bluuebunny/crossref_metadata_2025_split huggingface dataset:
A stochastic model for COVID-19 spread and the effects of Alert Level 4 in Aotearoa New Zealand
Authors: Plank Michael J. , Binny Rachelle N. , Hendy Shaun C. , Lustig Audrey , James Alex , Steyn Nicholas 
Published: April 2020

AbstractWhile case numbers remain low, population-wide control methods combined with efficient tracing, testing, and case isolation, offer the opportunity for New Zealand to contain and eliminate COVID-19. We use a stochastic model to investigate containment and elimination scenarios for COVID-19 in New Zealand, as the country considers the exit from its four week period of strong Level 4 population-wide control measures. In particular we consider how the effectiveness of its case isolation operations influence the outcome of lifting these strong population-wide controls. The model is parameterised for New Zealand and is initialised using current case data, although we do not make use of information concerning the geographic dispersion of cases and the model is not stratified for age or co-morbidities.We find that fast tracing and case isolation (i.e. operations that are sustained at rates comparable to that at the early stages of New Zealand’s response) can lead to containment or elimination, as long as strong population-wide controls remain in place. Slow case isolation can lead to containment (but not elimination) as long as strong Level 4 population-wide controls remain in place. However, we find that relaxing strong population-wide controls after four weeks will most likely lead to a further outbreak, although the speed of growth of this outbreak can be reduced by fast case isolation, by tracing, testing, or otherwise. We find that elimination is only likely if case isolation is combined with strong population-wide controls that are maintained for longer than four weeks.Further versions of this model will include an age-structured population as well as considering the effects of geographic dispersion and contact network structure, the possibility of regional containment combined with inter-regional travel restrictions, and the potential for harm to at risk communities and essential workers.Executive SummaryWhile New Zealand case numbers remain low, tracing, testing, and rapid case isolation, combined with population-wide control methods, offer an opportunity for the country to contain and eliminate COVID-19.Simulations using our model suggest that the current population-wide controls (Alert Level 4) have already had a significant effect on new case numbers (see figure below).We also find that fast case isolation, whether as a result of contact tracing, rapid testing, or otherwise, can lead to containment and possibly even elimination, when combined with strong population-wide controls.Slow case isolation can also lead to containment, but only as long as strong population wide controls remain in place. It is unlikely to lead to elimination.
A loss-of-function mutation in IL-17F enhances susceptibility of mice to oropharyngeal candidiasis
Authors: Zhou Chunsheng , Monin Leticia , Gordon Rachael , Aggor Felix E.Y. , Bechara Rami , Edwards Tara N. , Kaplan Daniel H. , Gingras Sebastien , Gaffen Sarah L. 
Published: April 2020

AbstractOropharyngeal candidiasis (OPC) is an opportunistic infection of the oral mucosa caused by the commensal fungusC. albicans. IL-17 receptor signaling is essential to prevent OPC in mice and humans, but the individual roles of its ligands, IL-17A, IL-17F and IL-17AF, are less clear. A homozygous IL-17F deficiency in mice does not cause OPC susceptibility, whereas mice lacking IL-17A are moderately susceptible. In humans, a rare heterozygous mutation in IL-17F (IL-17F.S65L) was identified that causes chronic mucocutaneous candidiasis, suggesting the existence of essential antifungal pathways mediated by IL-17F and/or IL-17AF. To investigate the role of IL-17F and IL-17AF in more detail, we exploited this ‘experiment of nature’ by creating a mouse line bearing the homologous mutation in IL-17F (Ser65Leu) by CRISPR/Cas9.The resultingIl17fS65L/S65Lmice showed increased susceptibility to OPC, but only in homozygous, not heterozygous, mutant mice. The mutation was linked to impaired CXC chemokine expression and neutrophil recruitment to the infected tongue but not to alterations in antimicrobial peptide expression. These findings suggest mechanisms by which the enigmatic cytokine IL-17F contributes to host defense against fungi.
In-depth Bioinformatic Analyses of Human SARS-CoV-2, SARS-CoV, MERS-CoV, and OtherNidoviralesSuggest Important Roles of Noncanonical Nucleic Acid Structures in Their Lifecycles
Authors: Bartas Martin , Brázda Václav , Bohálová Natália , Cantara Alessio , Volná Adriana , Stachurová Tereza , Malachová Kateřina , Jagelská Eva B. , Porubiaková Otília , Červeň Jiří , Pečinka Petr 
Published: April 2020

AbstractNoncanonical nucleic acid structures play important roles in the regulation of molecular processes. Considering the importance of the ongoing coronavirus crisis, we decided to evaluate genomes of all coronaviruses sequenced to date (stated more broadly, the orderNidovirales) to determine if they contain noncanonical nucleic acid structures. We discovered much evidence of putative G-quadruplex sites and even much more of inverted repeats (IRs) loci, which in fact are ubiquitous along the whole genomic sequence and indicate a possible mechanism for genomic RNA packaging. The most notable enrichment of IRs was found inside 5′UTR for IRs of size 12+ nucleotides, and the most notable enrichment of putative quadruplex sites (PQSs) was located before 3′UTR, inside 5′UTR, and before mRNA. This indicates crucial regulatory roles for both IRs and PQSs. Moreover, we found multiple G-quadruplex binding motifs in human proteins having potential for binding of SARS-CoV-2 RNA. Noncanonical nucleic acids structures inNidoviralesand in novel SARS-CoV-2 are therefore promising druggable structures that can be targeted and utilized in the future.
LADON, a natural antisense transcript ofNODAL, promotes an invasive behaviour in melanoma cells
Authors: Annie Dutriaux , Serena Diazzi , Sandrine Caburet , Chiara Bresesti , Sylvie Hardouin , Frédérique Deshayes , Jérôme Collignon , Domenico Flagiello 
Published: April 2020

SummaryThe TGFβ family member NODAL, known for its role during embryonic development, has also been associated with tumor progression in several cancers. Some of the evidence supporting its involvement in melanoma appeared contradictory, suggesting that NODAL in this context might rely on a non-canonical signalling mode. We found that NODAL inactivation in a metastatic melanoma cell line prevents the cells from acquiring invasive behaviour. However, we show that this phenotype does not result from the absence of NODAL, but from a defect in the expression of a natural antisense transcript of NODAL, here called LADON. We found that LADON promotes the mesenchymal to amoeboid transition that is critical to melanoma cell invasiveness, and that a WNT/β-CATENIN signalling-dependent increase in LADON expression is required to complete this transition. LADON’s downstream effectors include, among others, the proto-oncogene MYCN. These results identify LADON as a player in the regulatory network that governs tumor progression in melanoma, and possibly in other types of cancer.
Distinct evolutionary paths in chronic lymphocytic leukemia during resistance to graft-versus-leukemia
Authors: Bachireddy Pavan , Ennis Christina , Nguyen Vinhkhang N. , Clement Kendell , Gohil Satyen H. , Shukla Sachet A. , Forman Juliet , Barkas Nikolas , Freeman Samuel , Bavli Natalie , Elagina Liudmila , Leshchiner Ignaty , Mohammad Arman W. , Rassenti Laura Z , Kipps Thomas J , Brown Jennifer R. , Getz Gad A. , Ho Vincent T. , Gnirke Andreas , Neuberg Donna , Soiffer Robert J. , Ritz Jerome , Alyea Edwin P. , Kharchenko Peter V. , Wu Catherine J. 
Published: April 2020

AbstractResistance to the graft-versus-leukemia (GvL) effect remains the major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive hematologic malignancies. The basis of GvL resistance for advanced lymphoid malignancies remains incompletely understood. We hypothesized that for patients with chronic lymphocytic leukemia (CLL) treated with allo-HSCT, leukemic cell-intrinsic features shape GvL outcomes by directing the evolutionary trajectories of CLL cells. Integrated genetic, transcriptomic and epigenetic analyses of CLL cells from 10 patients revealed that the clinical kinetics of post- HSCT relapse are shaped by distinct molecular dynamics and suggest that the selection pressures of the GvL bottleneck are unlike those imposed by chemotherapy. No selective advantage for HLA loss was observed, even when present in pre-transplant subpopulations. Regardless of post-transplant relapse kinetics, gain of stem cell modules was a common signature associated with leukemia relapse. These data elucidate the biological pathways that underlie GvL resistance and post-transplant relapse.One Sentence SummaryWe find that the clinical kinetics of chronic lymphocytic leukemia relapse after stem cell transplant are underwritten by distinct genetic and epigenetic evolutionary trajectories and suggest that the selection pressures of the post-transplant, immunologic bottleneck are unlike those imposed by chemotherapy.
The Development of Cognitive Control in Children with Autism Spectrum Disorders or Obsessive-Compulsive Disorder: A Longitudinal fMRI study
Authors: Gooskens Bram , Bos Dienke J. , Naaijen Jilly , Akkermans Sophie E.A. , Kaiser Anna , Hohmann Sarah , Bruchhage Muriel M.K. , Banaschewski Tobias , Brandeis Daniel , Williams Steven C.R. , Lythgoe David J. , Buitelaar Jan K. , Oranje Bob , Durston Sarah ,   the TACTICS consortium
Published: April 2020

AbstractRepetitive behavior is a core symptom of Autism Spectrum Disorder (ASD) and Obsessive-Compulsive Disorder (OCD), and has been associated with impairments in cognitive control. However, it is unclear how cognitive control and associated neural circuitry relate to the development of repetitive behavior in children with these disorders. In a multicenter, longitudinal study (TACTICS; Translational Adolescent and Childhood Therapeutic Interventions in Compulsive Syndromes), the development of cognitive control was assessed during late childhood using a longitudinal fMRI design with a modified stop-signal task in children with ASD or OCD, and typically developing (TD) children (baseline: N=122 (8-12y), follow-up: N=72 (10-14y), average interval: 1.2y). Stop-signal reaction time (SSRT) decreased over development, regardless of diagnosis. Repetitive behavior in children with ASD and OCD was not associated with performance on the stop-signal task. There were no whole-brain between-group differences in brain activity, but ROI-analyses showed increases in activity in right precentral gyrus over development for children with OCD. In sum, even though subtle differences were observed in the development of brain activity in children with OCD, the findings overall suggest that the development of cognitive control, as assessed by the stop signal task, is similar in children with and without ASD or OCD.
DivIVA is essential inDeinococcus radioduransand its C terminal domain regulates new septum orientation during cell division
Authors: Chaudhary Reema , Kota Swathi , Misra Hari S 
Published: April 2020

AbstractFtsZ assembly at mid cell position in rod shaped bacteria is regulated by gradient of MinCDE complex across the poles. In round shaped bacteria, which lack predefined poles and the next plane of cell division is perpendicular to previous plane, the determination of site for FtsZ assembly is intriguing.Deinococcus radioduransa coccus shaped bacterium, is characterized for its extraordinary resistance to DNA damage. Here we report that DivIVA a putative component of Min system in this bacterium (drDivIVA) interacts with cognate cell division and genome segregation proteins. The deletion of full length drDivIVA was found to be indispensable while its C-terminal deletion (ΔdivIVAC) was dispensable but produced distinguishable phenotypes like slow growth, altered plane for new septum formation and angular septum. Both wild type and mutant showed FtsZ foci formation and their gamma radiation responses were nearly identical. But unlike in wild type, the FtsZ localization in mutant cells was found to be away from orthogonal axis with respect to plane of previous septum. Notably, DivIVA-RFP localizes to membrane during cell division and then perpendicular to previous plane of cell division.In transexpression of drDivIVA in ΔdivIVACbackground could restore the wild type pattern of septum formation perpendicular to previous septum. These results suggested that DivIVA is an essential protein inD. radioduransand the C-terminal domain that contributes to its interaction with MinC determines the plane of new septum formation, possibly by controlling MinC oscillation through orthogonal axis in the cells.
A 63-bp insertion in exon 2 of the porcineKIF21Agene is associated with arthrogryposis multiplex congenita
Authors: Fang Zih-Hua , Nosková Adéla , Crysnanto Danang , Neuenschwander Stefan , Vögeli Peter , Pausch Hubert 
Published: April 2020

SummaryArthrogryposis multiplex congenita (AMC) is a recessively inherited fatal disease detected almost 20 years ago in the Swiss Large White pig population. A diagnostic marker test enabled the identification of carrier animals, but the underlying causal mutation remains unknown. To identify the mutation underlying AMC, we collected whole-genome genotyping and sequencing data for 11 affected piglets and 23 healthy pigs. Haplotype-based case-control association testing using 47,829 SNPs confirmed that AMC maps to SSC5 (P= 9.4 ×10−13). Subsequent autozygosity mapping revealed a common 6.06 Mb region (from 66,757,970 to 72,815,151 bp) of extended homozygosity in 11 piglets affected by AMC. We detected a 63-bp insertion in the second exon ofKIF21Agene encoding Kinesin Family Member 21A using whole-genome sequences of a carrier boar, two of its affected and two heterozygous piglets. This insertion was compatible with the recessive inheritance of AMC. The 63-bp insertion likely represents a loss-of-function allele because it is predicted to introduce a premature stop codon inKIF21Agene (p.Val41_Phe42insTer) that truncates 1,614 amino acids (∼ 97%) from the protein. Lack of KIF21A protein is lethal in mice, thus providing additional evidence that a loss-of function allele ofKIF21Amight cause fatal AMC in pigs. We found that this deleterious allele still segregates at low frequency in the Swiss Large White pig population. The unambiguous detection of carrier animals can now facilitate the eradication of the deleterious allele from the population.
Zebrafish IL-4-like cytokines and IL-10 suppress inflammation but only IL-10 is essential for gill homeostasis
Authors: Bottiglione Federica , Dee Christopher T. , Lea Robert , Zeef Leo , Badrock Andrew P. , Wane Madina , Bugeon Laurence , Dallman Margaret J. , Allen Judith , Hurlstone Adam F. L. 
Published: April 2020

AbstractHealthy fish stocks are central to global food security. Key to fish health is robust immunity at mucosal surfaces, and especially at the gills. However, a balance must be struck between tolerating commensal microorganisms and reacting appropriately toward pathogens. In mammals, IL-4 and IL-13 in concert with IL-10 are essential for balancing immune response to pathogens and suppressing inflammation. Whether their fish counterparts perform similar roles is an open question. Here, we have generated IL-4/13A and IL-4/13B mutant zebrafish and, together with existing IL-10 mutants, characterized the consequences of loss-of-function of these cytokines. We demonstrate that these cytokines are required to suppress inflammation. Further, IL-4/13A and IL-4/13B are required for the maintenance of a Th2-like phenotype in the gills. As in mammals, IL-10 appears to have a more striking anti-inflammatory function than IL-4-like cytokines. Thus, both IL-10 and IL-4/13 paralogues in zebrafish exhibit aspects of conserved function with their mammalian counterparts.
Kill and cure: genomic phylogeny and bioactivity of a diverse collection ofBurkholderia gladiolibacteria capable of pathogenic and beneficial lifestyles
Authors: Jones Cerith , Webster Gordon , Mullins Alex J. , Jenner Matthew , Bull Matthew J. , Dashti Yousef , Spilker Theodore , Parkhill Julian , Connor Thomas R. , LiPuma John J. , Challis Gregory L. , Mahenthiralingam Eshwar 
Published: April 2020

ABSTRACTBurkholderia gladioliis one of few bacteria with a broad ecology spanning disease in humans, animals, and plants, and encompassing beneficial interactions with multiple eukaryotic hosts. It is a plant pathogen, a bongkrekic acid toxin producing food-poisoning agent, and a lung pathogen in people with cystic fibrosis (CF). Contrasting beneficial traits include antifungal production exploited by insects to protect their eggs, plant protective abilities and antibiotic biosynthesis. We explored the ecological diversity and specialized metabolite biosynthesis of 206B. gladiolistrains, phylogenomically defining 5 evolutionary clades. Historical disease pathovars (pv)B. gladiolipv.allicolaandB. gladiolipv.cocovenenanswere phylogenetically distinct, whileB. gladiolipv.gladioliandB. gladiolipv.agaricicolawere indistinguishable. Soft-rot disease and CF infection pathogenicity traits were conserved across all pathovars. Biosynthetic gene clusters for toxoflavin, caryoynencin and enacyloxin were dispersed acrossB. gladioli, but bongkrekic acid and gladiolin production were clade specific. Strikingly, 13% of CF-infection strains characterised (n=194) were bongkrekic acid toxin positive, uniquely linking this food-poisoning risk factor to chronic lung disease. Toxin production was suppressed by exposing strains to the antibiotic trimethoprim, providing a potential therapeutic strategy to minimise poisoning risk in CF.
Dynamics of viral index infections in novel hosts
Authors: Mollentze Nardus , Streicker Daniel G. , Murcia Pablo R. , Hampson Katie , Biek Roman 
Published: April 2020

AbstractWhether a pathogen entering a new host species results in a single infection or in onward transmission, and potentially an outbreak, depends upon the progression of infection in the index case. Although index infections are rarely observable in nature, experimental inoculations of pathogens into novel host species have a long history in biomedical research. This provides a rich and largely unexploited data source for meta-analyses to identify the host and pathogen determinants of variability in infection outcomes. Here, we analysed the progressions of 514 experimental cross-species inoculations of rabies virus, a widespread zoonotic pathogen which in nature exhibits both dead end infections and varying levels of sustained transmission in novel hosts. Inoculations originating from bats rather than carnivores, and from warmer to cooler-bodied species caused infections with shorter incubation periods that were associated with diminished virus excretion. Inoculations between distantly related hosts tended to result in shorter clinical disease periods, which will also impede transmission. All effects were modulated by infection dose and together suggest that increased virulence as host species become more dissimilar is the limiting factor preventing onward transmission. These results explain observed constraints on rabies virus host shifts, allow us to evaluate the risk of novel reservoirs establishing, and give mechanistic insights into why host shifts are less likely between genetically distant species. More generally, our study highlights meta-analyses of experimental infections as a tractable approach to quantify the complex interactions between virus, reservoir, and novel host that shape the outcome of cross-species transmission.Significance statementEmerging disease epidemics often result from a pathogen establishing transmission in a novel host species. However, most cross-species transmissions fail to establish in the newly infected species for reasons that remain poorly understood. Examining cross-species inoculations involving rabies, a widespread viral zoonosis, we show that mismatches in virulence, which are predictable from host and viral factors, make sustained transmission in the novel host less likely. In particular, disease progression was accelerated and virus excretion decreased when the reservoir and novel host were physiologically or genetically more dissimilar. These mechanistic insights help to explain and predict host shift events and highlight meta-analyses of existing experimental inoculation data as a powerful and generalisable approach for understanding the dynamics of index infections in novel species.
Altered hypothalamic DNA methylation and stress-induced hyperactivity in a novel model of early life stress
Authors: Fitzgerald Eamon , Sinton Matthew C , Wernig-Zorc Sara , Morton Nicholas M , Holmes Megan C , Boardman James P , Drake Amanda J 
Published: April 2020

AbstractEarly life stress during childhood is associated with a number of psychiatric disorders that manifest across the life course. Preterm birth is a profound stressor, and an important cause of cognitive impairment, as well as neurodevelopmental and psychiatric disorders. However, the mechanisms that link events during the early neonatal period with later functional problems are poorly understood. We developed a novel mouse model of early life stress (modified maternal separation; MMS) with specific relevance to preterm birth (PTB) and hypothesised it would affect the hypothalamic transcriptome and DNA methylome and impact on behaviour in adulthood. MMS consisted of repeatedly stimulating pups for 1.5 hours/day, whilst separated from their mother, from postnatal day (P)4-6. 3’ RNA sequencing and DNA methylation immunoprecipitation (meDIP) sequencing was performed on the hypothalamus at P6. Behaviour was assessed with the elevated plus and open field mazes, and in-cage monitoring at 3-4 months of age. Although MMS was only associated with subtle changes in gene expression there were widespread alterations in DNA methylation. Notably, differentially methylated regions were enriched for synapse-associated loci. MMS also resulted in hyperactivity in the elevated plus and open field mazes, but in-cage monitoring revealed that this was not representative of habitual hyperactivity. In conclusion we describe a novel model of early life stress with relevance to PTB, with marked effects on DNA methylation in the hypothalamus and with stress-specific hyperactivity in young adulthood. We suggest that these results have implications for the understanding of early life stress mediated effects on brain development.