bluuebunny/crossref_metadata_2025 huggingface dataset:
First reported detection of the mobile colistin resistance genes,mcr-8 andmcr-9, in the Irish environment
Authors: Cahill Niamh , Hooban Brigid , Fitzhenry Kelly , Joyce Aoife , O’Connor Louise , Miliotis Georgios , McDonagh Francesca , Burke Liam , Chueiri Alexandra , Farrell Maeve Louise , Bray James E. , Delappe Niall , Brennan Wendy , Prendergast Deirdre , Gutierrez Montserrat , Burgess Catherine , Cormican Martin , Morris Dearbháile
Published: November 2022

The emergence and dissemination of mobile colistin resistance (mcr) genes across the globe poses a significant threat to public health, as colistin remains one of the last line treatment options for multi-drug resistant infections. Environmental samples (157 water and 157 wastewater) were collected in Ireland between 2018 and 2020. Samples collected were assessed for the presence of antimicrobial resistant bacteria using Brilliance ESBL, Brilliance CRE, mSuperCARBA and McConkey agar containing a ciprofloxacin disc. All water and integrated constructed wetland influent and effluent samples were filtered and enriched in buffered peptone water prior to culture, while wastewater samples were cultured directly. Isolates collected were identified via MALDI-TOF, were tested for susceptibility to 16 antimicrobials, including colistin, and subsequently underwent whole genome sequencing. Overall, eightmcrpositive Enterobacterales (onemcr-8 and sevenmcr-9) were recovered from six samples (freshwater (n=2), healthcare facility wastewater (n=2), wastewater treatment plant influent (n=1) and integrated constructed wetland influent (piggery farm waste) (n=1)). While themcr-8 positiveK. pneumoniaedisplayed resistance to colistin, all sevenmcr-9 harbouring Enterobacterales remained susceptible. All isolates demonstrated multi-drug resistance and through whole genome sequencing analysis, were found to harbour a wide variety of antimicrobial resistance genes i.e., 30 ± 4.1 (10-61), including the carbapenemases,blaOXA-48(n=2) andblaNDM-1(n=1), which were harboured by three of the isolates. Themcrgenes were located on IncHI2, IncFIIK and IncI1-like plasmids. The findings of this study highlight potential sources and reservoirs ofmcrgenes in the environment and illustrate the need for further research to gain a better understanding of the role the environment plays in the persistence and dissemination of antimicrobial resistance.
OsPSTOL1is prevalent in upland rice and its expression in wheat enhances root growth and hastens low phosphate signaling
Authors: Kettenburg Alek Thomas , Lopez Miguel Angel , Yogendra Kalenahalli , Prior Matthew J. , Rose Teresa , Bimson Sabrina , Heuer Sigrid , Roy Stuart John , Bailey-Serres Julia
Published: November 2022

PHOSPHORUS-STARVATION TOLERANCE 1(OsPSTOL1) benefits crown root growth and phosphorus (P) sufficiency in rice (Oryza sativaL.). To better understand the importance of this variably present gene, we carried out a biogeographic survey of landraces and cultivars, confirming that functionalOsPSTOL1alleles prevail in low nutrient and drought-prone rainfed ecosystems, whereas loss-of-function alleles and absence haplotypes predominate in control-irrigated paddy varieties of east Asia. To address the evolutionary history ofOsPSTOL1and related genes in cereal crops, phylogenetic and transcript meta-analyses were performed. Finally, to evaluate its potential value in another Gramineae, wheat (Triticum aestivumL.) lines overexpressingOsPSTOL1were evaluated under field and controlled low P conditions.OsPSTOL1enhances growth, crown root number, and overall root plasticity under low P in wheat. Survey of root and shoot crown transcriptomes at two developmental stages identifies transcription factors that are differentially regulated inOsPSTOL1wheat that are similarly controlled by the gene in rice. In wheat,OsPSTOL1alters the timing and amplitude of regulators of root development in dry soils and hastens induction of the core P-starvation response. Based on these findings,OsPSTOL1and related genes may aid more sustainable cultivation of cereal crops.

Summary statement

Might a rice gene that controls root plasticity confer a similar benefit in another grain crop. Here, we evaluate the genetic variation and evolutionary history ofOsPSTOL1and demonstrate its impact in wheat.
EvoAug: improving generalization and interpretability of genomic deep neural networks with evolution-inspired data augmentations
Authors: Lee Nicholas Keone , Tang Ziqi , Toneyan Shushan , Koo Peter K
Published: November 2022

Deep neural networks (DNNs) hold promise for functional genomics prediction, but their generalization capability may be limited by the amount of available data. To address this, we propose EvoAug, a suite of evolution-inspired augmentations that enhance the training of genomic DNNs by increasing genetic variation. However, random transformation of DNA sequences can potentially alter their function in unknown ways. Thus, we employ a fine-tuning procedure using the original non-transformed data to preserve functional integrity. Our results demonstrate that EvoAug substantially improves the generalization and interpretability of established DNNs across prominent regulatory genomics prediction tasks, offering a robust solution for genomic DNNs.
Understanding the role and adoption of artificial intelligence techniques in rheumatology research: an in-depth review of the literature
Authors: Madrid-García Alfredo , Merino-Barbancho Beatriz , Rodríguez-González Alejandro , Fernández-Gutiérrez Benjamín , Rodríguez-Rodríguez Luis , Menasalvas-Ruiz Ernestina
Published: November 2022

The major and upward trend in the number of published research related to rheumatic and musculoskeletal diseases, in which artificial intelligence plays a key role, has exhibited the interest of rheumatology researchers in using these techniques to answer their research questions. In this review, we analyse the original research articles that combine both worlds in a five-year period (2017-2021). In contrast to other published papers on the same topic, we first studied the review and recommendation articles that were published during that period, including up to October 2022, as well as the publication trends. Secondly, we review the published research articles and classify them into one of the following categories: disease classification, disease prediction, predictors identification, patient stratification and disease subtype identification, disease progression and activity, and treatment response. Thirdly, we provide a table with illustrative studies in which artificial intelligence techniques have played a central role in more than twenty rheumatic and musculoskeletal diseases. Finally, the findings of the research articles, in terms of disease and/or data science techniques employed, are highlighted in a discussion. Therefore, the present review aims to characterise how researchers are applying data science techniques in the rheumatology medical field. The most immediate conclusions that can be drawn from this work are: multiple and novel data science techniques have been used in a wide range of rheumatic and musculoskeletal diseases including rare diseases; the sample size and the data type used are heterogeneous, and new technical approaches are expected to arrive in the short-middle term.

Highlights

The rheumatology research community is increasingly adopting novel AI techniques

There is an upward trend in the number of articles that combine AI and rheumatology

Rheumatic and musculoskeletal rare diseases are gaining from AI techniques

Independent validation of the models should be promoted
How to start a LINE: 5’ switching rejuvenates LINE retrotransposons in tobacco and relatedNicotianaspecies
Authors: Hartig Nora , Seibt Kathrin M. , Heitkam Tony
Published: November 2022

In contrast to their conserved mammalian counterparts, plant long interspersed nuclear elements (LINEs) are highly variable, splitting into many low-copy families. Curiously, LINE families from the RTE clade retain a stronger sequence conservation and hence reach higher copy numbers. The cause of this RTE-typical property is not yet understood, but would help clarifying why some transposable elements are removed quickly whereas others persist in plant genomes. Here, we bring forward the first detailed study of RTE LINE structure, diversity and evolution in plants. For this, we argue that the Nightshade family is the ideal taxon to follow the evolutionary trajectories of RTE LINEs, given their high abundance, recent activity and partnership to non-autonomous elements.

Using bioinformatic, cytogenetic and molecular approaches, we detect 4029 full-length RTE LINEs across theSolanaceae. We finely characterize and manually curate a core group of 458 full-length LINEs in allotetraploid tobacco, show amplification after polyploidization, and trace hybridization events by RTE LINE composition of parental genomes. Finally, we reveal the role of the untranslated regions (UTRs) as causes for the unique RTE LINE amplification and evolution pattern in plants: On one hand, we detect a highly conserved motif at the 3’ UTR, suggesting strong selective constraints acting on the RTE terminus. On the other hand, we observed successive rounds of 5’ UTR cycling, constantly rejuvenating the promoter sequences. This interplay between exchangeable promoters and conserved LINE bodies and 3’ UTR likely allows RTE LINEs to persist and thrive in plant genomes.
Vitamin B5, a Coenzyme A precursor, rescues TANGO2 deficiency disease-associated defects inDrosophilaand human cells
Authors: Asadi Paria , Milev Miroslav P. , Saint-Dic Djenann , Gamberi Chiara , Sacher Michael
Published: November 2022

Mutations in theTransportandGolgiOrganization 2 (TANGO2) gene are associated with intellectual deficit, neurodevelopmental delay and regression. Individuals can also present with an acute metabolic crisis that includes rhabdomyolysis, cardiomyopathy and cardiac arrhythmias, the latter of which are potentially lethal. While preventing metabolic crises has the potential to reduce mortality, no treatments currently exist for this condition. The function of TANGO2 remains unknown but is suspected to be involved in some aspect of lipid metabolism. Here, we describe a model ofTANGO2-related disease in the fruit flyDrosophila melanogasterthat recapitulates crucial disease traits. Pairing a new fly model with human cells, we examined the effects of vitamin B5, a Coenzyme A (CoA) precursor, on alleviating the cellular and organismal defects associated withTANGO2deficiency. We demonstrate that vitamin B5 specifically improves multiple defects associated with TANGO2 loss-of-function inDrosophilaand rescues membrane trafficking defects in human cells. We also observed a partial rescue of one of the fly defects by vitamin B3, though to a lesser extent than vitamin B5. Our data suggest that a B complex supplement containing vitamin B5/pantothenate may have therapeutic benefits in individuals with TANGO2-deficiency disease. Possible mechanisms for the rescue are discussed including restoration of lipid homeostasis.

SYNOPSIS

Using aDrosophilafruit fly model that recapitulates many defective phenotypes associated with TANGO2 deficiency disease (TDD), we show that treatment with vitamin B5 rescues these defects and suggest a multivitamin or B complex vitamin containing vitamin B5 may prevent the potentially lethal metabolic crises associated with TDD.
Oocytes can repair DNA damage during meiosis via a microtubule-dependent recruitment of CIP2A-MDC1-TOPBP1 complex from spindle pole to chromosomes
Authors: Leem Jiyeon , Kim Jae-Sung , Oh Jeong Su
Published: November 2022

Because DNA double-strand breaks (DSBs) greatly threaten genomic integrity, effective DNA damage sensing and repair are essential for cellular survival in all organisms. However, DSB repair mainly occurs during the interphase and is repressed during mitosis. Here, we show that, unlike mitotic cells, oocytes can repair DSBs during meiosis through microtubule-dependent chromosomal recruitment of the CIP2A-MDC1-TOPBP1 complex from spindle poles. After DSB induction, we observed spindle shrinkage and stabilization, as well as BRCA1 and 53BP1 recruitment to chromosomes and subsequent DSB repair during meiosis I. Moreover, p-MDC1 and p-TOPBP1 were recruited from spindle poles to chromosomes in a CIP2A-dependent manner. This pole-to-chromosome relocation of the CIP2A-MDC1-TOPBP1 complex was impaired not only by depolymerizing microtubules but also by depleting CENP-A or HEC1, indicating that the kinetochore/centromere serves as a structural hub for microtubule-dependent transport of the CIP2A-MDC1-TOPBP1 complex. Mechanistically, DSB-induced CIP2A-MDC1-TOPBP1 relocation is regulated by PLK1 but not by ATM activity. Our data provide new insights into the critical crosstalk between chromosomes and spindle microtubules in response to DNA damage to maintain genomic stability during oocyte meiosis.
Drivers of dispersal and diversification in bromeliads
Authors: Kessous Igor M. , Farooq Harith , Testo Weston , Jiménez María Fernanda T. , Neves Beatriz , Pinto Alessandra R. , Salgueiro Fabiano , Costa Andrea F. , Bacon Christine D.
Published: November 2022

Dispersal strategies strongly influence an array of plant traits, especially the shape and function of fruits and seeds, and can be important drivers of diversification dynamics. In this study we investigated how fruit morphology and habitat influence dispersal capacity and diversification rate in bromeliads. We hypothesize that (1) the evolution of berry fruits increased dispersal capacity and diversification rates; and (2) climatic factors contribute to increased dispersal capacity and diversification rates.

To understand the influence of fruit and habitat traits on evolutionary dynamics, we generated a time-calibrated phylogeny including 1,268 species of bromeliads and integrated that evolutionary framework with distribution, habitat, and morphological trait data.

We find that lineages with berry fruits have the highest rates of diversification. We also identify significant correlation between diversification rates and both elevation and forest canopy height. We demonstrate that dispersal capacity is not related to fruit morphology and covaries with forest canopy height and mean annual temperature.

We show that factors influencing the dispersal capacity and diversification are heterogeneous among the subfamilies. These new insights into the rise and spread of bromeliads emphasize the importance of considering the plurality of morphological and ecological features to improve the understanding of the evolutionary dynamics.
Epigenetic silencing by SMYD3 represses tumor intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck
Authors: Nigam N , Bernard B , Kim S , Burkitt K , Tsai D , Robbins Y , Sievers C , Clint A , Bennett RL , Tettey TT , Carter B , Bao R , Rinaldi L , Lingen M.W. , Sater H , Edmondson EF , Cheng H , Luo X , Brennan K , Chen C , Sevilla S , Murali M , Sakata S , Takeuchi K , Nakamura Y , Uppaluri R , Sunwoo JB , Van Waes C , Licht JD , Hager GL , Saloura V
Published: November 2022

Cancers often display immune escape, but the mechanisms and potential for reversibility are incompletely understood. Epigenetic dysregulation has been implicated in the immune escape of various cancer types. We have identified the epigenetic modifier SET and MYND-domain containing protein 3 (SMYD3) as a mediator of immune escape in human papilloma virus (HPV)- negative head and neck squamous cell carcinoma (HNSCC), an aggressive disease with poor prognosis and low response to immunotherapy with pembrolizumab, a programmed-death-1 (PD-1) targeting antibody. SMYD3 loss increased the sensitivity of HNSCC cancer cells to IFN-β, resulting in upregulation of type I IFN response and antigen presentation machinery genes. We found that SMYD3 regulates the transcription of Ubiquitin-Like PHD And RING Finger Domain- Containing Protein 1 (UHRF1), a key epigenetic reader of trimethylated lysine 9 on histone H3 (H3K9me3), which binds to H3K9me3-enriched promoters of key immune-related genes and silences their expression. SMYD3 further maintains the repression of immune-related genes through the deposition of H4K20me3 within the gene body regions of these genes. In an anti-PD-1 immune checkpoint resistant syngeneic mouse model of HPV-negative HNSCC, Smyd3 depletion induced influx of CD8+ T-cells, upregulated PD-L1 and MHC class I molecules, and increased sensitivity to anti-PD-1 therapy. SMYD3 overexpression was associated with decreased CD8 T-cell infiltration in tumor samples from patients with HPV-negative HNSCC, and was associated with poor response to pembrolizumab. Overall, these data highlight a previously unreported function of SMYD3 as a master epigenetic regulator of anti-tumor immune response in HPV-negative HNSCC and provide a rationale for translational approaches combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in this devastating disease.
An immune-suppressing protein in human endogenous retroviruses
Authors: Zhang Huan , Ni Shengliang , Frith Martin C.
Published: November 2022

Retroviruses are important contributors to disease and evolution in vertebrates. Sometimes, retrovirus DNA is heritably inserted in a vertebrate genome: an endogenous retrovirus (ERV). Vertebrate genomes have many such virus-derived fragments, usually with mutations disabling their original functions.

Some primate ERVs appear to encode an overlooked protein. This protein is homologous to protein MC132 from Molluscum contagiosum virus, which is a human poxvirus, not a retrovirus. MC132 suppresses the immune system by targeting NF-κB, and it had no known homologs until now. The ERV homologs of MC132 in the human genome are mostly disrupted by mutations, but there is an intact copy on chromosome 4. We found homologs of MC132 in ERVs of apes, monkeys, and bushbaby, but not tarsiers, lemurs or non-primates. This suggests that some primate retroviruses had, or have, an extra immune-suppressing protein, which underwent horizontal genetic transfer between unrelated viruses.
Shield co-opts an RmuC domain to mediate phage defence acrossPseudomonasspecies
Authors: Macdonald Elliot , Strahl Henrik , Blower Tim R. , Palmer Tracy , Mariano Giuseppina
Published: November 2022

Competitive bacteria-bacteriophage interactions have resulted in the evolution of a plethora of bacterial defense systems preventing phage propagation. In recent years, computational and bioinformatic approaches have underpinned the discovery of numerous novel bacterial defense systems. Anti-phage systems are frequently encoded together in genomic loci termed defense islands. Here we report the identification and characterisation of a novel anti-phage system, which we have termed Shield, that forms part of thePseudomonasdefensive arsenal. The Shield system comprises a membrane-bound protein, ShdA, harboring an RmuC domain. Heterologous production of ShdA alone is sufficient to mediate bacterial immunity against a panel of phages. We show that ShdA homologues can degrade phage DNAin vitroand, when expressed in a heterologous host, can alter the organisation of chromosomal DNA to a nucleoid structure. Further analysis reveals that Shield can be divided into four subtypes, three of which contain additional components that in some cases can modulate the activity of ShdA and/or provide additional lines of phage defence. Collectively, our results identify a new player within thePseudomonasbacterial immunity arsenal that displays a novel mechanism of protection, and reveals a surprising role of RmuC domains in phage defence.

SIGNIFICANCE

The evolutionary pressure exerted by bacteriophages has driven bacteria to acquire numerous defense systems. Recent studies have highlighted the extraordinary diversity of these systems, uncovering exciting links between bacterial and eukaryotic immunity. Here we describe a novel anti-phage system, named Shield, found withinPseudomonasspecies. We identify several Shield subtypes, all harboring the same core component, and describe its mode of action. The growing instance of multidrug-resistant bacterial infections urgently requires the development of alternative treatments. Phage therapy is a particularly pertinent approach to treat multi-drug resistantPseudomonas aeruginosastrains causing severe lung infection in cystic fibrosis patients. A detailed understanding of bacterial immunity and phage counter-strategies is an essential step to underpin the rational design of phage therapy to fight disease.
Autophagy protects against high-doseMycobacterium tuberculosisinfection
Authors: Feng Siwei , Nehls E. Michael , Kinsella Rachel L. , Chavez Sthefany M. , Naik Sumanta K. , McKee Samuel R. , Dubey Neha , Samuels Amanda , Swain Amanda , Cui Xiaoyan , Hendrix Skyler V. , Woodson Reilly , Kreamalmeyer Darren , Smirnov Asya , Artyomov Maxim N. , Virgin Herbert W. , Wang Ya-Ting , Stallings Christina L.
Published: November 2022

Host autophagy had been associated with the control ofMycobacterium tuberculosis(Mtb) infection due to its ability to sequesters microorganisms through a process termed “xenophagy”1–4. Xenophagy purportedly limits Mtb replication within infected macrophages1–4. However, studies in mice using a standard low-dose infection model demonstrated that xenophagy in infected phagocytes is not required to control Mtb pathogenesis5,6. Instead, an autophagy-independent function of ATG5 in myeloid cells controls low-dose Mtb infection through limiting neutrophilic inflammation5. Hitherto, anin vivorole for autophagy during Mtb infection remained to be elucidated. We report herein that autophagy in myeloid cells mediates protection against high-dose Mtb infection, providing the first evidence for a role for autophagy in myeloid cells during Mtb infectionin vivo. With the exception of ATG5, the autophagy proteins required to control high-dose Mtb infection are dispensable for host defense against a standard low-dose Mtb infection. Specifically, autophagy is required in CD11c+cells, but is dispensable in neutrophils, to control a high-dose Mtb infection in the lung. The role for autophagy is not to directly degrade Mtb in macrophages through xenophagy, but mainly to limit myeloid-derived suppressor cell accumulation and to promote sustained protective T cell responses. Together, our data highlight a novel role for autophagy in controlling Mtb infection, distinct from that of Atg5 during low-dose Mtb infection, or any previously reported roles for autophagy. In addition, our finding that the result of a pathogen-plus-susceptibility gene interaction is dependent on pathogen burden has important implications on our understanding of how Mtb infection in humans can lead to a spectrum of outcomes, the variables that contribute to autophagy gene function during infection and inflammation, and the potential use of autophagy modulators in clinical medicine.
Different ways of evolving tool-using brains in teleosts and amniotes
Authors: Estienne Pierre , Simion Matthieu , Hagio Hanako , Yamamoto Naoyuki , Jenett Arnim , Yamamoto Kei
Published: November 2022

In mammals and birds, tool-using species are characterized by a high degree of encephalization with a relatively large telencephalon containing a higher proportion of total brain neurons compared to other species. Some teleost species in the wrasse family have convergently evolved tool-using abilities. In this study, we compared the brains of tool-using wrasses with various teleost species from a broad phylogenetic range. Using the isotropic fractionator, we show that in the tool-using wrasses, the telencephalon and the ventral part of the forebrain and midbrain are significantly enlarged compared to other teleost species but do not contain a larger proportion of cells. Instead, we found with tract tracing and selective neuronal fiber visualization that this size difference is due to large fiber tracts connecting the dorsal part of the telencephalon (pallium) to the inferior lobe (IL), a ventral mesencephalic structure absent in amniotes. The high degree of connectivity between the IL and the pallium in tool-using wrasses suggests that this unique teleostean structure could contribute to higher-order cognitive functions. Given remarkable differences in their overall brain organization, we conclude that, unlike in amniotes, the evolution of non-telencephalic structures might have been key in the emergence of higher-order cognitive functions in teleosts.
Loss ofMfn1but notMfn2enhances adipogenesis
Authors: Mann JP , Tabara LC , Alvarez-Guaita A , Dong L , Haider A , Lim K , Tandon P , Minchin JEN , O’Rahilly S , Patel S , Fazakerley DJ , Prudent J , Semple RK , Savage DB
Published: November 2022

Objective

A biallelic missense mutation in mitofusin 2 (MFN2) causes multiple symmetric lipomatosis and partial lipodystrophy, implicating disruption of mitochondrial fusion or interaction with other organelles in adipocyte differentiation, growth and/or survival. In this study, we aimed to document the impact of loss of mitofusin 1 (Mfn1) or 2 (Mfn2)on adipogenesis in cultured cells.

Methods

We characterised adipocyte differentiation of wildtype (WT),Mfn1-/-andMfn2-/-mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes in which Mfn1 or 2 levels were reduced using siRNA.

Results

Mfn1-/-MEFs displayed striking fragmentation of the mitochondrial network, with surprisingly enhanced propensity to differentiate into adipocytes, as assessed by lipid accumulation, expression of adipocyte markers (Plin1, Fabp4, Glut4, Adipoq), and insulin-stimulated glucose uptake. RNA sequencing revealed a corresponding pro-adipogenic transcriptional profile includingPpargupregulation.Mfn2-/-MEFs also had a disrupted mitochondrial morphology, but in contrast toMfn1−/-MEFs they showed reduced expression of adipocyte markers and no increase in insulin-stimulated glucose uptake.Mfn1andMfn2siRNA mediated knockdown studies in 3T3-L1 adipocytes generally replicated these findings.

Conclusions

Loss ofMfn1but notMfn2in cultured pre-adipocyte models is pro-adipogenic. This suggests distinct, non-redundant roles for the two mitofusin orthologues in adipocyte differentiation.
Logical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes
Authors:   Carlos Company, Jürgen Schmitt Matthias , Dramaretska Yuliia , Kertalli Sonia , Jiang Ben , Serresi Michela , Barozzi Iros , Gargiulo Gaetano
Published: November 2022

Descriptive data are rapidly expanding in biomedical research. Instead, functional validation methods with sufficient complexity remain underdeveloped. Transcriptional reporters allow experimental characterization and manipulation of developmental and disease cell states, but their design lacks flexibility. Here, we report logical design of syntheticcis-regulatory DNA(LSD), a computational framework leveraging phenotypic biomarkers andtrans-regulatory networks as input to design reporters marking the activity of selected cellular states and pathways. LSD uses bulk or single-cell biomarkers and a reference genome or customcis-regulatory DNA datasets with user-defined boundary regions. By benchmarking validated reporters, we integrated LSD with a computational classifier to rank phenotypic specificity of putativecis-regulatory DNA. Experimentally, LSD-designed reporters targeting a wide range of cell states are functional without minimal promoters.In silico, an LSD-unsupervised mesenchymal glioblastoma reporter outperformed previously validated ones. In genome-scale CRISPRa screens, it discovered known and novelbona fidecell-state-drivers. Thus, LSD captures core principles ofcis-regulation and is broadly applicable to studying complex cell states and mechanisms of transcriptional regulation.
Systematic analysis and optimization of early warning signals for critical transitions
Authors: Proverbio Daniele , Skupin Alexander , Gonçalves Jorge
Published: November 2022

Abrupt shifts between alternative regimes occur in complex systems, from cell regulation to brain functions to ecosystems. Several model-free Early Warning Signals (EWS) have been proposed to detect impending transitions, but failure or poor performance in some systems have called for better investigation of their generic applicability. In particular, there are still ongoing debates whether such signals can be successfully extracted from data. In this work, we systematically investigate properties and performance of dynamical EWS in different deteriorating conditions, and we propose an optimised combination to trigger warnings as early as possible, eventually verified on experimental data. Our results explain discrepancies observed in the literature between warning signs extracted from simulated models and from real data, provide guidance for EWS selection based on desired systems and suggest an optimised composite indicator to alert for impending critical transitions.

Highlights

How to extract early warning signals (EWS) against critical transitions from data is still poorly understood

A mathematical framework assesses and explains the performance of EWS in noisy deteriorating conditions

Composite indicators are optimised to alert for impending shifts

The results are applicable to wide classes of systems, as shown with models and on empirical data.
V0-ATPase downregulation induces MVID-like brush border defects independently of apical trafficking in the mammalian intestine
Authors: Bidaud-Meynard Aurélien , Nicolle Ophélie , Bourdais Anne , Duclos Maela , Saleh Jad , Ruemmele Frank , Farin Henner F , Delacour Delphine , Moshous Despina , Michaux Grégoire
Published: November 2022

Intestinal microvillus atrophy is a major cause of enteropathies such as idiopathic or congenital diarrhea that are often associated with severe morbidity. It can be caused by genetic disorders, inflammatory diseases, toxins or pathogens. In particular, Microvillus inclusion disease (MVID) is characterized by a chronic intractable diarrhea and a severe microvillus atrophy. It is triggered by mutations inMYO5B, STX3, MUNC18.2orUNC45Awhich alter epithelial polarity by affecting apical trafficking in intestinal epithelial cells. Furthermore, we recently established that the depletion of the V0sector of the V-ATPase complex induces an MVID-like phenotype inC. elegans. In this study we investigated the function of the V0-ATPase complex in mouse intestinal organoids. We found that its depletion also triggers a very severe microvillus atrophy in this model. Furthermore, we established that the polarity of intestinal cells is affected in a patient carrying mutations inTCIRG1which encodes a V0-ATPase subunit. However, V0- ATPase depletion does not recapitulate other MVID-specific phenotypes such as subapical vesicle accumulation and Rab11+ endosomes mislocalization. Finally, we found that the apical localization of the V0-ATPase is disrupted in MVID patients. Altogether these results suggest a role for the V0-ATPase in microvillus atrophy which might be independent from apical trafficking.
Size compensation in Drosophila after generalised cell death
Authors: Pinal Noelia , Azpiazu Natalia , Morata Ginés
Published: November 2022

Regeneration is a response mechanism to restore tissues that have been damaged or lost by mechanical or physiological insults. We are studying in the wing imaginal disc ofDrosophilathe regenerative response to a high dose of Ionizing Radiation (IR), which we estimate kills at least 35% of the cells. After such treatment irradiated discs are able to restore normal size and shape, indicating there is a mechanism to replace the lost cells. We have tested the role of the Jun N-terminal Kinase (JNK), Janus Kinase (JAK/STAT) and Wingless (Wg) pathways, which have been shown to promote cell proliferation in regenerating tissues. We find that there is size compensation after IR in the absence of function of these pathways, strongly suggesting that they are not necessary for the compensation. We also find that the proliferation rate is not increased after IR. We argue that after generalized death caused by IR there is not a specific mechanism to promote cell proliferation. The irradiated discs suffer a developmental delay and then resume growth at normal rate until they reach the final stereotyped size. The delay appears to be associated with a developmental reversion, as irradiated discs undergo rejuvenation towards an earlier developmental stage. The response to generalized damage is fundamentally different from that to localized damage, which requires activity of JNK and Wg.
Differentiation of rhizosphere fungal assemblages by host ploidy level in mixed-ploidyLarrea tridentatapopulations
Authors: Gerstner Benjamin , Mann Michael , Laport Robert G. , Whitney Kenneth D.
Published: November 2022

Polyploidy—whole genome duplication—is common in plants. Studies over the last several decades have documented numerous mixed-ploidy populations. Whether arising via recurrent whole genome duplication events within a population, or from secondary contact, the persistence of mixed populations depends on the ability of the minority cytotype to overcome the negative frequency dependent effects of outcrossing with other ploidies, known as Minority Cytotype Exclusion. One mechanism of overcoming Minority Cytotype Exclusion is microbially-mediated niche differentiation (MMND), wherein cytotypes occupy different niches via interactions with different sets of microbes. Inherently cryptic, MMND is underexplored in polyploid plant populations. Here, we search for evidence of MMND in creosotebush (Larrea tridentata), a dominant desert shrub of the southwestern U.S. and northern Mexico. We sequenced fungi from rhizosphere soils of diploid, autotetraploid, and autohexaploid plants growing in two naturally-occurring mixed-cytotype populations. Within populations, we found substantial fungal assemblage overlap across host plant cytotypes. However, using indicator species analysis, we identified some fungi that are differentiated by host plant cytotype, satisfying a precondition for MMND. Future study is needed to determine the degree of niche differentiation conferred, if any, and whether the identified fungi play a role in the long-term persistence of multiple cytotypes within populations.
Methadone alters transcriptional programs associated with synapse formation in human cortical organoids
Authors: Dwivedi Ila , Zhou Dan , Caldwell Andrew B. , Subramaniam Shankar , Haddad Gabriel G.
Published: November 2022

Opioid use disorder (OUD) among pregnant women has become an epidemic in the United States. Pharmacological interventions for OUD involve methadone, a synthetic opioid analgesic that attenuates withdrawal symptoms and behaviors linked with maternal drug abuse. However, methadone’s ability to readily accumulate in neural tissue, and cause long-term neurocognitive sequelae, has led to concerns regarding its effect on prenatal brain development. We took advantage of human cortical organoid (hCO) technology to probe how this drug impacts the earliest mechanisms giving rise to the cerebral cortex. To this end, we conducted bulk mRNA sequencing of 2-month-old hCOs derived from two cell lines that were chronically treated with a clinically relevant dose of 1μM methadone for 50 days. Differential expression and gene ontology analyses revealed a robust transcriptional response to methadone associated with functional components of the synapse, the underlying extracellular matrix (ECM), and cilia. Further unsupervised co-expression network and predictive protein-protein interaction analyses demonstrated that these changes occurred in concert, centered around a regulatory axis consisting of growth factors, developmental signaling pathways, and matricellular proteins. Our results demonstrate that exposure to methadone during early cortico-genesis fundamentally alters transcriptional programs associated with synapse formation, and that these changes arise by modulating extra-synaptic molecular mechanisms in the ECM and cilia. These findings provide novel insight into methadone’s putative effect on cognitive and behavioral development and a basis for improving interventions for maternal opioid addiction.
African eggplant-associated virus: characterization of a novel tobamovirus identified fromSolanum macrocarponand assessment of its potential impact on tomato and pepper crops
Authors: Giesbers Anne K.J. , Roenhorst Annelien , Schenk Martijn F. , Westenberg Marcel , Botermans Marleen
Published: November 2022

A novel tobamovirus was identified in a fruit ofSolanum macrocarponimported into the Netherlands in 2018. This virus was further characterized in terms of host range, pathotype and genomic properties, because many tobamoviruses have the potential to cause severe damage in important crops. In the original fruit, two different genotypes of the novel virus were present. The virus was able to infect multiple plant species from theSolanaceaefamily after mechanical inoculation, as well as a member of theApiaceaefamily. These species included economically important crops such as tomato and pepper, as well as eggplant and petunia. Both tomato and pepper germplasm were shown to harbor resistance against the novel virus. Since most commercial tomato and pepper varieties grown in European greenhouses harbor these relevant resistances, the risk of infection and subsequent impact on these crops is likely to be low in Europe. Assessment of the potential threat to eggplant, petunia, and other susceptible species needs further work. In conclusion, this study provides a first assessment of the potential phytosanitary risks of a newly discovered tobamovirus, which was tentatively named African eggplant-associated virus.
Possible Self-awareness in Wild Adélie PenguinsPygoscelis adeliae¶
Authors: Dastidar Prabir Ghosh , Khan Azizuddin , Sinha Anindya
Published: November 2022

This preliminary study, conducted in January–February 2020, investigates the potential presence of self-awareness in a population of wild Adélie penguins on the Dog’s Neck Ice Shelf and on Svenner Island in East Antarctica. It is based on the responses and reactions of individual penguins to images, generated in mirrors during three experimental paradigms: a group-behaviour test; a modified mirror test and a hidden-head test. We believe that this set of experiments constitutes possibly the first investigations into the potential presence of self-awareness in any penguin species and is pioneering in conducting a set of cognitive experiments on free-ranging individuals of a nonhuman species in its natural environment, without any prior familiarisation, conditioning or acclimatisation to the experimental paradigms employed. Future studies, integrating the socioecology and cognitive ethology of penguins, may provide insights into whether our experimental paradigms could provide evidence to confirm the presence of self-awareness and even of self-recognition in this species and examine whether the observed social awareness may have evolved due to the social needs of individual penguins to engage in cooperative behaviour with conspecific individuals, while maintaining their independent decision-making capacities, throughout their communal lives.
Tax rate motivated profit shifting and base erosion by multinational corporations: Indian evidence
Authors: Gill Suveera , Arora Taruntej Singh , Gandhi Karan
Published: November 2022

Purpose

Profit shifting is a matter of great concern for governments internationally. It leads to the loss of tax revenues and puts multinational corporations (MNCs) in a disparate position. Lately, due to the aggressive stance of the Indian taxman, several Indian MNCs are planning to minimise their tax outflows. This paper aims to study profit-shifting drawing from the institutional theory for the Indian MNCs.

Design/methodology/approach

The sample comprises 679 MNCs listed on the Bombay Stock Exchange or the National Stock Exchange with either Indian parents with foreign subsidiaries (553) or Indian subsidiaries of a foreign parent (126) for FY 2013–14 to FY 2018–19. A fixed-effect panel regression technique was invoked to examine tax rate differential motivated profit-shifting undertaken by MNCs with the moderating effect of international presence and patents.

Findings

The results suggest that MNCs shift their profits to take advantage of differences in global tax rates when they have an international presence in at least five tax countries. Further, profit shifting is likely towards no-tax compared to low-tax countries, with the presence of patents in an MNC group having no significant impact.

Originality/value

Losses to the government revenue due to profit shifting by MNCs are rather severe in emerging economies. The study provides the first empirical evidence of the direction of profit shifting with the moderating effect of the extent of global presence and group patents, which would interest scholars in the field. The findings provide valuable insights to the policymakers, highlighting the urgent need to operationalise the general anti-avoidance taxation rules.
Value co-creation in the health-care ecosystem for sustained excellence: realization of patient-centered medicine through task shifting of nurses
Authors: Katsuda Atsushi , Naito Yoshiyuki , Ishihara Toshihiko
Published: November 2022

Purpose

In Japan, health-care systems have long been supported by physicians' long working hours. To solve this problem, there is an urgent need to improve the working environment for physicians while practicing patient-centered medicine and controlling health-care costs. This paper aims to examine the effect of task shifting to nurses and discuss its usefulness from the perspective of health-care value co-creation.

Design/methodology/approach

This paper analyzes task shifting to nurses in acute care hospitals in Japan as a solution for the shortage of anesthesiologists. The authors discuss how the value was created from the perspective of the health-care ecosystem, with conceptual consideration of the value co-creation mechanism through patient-centered practices.

Findings

The study showed that task shifting initiatives in Japan can improve the motivation of nurses through human resource development while maintaining high quality. The study also suggested that task shifting from physicians to nurses may contribute to improving net income and maintaining the health-care system.

Practical implications

The findings are highly reproducible and can be immediately applied to initiatives at other medical institutions in Japan. Furthermore, it is suggested that these findings might provide some perspective on the realignment of fragmented healthcare in the USA.

Originality/value

It was confirmed in practical terms that micro-level initiatives have an impact on the macro level as well. In addition, the academic presentation of the concept has contributed to the deepening of value research.
Evaluating quality management of road construction projects: a Delphi study
Authors: Willar Debby , Trigunarsyah Bambang , Dewi Anak Agung Diah Parami , Makalew Febriane
Published: November 2022

Purpose

There are various methods to assess the failure of a road construction project that does not meet quality and performance standards. This study aims to evaluate the factors affecting the quality management of road construction projects in Indonesia by identifying the critical challenges in implementing quality management processes and examining the countermeasures to address these problems.

Design/methodology/approach

In this research, the quality management processes in Indonesian road construction projects are evaluated using a mixed quantitative and qualitative approach. Quantitative data obtained from two rounds of Delphi questionnaire surveys as the primary data source, and focus group interviews as the qualitative data are used to achieve the aims of this study.

Findings

It is found that from as early as in the preconstruction stage of a project, the availability of quality standards and documentation is problematic when implementing quality management processes. The critical factor of the quality control activities of a project and the quality management roles and responsibilities of the stakeholders during road construction is the project team. This constraint deals with the interaction of the competency, commitment, and mutual cooperation among the main stakeholders to ensure that quality management processes are implemented. This implementation is a part of controlling the road pavement materials, supervising the project activities according to a specified standard, and reporting the project performance. The findings of this study add parameters relating to quality management and quality processes in a road construction project area.

Originality/value

This study is the first to evaluate the quality management processes in the construction of Indonesian road projects. The investigation identifies and evaluates the causes of the persistence of poor road quality. All revealed constraints are substantial factors that hinder the implementation of quality management processes when delivering quality road products. This study addresses the key influencing factors and scenarios related to quality management during road construction projects in Indonesia and other developing countries as practical examples and provides case-based insights for construction practitioners and civil engineering academics in developed countries.
Seroepidemiology of hepatitis A virus infection in Japan: An area of very low endemicity
Authors: Kiyohara Tomoko , Ishii Koji , Satake Masahiro , Matsubayashi Keiji , Suzuki Ryosuke , Sugiyama Ryuichi , Sunagawa Tomimasa , Muramatsu Masamichi
Published: November 2022

The incidence of hepatitis A virus (HAV) infection has declined significantly worldwide, including in Japan. A nationwide seroepidemiological study on hepatitis A in Japan has taken place almost every 10 years since 1973, and the last study was performed in 2003. In the present study, we describe the latest seroepidemiological pattern of hepatitis A in Japan using 7867 serum specimens obtained from healthy individuals collected between 2013 and 2017, approximately 10 years after the last study. Among them, 223 were anti‐HAV positive. About 68% of individuals aged 60 years and older had anti‐HAV antibodies, whereas only 1.1% of those aged below 60 years old had immunity; thus, almost all individuals younger than 60 years of age were HAV susceptible. In comparison with previous investigations, the susceptible population has increased and aged. According to data from the National Epidemiological Surveillance of Infectious Diseases (NESID) program, between 1989 and 2016, the proportion of patients with hepatitis A aged 60 years and older continuously increased with each year. The NESID data also suggested that recently, typical large foodborne outbreaks of hepatitis A have become rare, and cases tend to be reported among at‐risk groups; overseas travelers contributed to 25% of hepatitis A cases, and in 2018, the first nationwide hepatitis A outbreak that affected mostly men who have sex with men was reported. The purpose of this study was to determine the current status of HAV infection in Japan, based on both seroepidemiology and the national surveillance data from the NESID.