotic RNA interference pathways recognize targets by complementary base-pairing, which places the sequences of their guide RNAs at the center of self/nonself discrimination. Here, we explore the sequence space of PIWI-interacting RNAs (piRNAs), the genome defense of animals, and establish functional priority among individual sequences. Our results reveal that only the topmost abundant piRNAs are commonly present in every cell, whereas rare sequences generate cell-to-cell diversity in flies and mice. We identify a skewed distribution of sequence abundance as a hallmark of piRNA populations and show that quantitative differences of more than a 1000-fold are established by conserved mechanisms of biogenesis. Finally, our genomics analyses and direct reporter assays reveal that abundance determines function in piRNA-guided genome defense. Taken together, we identify an effective sequence space and untangle two classes of piRNAs that differ in complexity and function. The first class represents the topmost abundant sequences and drives silencing of genomic parasites. The second class sparsely covers an enormous sequence space. These rare piRNAs cannot function in every cell, every individual, or every generation but create diversity with potential for adaptation in the ongoing arms race with genome invaders.
Global quantification exposes abundant low-level off-target activity by base editors
Authors: Buchumenski Ilana , Roth Shalom Hillel , Kopel Eli , Katsman Efrat , Feiglin Ariel , Levanon Erez Y. , Eisenberg Eli
Published: October 2021

Base editors are dedicated engineered deaminases that enable directed conversion of specific bases in the genome or transcriptome in a precise and efficient manner, and hold promise for correcting pathogenic mutations. A major concern limiting application of this powerful approach is the issue of off-target edits. Several recent studies have shown substantial off-target RNA activity induced by base editors and demonstrated that off-target mutations may be suppressed by improved deaminases versions or optimized guide RNAs. Here, we describe a new class of off-target events that are invisible to the established methods for detection of genomic variations and were thus far overlooked. We show that nonspecific, seemingly stochastic, off-target events affect a large number of sites throughout the genome or the transcriptome, and account for the majority of off-target activity. We develop and employ a different, complementary approach that is sensitive to the stochastic off-target activity and use it to quantify the abundant off-target RNA mutations due to current, optimized deaminase editors. We provide a computational tool to quantify global off-target activity, which can be used to optimize future base editors. Engineered base editors enable directed manipulation of the genome or transcriptome at single-base resolution. We believe that implementation of this computational approach would facilitate design of more specific base editors.
Distributed learning episodes create a context fear memory outside the hippocampus that depends on perirhinal and anterior cingulate cortices
Authors: Shepherd Elizabeth H. , Fournier Neil M. , Sutherland Robert J. , Lehmann Hugo
Published: October 2021

Damage to the hippocampus (HPC) typically causes retrograde amnesia for contextual fear conditioning. Repeating the conditioning over several sessions, however, can eliminate the retrograde amnesic effects. This form of reinstatement thus permits modifications to networks that can support context memory retrieval in the absence of the HPC. The present study aims to identify cortical regions that support the nonHPC context memory. Specifically, the contribution of the perirhinal cortex (PRH) and the anterior cingulate cortex (ACC) were examined because of their established importance to context memory. The findings show that context memories established through distributed reinstatement survive damage limited only to the HPC, PRH, or ACC. Combined lesions of the HPC and PRH, as well as the HPC and ACC, caused retrograde amnesia, suggesting that network modifications in the PRH and ACC enable context fear memories to become resistant to HPC damage.
James March: a postmodern perspective on organization without management theory
Authors: Lambert Gilles
Published: October 2021

Purpose

In this paper, the authors look back at James March’s main contributions to the evolution of organizations and their decision-making. No other author in management science has been quoted as much. Yet, his view on these issues is often far removed from the dominant academic representations. This paper aims to evaluate the trace left by March for the future. His teachings remain of the utmost importance for both practitioners and academics in charge of modeling the real functioning of the organizations.

Design/methodology/approach

In this paper, the authors look back at James March’s main contributions to the evolution of organizations and their decision-making.

Findings

On the basis of an in-depth analysis of his study, the authors discuss the main concepts to which he has dedicated his life as a researcher. Whether it is for innovation and the process of exploration associated with it or for the ambiguity that persists in learning cycles, March always shows us the ambivalence of the concepts. The strength of March’s study is to encourage us to remain cautious in the diagnoses for the development of the companies by not venerating too strongly the notions seen exclusively as virtuous, such as innovation or by not too quickly condemning situations perceived as harmful, such as ambiguity. It is, therefore, subjective and unpredictable, making the idea of a unified theory of management inoperative (Joullié, 2018). March’s way of thinking is deeply postmodern in the sense of Foucault (1961), who saw the world as a representation.

Research limitations/implications

For this kind of paper based on a James March study’s survey, the main limitation is the variety of research methodology mobilized. Empirical confirmation sometimes is missing or is too short. The study remains essentially speculative as to its influence on future research. Some concepts, such as the concept of effectuation, which is a direct extension of March’s study, deserve to be tested empirically and theoretically in greater depth to assess their robustness.

Practical implications

All managerial implications are concerned with organizational change. His teachings remain of the utmost importance for both practitioners and academics in charge of modeling the real functioning of the organizations.

Social implications

Providing a guideline concerning research in the management of organizations. A better understanding of the real functioning of how decisions happen in companies, how they change in the real world.

Originality/value

The authors show that, contrary to the great paradigms of management sciences (Burrell and Morgan, 1979) developed since Taylor’s founding study, which remains performative in essence, March’s study initiates a viscerally postmodern vision of the organization. The authors believe that his contributions are essential because they are not based on a normative attempt to propose a universal theory but provide a compass that is essential to understanding how the organization study.
Do sponsors and democratic government influence the flipping activity of Pakistan IPO? Evidence from developing market
Authors: Anwar Ayesha , Mohd-Rashid Rasidah , Che Yahya Norliza , Ong Chui Zi
Published: October 2021

Purpose

This study aims to examine the impact of sponsors and democratic government on the flipping activity of initial public offerings (IPOs).

Design/methodology/approach

Based on the sample of 95 IPOs listed on the Pakistan Stock Exchange between January 2000 and December 2019, this study used multiple cross-sectional regression to examine the relationship between sponsors and democratic government on flipping activity.

Findings

The findings indicate a significant negative association between sponsors and the flipping activity of IPOs. Sponsor(s) signal quality by trying to share accurate information about company values. As a result, the confidence of rational investors in the company’s future prospectus increases and they hold their shares for future gains, which reduces the flipping activity. Also, democratic government, along with sponsors' participation, provides investors with liquidity immediately after listing.

Practical limitations/implications

The findings of this study have implications for investors as they may assist them make informed decisions about whether or not to invest in an IPO with high sponsor(s) ownership. In addition, issuers should consider the disclosure of sponsor information(s) as such information may directly affect the first day’s trading volumes.

Originality/value

To the best of the authors’ knowledge, this is the first research study that explores the correlation between sponsors and democratic government and flipping activity of IPO. This study is important for investors and issuers.
A guide to pre‐processing high‐throughput animal tracking data
Authors: Gupte Pratik Rajan , Beardsworth Christine E. , Spiegel Orr , Lourie Emmanuel , Toledo Sivan , Nathan Ran , Bijleveld Allert I.
Published: October 2021

Modern, high‐throughput animal tracking increasingly yields ‘big data’ at very fine temporal scales. At these scales, location error can exceed the animal's step size, leading to mis‐estimation of behaviours inferred from movement. ‘Cleaning’ the data to reduce location errors is one of the main ways to deal with position uncertainty. Although data cleaning is widely recommended, inclusive, uniform guidance on this crucial step, and on how to organise the cleaning of massive datasets, is relatively scarce.

A pipeline for cleaning massive high‐throughput datasets must balance ease of use and computationally efficiency, in which location errors are rejected while preserving valid animal movements. Another useful feature of a pre‐processing pipeline is efficiently segmenting and clustering location data for statistical methods while also being scalable to large datasets and robust to imperfect sampling. Manual methods being prohibitively time‐consuming, and to boost reproducibility, pre‐processing pipelines must be automated.

We provide guidance on building pipelines for pre‐processing high‐throughput animal tracking data to prepare it for subsequent analyses. We apply our proposed pipeline to simulated movement data with location errors, and also show how large volumes of cleaned data can be transformed into biologically meaningful ‘residence patches’, for exploratory inference on animal space use. We use tracking data from the Wadden Sea ATLAS system (WATLAS) to show how pre‐processing improves its quality, and to verify the usefulness of the residence patch method. Finally, with tracks from Egyptian fruit bats Rousettus aegyptiacus, we demonstrate the pre‐processing pipeline and residence patch method in a fully worked out example.

To help with fast implementation of standardised methods, we developed the R package atlastools, which we also introduce here. Our pre‐processing pipeline and atlastools can be used with any high‐throughput animal movement data in which the high data‐volume combined with knowledge of the tracked individuals' movement capacity can be used to reduce location errors. atlastools is easy to use for beginners while providing a template for further development. The common use of simple yet robust pre‐processing steps promotes standardised methods in the field of movement ecology and leads to better inferences from data.
Species interactions, environmental gradients and body size shape population niche width
Authors: Eloranta Antti P. , Finstad Anders G. , Sandlund Odd Terje , Knudsen Rune , Kuparinen Anna , Amundsen Per‐Arne
Published: October 2021

Competition for shared resources is commonly assumed to restrict population‐level niche width of coexisting species. However, the identity and abundance of coexisting species, the prevailing environmental conditions, and the individual body size may shape the effects of interspecific interactions on species’ niche width.

Here we study the effects of interspecific and intraspecific interactions, lake area and altitude, and fish body size on the trophic niche width and resource use of a generalist predator, the littoral‐dwelling large, sparsely rakered morph of European whitefish (Coregonus lavaretus; hereafter LSR whitefish). We use stable isotope, diet and survey fishing data from 14 subarctic lakes along an environmental gradient in northern Norway.

The isotopic niche width of LSR whitefish showed a humped‐shaped relationship with increasing relative abundance of sympatric competitors, suggesting widest population niche at intermediate intensity of interspecific interactions. The isotopic niche width of LSR whitefish tended to decrease with increasing altitude, suggesting reduced niche in colder, less productive lakes.

LSR whitefish typically shifted to a higher trophic position and increased reliance on littoral food resources with increasing body size, although between‐lake differences in ontogenetic niche shifts were evident. In most lakes, LSR whitefish relied less on littoral food resources than coexisting fishes and the niche overlap between sympatric competitors was most evident among relatively large individuals (>250 mm). Individual niche variation was highest among >200 mm long LSR whitefish, which likely have escaped the predation window of sympatric predators.

We demonstrate that intermediate intensity of interspecific interactions may broaden species’ niche width, whereas strong competition for limited resources and high predation risk may suppress niche width in less productive environments. Acknowledging potential humped‐shaped relationships between population niche width and interspecific interactions can help us understand species’ responses to environmental disturbance (e.g. climate change and species invasions) as well as the driving forces of niche specialization.
How wild bees find a way in European cities: Pollen metabarcoding unravels multiple feeding strategies and their effects on distribution patterns in four wild bee species
Authors: Casanelles‐Abella Joan , Müller Stefanie , Keller Alexander , Aleixo Cristiana , Alós Orti Marta , Chiron François , Deguines Nicolas , Hallikma Tiit , Laanisto Lauri , Pinho Pedro , Samson Roeland , Tryjanowski Piotr , Van Mensel Anskje , Pellissier Loïc , Moretti Marco
Published: October 2021

Urban ecosystems can sustain populations of wild bees, partly because of their rich native and exotic floral resources. A better understanding of the urban bee diet, particularly at the larval stage, is necessary to understand biotic interactions and feeding behaviour in urban ecosystems, and to promote bees by improving the management of urban floral resources.

We investigated the larval diet and distribution patterns of four solitary wild bee species with different diet specialization (i.e. Chelostoma florisomne, Osmia bicornis, Osmia cornuta and Hylaeus communis) along urban intensity gradients in five European cities (Antwerp, Paris, Poznan, Tartu and Zurich) using two complementary analyses. Specifically, using trap‐nests and pollen metabarcoding techniques, we characterized the species' larval diet, assessed diet consistency across cities and modelled the distribution of wild bees using species distribution models (SDMs).

Our results demonstrate that urban wild bees display different successful strategies to exploit existing urban floral resources: not only broad generalism (i.e. H. communis) but also intermediate generalism, with some degree of diet conservatism at the plant family or genus level (i.e. O. cornuta and O. bicornis), or even strict specialization on widely available urban pollen hosts (i.e. C. florisomne). Furthermore, we detected important diet variation in H. communis, with a switch from an herbaceous pollen diet to a tree pollen diet with increasing urban intensity.

Species distribution modelling indicated that wild bee distribution ranges inside urban ecosystems ultimately depend on their degree of specialization, and that broader diets result in less sensitivity to urban intensity.

Policy implications. Satisfying larval dietary requirements is critical to preserving and enhancing wild bee distributions within urban gradients. For high to intermediate levels of feeding specialization, we found considerable consistency in the preferred plant families or genera across the studied cities, which could be generalized to other cities where these bees occur. Identifying larval floral preferences (e.g. using pollen metabarcoding) could be helpful for identifying key plant taxa and traits for bee survival and for improving strategies to develop bee‐friendly cities.
Patient characteristics and treatment utilization in fatal stimulant‐involved overdoses in the United States Veterans Health Administration
Authors: Coughlin Lara N. , Zhang Lan , Bohnert Amy S. B. , Maust Donovan T. , Goldstick Jason , Lin Lewei ( Allison)
Published: October 2021

Background and Aims

This study aimed to (1) describe trends in stimulant‐alone and stimulant and other substance use overdose deaths from 2012 to 2018 and (2) measure patient and service use characteristics across stimulant‐related overdose death profiles.

Design

Retrospective cohort study of patients who died from stimulant‐involved overdose between annual years 2012 and 2018.

Setting

United States Veterans Health Administration (VHA).

A total of 3631 patients died from stimulant‐involved overdose, as identified through the National Death Index.

Measurements

Stimulant‐involved overdose deaths were categorized by stimulant type (cocaine or methamphetamine/other) and other substance co‐involvement. Cause of death data were linked to patient characteristics, including demographic and treatment use preceding overdose from VHA administrative data. We examined trends over time and compared treatment use factors between the following mutually exclusive overdose profiles: cocaine alone, methamphetamine alone, cocaine + opioid, methamphetamine + opioid, any stimulant + other substance and cocaine + methamphetamine.

Findings

The rate of overdose death was 3.06 times higher in 2018 than 2012, with increases across all toxicology profiles. Compared with cocaine‐involved overdoses, methamphetamine‐involved overdoses were less likely in people who were older [adjusted odds ratio (aOR) = 0.22, 95% confidence interval (CI) = 0.06–0.87 aged 65+ versus 18–29] and more likely among those who lived in rural areas (aOR = 2.73, 95% CI = 1.43–5.23). People who died from stimulant + opioid overdoses had lower odds of a stimulant use disorder diagnosis compared with stimulant alone deaths (cocaine: aOR = 0.55, 95% CI = 0.41–0.75, methamphetamine: aOR = 0.44, 95% CI = 0.29–0.68).

Conclusions

The rate of deaths among US Veterans from stimulant‐related overdose was three times higher in 2018 than 2012. Key differences in characteristics of patients across overdose toxicology profiles, such as geographic location and health‐care use, point to distinct treatment needs based on stimulant use type.
CD103 integrin identifies a high IL‐10‐producing FoxP3+regulatory T‐cell population suppressing allergic airway inflammation
Authors: Tagkareli Sofia , Salagianni Maria , Galani Ioanna‐Evdokia , Manioudaki Maria , Pavlos Eleftherios , Thanopoulou Kalliopi , Andreakos Evangelos
Published: October 2021

Background

Although FoxP3+regulatory T (Treg) cells constitute a highly heterogeneous population, with different regulatory potential depending on the disease context, distinct subsets or phenotypes remain poorly defined. This hampers the development of immunotherapy for allergic and autoimmune disorders. The present study aimed at characterizing distinct FoxP3+Treg subpopulations involved in the suppression of Th2‐mediated allergic inflammation in the lung.

Methods

We used an established mouse model of allergic airway disease based on ovalbumin sensitization and challenge to analyze FoxP3+Tregs during the induction and resolution of inflammation, and identify markers that distinguish their most suppressive phenotypes. We also developed a new knock‐in mouse model (Foxp3creCd103dtr) enabling the specific ablation of CD103+FoxP3+Tregs for functional studies.

Results

We found that during resolution of allergic airway inflammation in mice >50% of FoxP3+Treg cells expressed the integrin CD103 which marks FoxP3+Treg cells of high IL‐10 production, increased expression of immunoregulatory molecules such as KLRG1, ICOS and CD127, and enhanced suppressive capacity for Th2‐mediated inflammatory responses. CD103+FoxP3+Tregs were essential for keeping allergic inflammation under control as their specific depletion inFoxp3creCd103dtrmice lead to severe alveocapillary damage, eosinophilic pneumonia, and markedly reduced lifespan of the animals. Conversely, adoptive transfer of CD103+FoxP3+Tregs effectively treated disease, attenuating Th2 responses and allergic inflammation in an IL‐10‐dependent manner.

Conclusions

Our study identifies a novel regulatory T‐cell population, defined by CD103 expression, programmed to prevent exuberant type 2 inflammation and keep homeostasis in the respiratory tract under control. This has important therapeutic implications.