bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of phenotypic variation on consumer coexistence and prey community structure
Authors: Hogle Shane L. , Hepolehto Iina , Ruokolainen Lasse , Cairns Johannes , Hiltunen Teppo
Published: June 2021

A popular idea in ecology is that trait variation among individuals from the same species may promote the coexistence of competing species. However, theoretical and empirical tests of this idea have yielded inconsistent findings. We manipulated intraspecific trait diversity in a ciliate competing with a nematode for bacterial prey in experimental microcosms. We found that intraspecific trait variation inverted the original competitive hierarchy to favor the consumer with variable traits, ultimately resulting in competitive exclusion. This competitive outcome was driven by foraging traits (size, speed, and directionality) that increased the ciliate’s fitness ratio and niche overlap with the nematode. The interplay between consumer trait variation and competition resulted in non-additive cascading effects - mediated through prey defense traits - on prey community assembly. Our results suggest that predicting consumer competitive population dynamics and the assembly of prey communities will require understanding the complexities of trait variation within consumer species.
SignalP 6.0 achieves signal peptide prediction across all types using protein language models
Authors: Teufel Felix , Armenteros José Juan Almagro , Johansen Alexander Rosenberg , Gíslason Magnús Halldór , Pihl Silas Irby , Tsirigos Konstantinos D. , Winther Ole , Brunak Søren , von Heijne Gunnar , Nielsen Henrik
Published: June 2021

Signal peptides (SPs) are short amino acid sequences that control protein secretion and translocation in all living organisms. As experimental characterization of SPs is costly, prediction algorithms are applied to predict them from sequence data. However, existing methods are unable to detect all known types of SPs. We introduce SignalP 6.0, the first model capable of detecting all five SP types. Additionally, the model accurately identifies the positions of regions within SPs, revealing the defining biochemical properties that underlie the function of SPs in vivo. Results show that SignalP 6.0 has improved prediction performance, and is the first model to be applicable to metagenomic data.

SignalP 6.0 is available at https://services.healthtech.dtu.dk/service.php?SignalP-6.0
Normal Aging in Mice is Associated with a Global Reduction in Cortical Spectral Power and Network-Specific Declines in Functional Connectivity
Authors: Albertson Asher J. , Landsness Eric C. , Tang Michelle J. , Yan Ping , Miao Hanyang , Rosenthal Zachary P. , Kim Byungchan , Culver Joseph C. , Bauer Adam Q , Lee Jin-Moo
Published: June 2021

Normal aging is associated with a variety of neurologic changes including declines in cognition, memory, and motor activity. These declines correlate with neuronal changes in synaptic structure and function. Degradation of brain network activity and connectivity represents a likely mediator of age-related functional deterioration resulting from these neuronal changes. Human studies have demonstrated both general decreases in spontaneous cortical activity and disruption of cortical networks with aging. Current techniques used to study cerebral network activity are hampered either by limited spatial resolution (e.g. electroencephalography, EEG) or limited temporal resolution (e.g., functional magnetic resonance imaging, fMRI). Here we utilize mesoscale imaging of neuronal activity in Thy1-GCaMP6f mice to characterize neuronal network changes in aging with high spatial resolution across a wide frequency range. We show that while evoked activity is unchanged with aging, spontaneous neuronal activity decreases across a wide frequency range (0.01-4Hz) involving all regions of the cortex. In contrast to this global reduction in cortical power, we found that aging is associated with functional connectivity (FC) deterioration of select networks including somatomotor, cingulate, and retrosplenial nodes. These changes are corroborated by reductions in homotopic FC and node degree within somatomotor and visual cortices. Finally, we found that whole cortex delta power and delta band node degree correlate with exploratory activity in young but not aged animals. Together these data suggest that aging is associated with global declines in spontaneous cortical activity and focal deterioration of network connectivity, and that these reductions may be associated with age-related behavioral declines.
Targeted Delivery of Chloroquine to Plasmacytoid Dendritic Cells Enhances Inhibition of the Type I Interferon Response
Authors: Allen Marilyn E. , Golding Amit , Rus Violeta , Karabin Nicholas B. , Li Sophia , Lescott Chamille J. , Bobbala Sharan , Scott Evan A. , Szeto Gregory L.
Published: June 2021

Systemic lupus erythematosus (SLE) causes damaging inflammation in multiple organs via the accumulation of immune complexes. These complexes activate plasmacytoid DCs (pDCs) via TLR7 and TLR9, contributing to disease pathogenesis by driving secretion of inflammatory type I IFNs. Antimalarial drugs, such as chloroquine (CQ), are TLR antagonists used to alleviate inflammation in SLE. However, they require ~3 months of continuous use before achieving therapeutic efficacy and can accumulate in the retinal pigment epithelium with chronic use resulting in retinopathy. We hypothesized that poly(ethylene glycol)-b-poly(propylene sulfide) (PEG-b-PPS) filamentous nanocarriers, filomicelles (FMs) could improve drug activity and reduce toxicity by directly delivering CQ to pDCs via passive, morphology-based targeting. Healthy human PBMCs were treated with soluble CQ or CQ-loaded FMs, stimulated with TLR agonists or SLE patient sera, and type I IFN secretion was quantified via multi-subtype IFN-α ELISA and MX1 gene expression using real-time RT-qPCR. Our results showed that 50 µg CQ/mg FM decreased MX1 expression and IFN-α production after TLR activation with either synthetic nucleic acid agonists or immune complex rich sera from SLE patients. Cellular uptake and biodistribution studies showed that FMs preferentially accumulate in human pDCs in vitro and in tissues frequently damaged in SLE patients (i.e., liver and kidneys) while sparing the eye in vivo. These results showed that nanocarrier morphology enables drug delivery, and CQ-FMs may be equally effective and more targeted than soluble CQ at inhibiting SLE-relevant pathways.
A de novo genome assembly and annotation of the southern flying squirrel (Glaucomys volans)
Authors: Wolf J.F. , Bowman J. , Keobouasone S. , Taylor R.S. , Wilson P.J.
Published: June 2021

Northern (Glaucomys sabrinus) and southern (Glaucomys volans) flying squirrels are widespread species distributed across much of North America. Northern flying squirrels are common inhabitants of the boreal forest, also occurring in coniferous forest remnants farther south, whereas the southern flying squirrel range is centered in eastern temperate woodlands. These two flying squirrel species exhibit a hybrid zone across a latitudinal gradient in an area of recent secondary contact.Glaucomyshybrid offspring are viable and can successfully backcross with either parental species, however, the fitness implications of such events are currently unknown. Some populations ofG. sabrinusare endangered, and thus, interspecific hybridization is a key conservation concern in flying squirrels. We sequenced and assembled ade novolong-read genome from aG. volansindividual sampled in southern Ontario, Canada, while four short-read genomes (2G. sabrinusand 2G. volans, all from Ontario) were re-sequenced on Illumina platforms. The final genome assembly consisted of approximately 2.40Gb with a scaffold N50 of 455.26Kb. Benchmarking Universal Single-Copy Orthologs reconstructed 3,742 (91.2%) complete mammalian genes and genome annotation using RNA-seq identified the locations of 19,124 protein-coding genes. The four short-read individuals were aligned to our reference genome to investigate the demographic history of the two species. A Principal Component Analysis clearly separated re-sequenced individuals, while inferring population size history using the Pairwise Sequentially Markovian Coalescent model noted an approximate species split one million years ago, and a single, possibly recently introgressed individual.
Genetic analysis of praziquantel response in schistosome parasites implicates a Transient Receptor Potential channel
Authors: Le Clec’h Winka , Chevalier Frédéric D. , Mattos Ana Carolina A. , Strickland Amanda , Diaz Robbie , McDew-White Marina , Rohr Claudia M. , Kinung’hi Safari , Allan Fiona , Webster Bonnie L , Webster Joanne P , Emery Aidan M , Rollinson David , Djirmay Amadou Garba , Al Mashikhi Khalid M , Yafae Salem Al , Idris Mohamed A , Moné Hélène , Mouahid Gabriel , LoVerde Philip , Marchant Jonathan S. , Anderson Timothy J.C.
Published: June 2021

Mass treatment with praziquantel (PZQ) monotherapy is the mainstay for schistosomiasis treatment. This drug shows imperfect cure rates in the field and parasites showing reduced PZQ response can be selected in the laboratory, but the extent of resistance in Schistosoma mansoni populations is unknown. We examined the genetic basis of variation in PZQ response in a S. mansoni population (SmLE-PZQ-R) selected with PZQ in the laboratory: 35% of these worms survive high dose (73 µg/mL) PZQ treatment. We used genome wide association to map loci underlying PZQ response. The major chr. 3 peak contains a transient receptor potential (Sm.TRPMPZQ) channel (Smp_246790), activated by nanomolar concentrations of PZQ. PZQ response shows recessive inheritance and marker-assisted selection of parasites at a single Sm.TRPMPZQ SNP enriched populations of PZQ-resistant (PZQ-ER) and sensitive (PZQ-ES) parasites showing >377 fold difference in PZQ response. The PZQ-ER parasites survived treatment in rodents better than PZQ-ES. Resistant parasites show 2.25-fold lower expression of Sm.TRPMPZQ than sensitive parasites. Specific chemical blockers of Sm.TRPMPZQ enhanced PZQ resistance, while Sm.TRPMPZQ activators increased sensitivity. A single SNP in Sm.TRPMPZQ differentiated PZQ-ER and PZQ-ES lines, but mutagenesis showed this was not involved in PZQ-response, suggesting linked regulatory changes. We surveyed Sm.TRPMPZQ sequence variation in 259 parasites from the New and Old World revealing one nonsense mutation that results in a truncated protein with no PZQ-binding site. Our results demonstrate that Sm.TRPMPZQ underlies variation in PZQ response in S. mansoni and provides an approach for monitoring emerging PZQ-resistance alleles in schistosome elimination programs.

One Sentence Summary

A transient receptor potential channel determines variation in praziquantel-response in Schistosoma mansoni.
Impact of SNP calling quality on the detection of transmission ratio distortion in goats
Authors: Luigi-Sierra María Gracia , Casellas Joaquim , Martínez Amparo , Delgado Juan Vicente , Álvarez Javier Fernández , Such Francesc Xavier , Jordana Jordi , Amills Marcel
Published: June 2021

Transmission ratio distortion (TRD) is the preferential transmission of one specific allele to offspring at the expense of the other one. The existence of TRD is mostly explained by the segregation of genetic variants with deleterious effects on the developmental processes that go from the formation of gametes to fecundation and birth. A few years ago, a statistical methodology was implemented in order to detect TRD signals on a genome-wide scale as a first step to uncover the biological basis of TRD and reproductive success in domestic species. In the current work, we have analyzed the impact of SNP calling quality on the detection of TRD signals in a population of Murciano-Granadina goats. Seventeen bucks and their offspring (N=288) were typed with the Goat SNP50 BeadChip, while the genotypes of the dams were lacking. Performance of a genome-wide scan revealed the existence of 36 SNPs showing significant evidence of TRD. When we calculated GenTrain scores for each one of the SNPs, we observed that 25 SNPs showed scores below 0.8. The allele frequencies of these SNPs in the offspring were not correlated with the allele frequencies estimated in the dams with statistical methods, thus evidencing that flawed SNP calling quality might lead to the detection of spurious TRD signals. We conclude that, when performing TRD scans, the GenTrain scores of markers should be taken into account to discriminate SNPs that are truly under TRD from those yielding spurious signals due to technical problems.
Motif-based phosphoproteome clustering improves modeling and interpretation
Authors: Creixell Marc , Meyer Aaron S.
Published: June 2021

Cell signaling is orchestrated in part through a network of protein kinases and phosphatases. Dysregulation of kinase signaling is widespread in diseases such as cancer and is readily targetable through inhibitors of kinase enzymatic activity. Mass spectrometry-based analysis of kinase signaling can provide a global view of kinase signaling regulation but making sense of these data is complicated by its stochastic coverage of the proteome, measurement of substrates rather than kinase signaling itself, and the scale of the data collected. Here, we implement a dual data and motif clustering strategy (DDMC) that simultaneously clusters substrate peptides into similarly regulated groups based on their variation within an experiment and their sequence profile. We show that this can help to identify putative upstream kinases and supply more robust clustering. We apply this clustering to large-scale clinical proteomic profiling of lung cancer and identify conserved proteomic signatures of tumorigenicity, genetic mutations, and tumor immune infiltration. We propose that DDMC provides a general and flexible clustering strategy for the analysis of phosphoproteomic data.

One-sentence Summary

DDMC is a general and flexible strategy for phosphoproteomic analysis by clustering phosphopeptides using both their phosphorylation abundance and sequence motifs.
Imaging of the pial arterial vasculature of the human brain in vivo using high-resolution 7T time-of-flight angiography
Authors: Bollmann Saskia , Mattern Hendrik , Bernier Michaël , Robinson Simon D. , Park Daniel , Speck Oliver , Polimeni Jonathan R.
Published: June 2021

The pial arterial vasculature of the human brain is the only blood supply to the neocortex, but quantitative data on the morphology and topology of these mesoscopic arteries (diameter 50– 300 µm) remains scarce. Because it is commonly assumed that blood flow velocities in these vessels are prohibitively slow, non-invasive time-of-flight MRI angiography (TOF-MRA)—which is well-suited to high 3D imaging resolutions—has not been applied to imaging the pial arteries. Here, we provide a theoretical framework that outlines how TOF-MRA can visualize small pial arteries in vivo, by employing extremely small voxels at the size of individual vessels. We then provide evidence for this theory by imaging the pial arteries at 140-µm isotropic resolution using a 7T MRI scanner and prospective motion correction, and show that pial arteries one voxel-width in diameter can be detected. We conclude that imaging pial arteries is not limited by slow blood flow, but instead by achievable image resolution. This study represents the first targeted, comprehensive account of imaging pial arteries in vivo in the human brain. This ultra-high-resolution angiography will enable the characterization of pial vascular anatomy across the brain to investigate patterns of blood supply and relationships between vascular and functional architecture.
Dietary modulation alters susceptibility to Listeria monocytogenes and Salmonella typhimurium in a gut microbiota-independent manner
Authors: Wolter Mathis , Steimle Alex , Zimmer Jacques , Desai Mahesh S.
Published: June 2021

Food safety has considerably improved worldwide, yet infections with food-borne human enteric pathogens, such as Listeria spp. and Salmonella spp., still cause numerous hospitalizations and fatalities. Thus, the need to shed more light on the mechanisms of enteropathogenesis is apparent. Since dietary alterations, including fiber deficiency, might impact the colonization resistance by the gut microbiota, studying diet–microbiota–pathogen axis holds promise in further understanding the pathogenesis mechanisms. Using a gnotobiotic mouse model containing a 14-member synthetic human gut microbiota (14SM), we have previously shown that dietary fiber deprivation promotes proliferation of mucin-degrading bacteria leading to a microbiota-mediated erosion of the colonic mucus barrier, which results in an increased susceptibility towards the rodent enteric pathogen Citrobacter rodentium. Here, we sought to understand how low-fiber diet affects susceptibility to Listeria monocytogenes and Salmonella typhimurium infections in our 14SM gnotobiotic mouse model, in BALB/c and C57BL/6N backgrounds, respectively. Intriguingly and in contrast to our results with C. rodentium, we observe that depriving mice of dietary fiber protected them from infections with the pathogens compared to mice fed a standard chow. The microbiota delayed the overall pathogenicity as compared to the onset of disease observed in germ-free control mice; nevertheless, we observe the same effect of diet in germ-free mice, suggesting that the susceptibility is microbiota independent. Our study points out an important observation that dietary fiber plays a crucial role on either the host susceptibility, the virulence of these pathogens, or both, which would be judicious to design and interpret future studies.

Importance

Human enteric pathogens Listeria monocytogenes and Salmonella typhimurium are employed as classical models in rodent hosts to understand the pathogenesis mechanisms of food-borne pathogens. Research in the past decade has stressed importance of the composition of the gut microbiota in modulating susceptibility to these pathogens. Our results—using gnotobiotic mice and germ-free control animals—additionally suggest that the dietary fiber components dominate the impact of enteropathogenic virulence over the pathogenicity-modulating properties of the gut microbiota. The significance of our research is in the need to carefully choose a certain chow when performing the enteropathogen-associated mouse experiments and to cautiously match the rodent diets when trying to replicate experiments across different laboratories. Finally, our data underscore the importance of germ-free control animals to study these pathogens, as our findings would have been prone to misinterpretation in the absence of these controls.
Equine intestinal O-seroconverting temperate coliphage Hf4s: genomic and biological characterization
Authors: Kulikov Eugene E. , Golomidova Alla K. , Efimov Alexandr D. , Belalov Ilya S. , Letarova Maria A. , Zdorovenko Evelina L. , Knirel Yuriy A. , Dmitrenok Andrey S. , Letarov Andrey V.
Published: June 2021

Tailed bacteriophages constitute the bulk of the intestinal viromes of the vertebrate animals. However, the relationships between lytic and lysogenic lifestyles of the phages in these ecosystems are not always clear and may vary between the species or even between the individuals. The human intestinal (fecal) viromes are believed to be dominated by temperate phages, while in the horse feces the virulent phages are more prevalent. Almost all the isolates of horse fecal coliphages are virulent. Phage Hf4s is the first temperate equine intestinal coliphage characterized. It was isolated from the horse feces on the indigenous equine E. coli 4s strain. It is a podovirus, related to Lederbergvirus genus (including the well–characterized Salmonella phage P22). Hf4s recognizes the host O antigen as its primary receptor and possesses a functional O-antigen seroconversion cluster that renders the lysogens protected from the superinfection by the same phage and also abolishes the adsorption of some indigenous equine virulent coliphages, such as DT57C, while the other phages, such as G7C or phiKT retain the ability to infect E. coli 4s (Hf4s) lysogens.

Importance

The relationships between virulent and temperate bacteriophages and their impact on high-density symbiotic microbial ecosystems of the animal are not always clear and may vary between the species or even between the individuals. The horse intestinal virome is dominated by the virulent phages, and Hf4s is the first temperate equine intestinal coliphage characterized. It recognizes the host O antigen as its primary receptor and possesses a functional O-antigen seroconversion cluster that renders the lysogens protected from the superinfection by some indigenous equine virulent coliphages, such as DT57C, while the other phages, such as G7C or phiKT retain the ability to infect E. coli 4s (Hf4s) lysogens. microbial viruses in the mammal intestinal ecosystems.
Amyloid aggregation of Streptococcus mutans Cnm influences its collagen-binding activity
Authors: de Mojana di Cologna Nicholas , Samaddar Sandip , Valle Carolina A. , Vargas Jonathan , Aviles-Reyes Alejandro , Morales Joyce , Ganguly Tridib , Pileggi Roberta , Brady L. Jeannine , Lemos José A. , Abranches Jacqueline
Published: June 2021

The glycosylated collagen- and laminin-binding surface adhesin Cnm is present in approximately 20% of S. mutans clinical isolates and is associated with systemic infections and increased caries risk. Other surface-associated collagen-binding proteins of S. mutans such as P1 and WapA have been demonstrated to form an amyloid quaternary structure with functional implications within biofilms. In silico analysis predicted that the β-sheet rich N-terminal collagen-binding domain (CBD) of Cnm has propensity for amyloid aggregation, whereas the threonine-rich C-terminal domain was predicted to be disorganized. In this study, thioflavin-T fluorescence and electron microscopy were used to show that Cnm forms amyloids either in its native glycosylated or recombinant non-glycosylated forms and that the CBD of Cnm is the main amyloidogenic unit of Cnm. We then performed a series of in vitro, ex vivo and in vivo assays to characterize the amylogenic properties of Cnm. In addition, Congo red birefringence indicated that Cnm is a major amyloidogenic protein of S. mutans biofilms. Competitive binding assays using collagen-coated microtiter plates and dental roots, a substrate rich in collagen, revealed that Cnm monomers inhibit S. mutans binding to collagenous substrates whereas Cnm amyloid aggregates lose this property. Thus, while Cnm contributes to recognition and initial binding of S. mutans to collagen-rich surfaces, Cnm amyloid aggregation appears to represent a mechanism to modulate this activity in mature biofilms.

IMPORTANCE

Streptococcus mutans is a keystone pathogen that promotes caries by acidifying the dental biofilm milieu. The collagen- and laminin-binding glycoprotein Cnm is a virulence factor found in about 20% of the clinical isolates of S. mutans. Expression of Cnm by S. mutans is associated with niche expansion, allowing colonization of multiple sites in the body including collagen-rich surfaces such as dentin and heart valves. Here, we demonstrate for the first time that Cnm function appears to be modulated by its aggregation status. As a monomer, its primary function is to promote attachment to collagenous substrates via its collagen binding domain (CBD). However, in later stages of biofilm maturation, the same CBD of Cnm self-assembles into amyloid fibrils, losing the ability to bind to collagen and likely becoming a component of the biofilm matrix. Our findings shed light into the role of functional amyloids in S. mutans pathobiology and ecology.
scSVAS: CNV clonal visualization online platform for large scale single-cell genomics
Authors: Chen Lingxi , Qing Yuhao , Li Ruikang , Li Chaohui , Li Hechen , Feng Xikang , Li Shuai Cheng
Published: June 2021

The recent advance of single-cell copy number variation analysis plays an essential role in addressing intra-tumor heterogeneity, identifying tumor subgroups, and restoring tumor evolving trajectories at single-cell scale. Pleasant visualization of copy number analysis results boosts productive scientific exploration, validation, and sharing. Several single-cell analysis figures have the effectiveness of visualizations for understanding single-cell genomics in published articles and software packages. However, they almost lack real-time interaction, and it is hard to reproduce them. Moreover, existing tools are time-consuming and memory-intensive when they reach large-scale single-cell throughputs. We present an online visualization platform, scSVAS, for real-time interactive single-cell genomics data visualization. scSVAS is specifically designed for large-scale single-cell analysis. Compared with other tools, scSVAS manifests the most comprehensive functionalities. After uploading the specified input files, scSVAS deploys the online interactive visualization automatically. Users may make scientific discoveries, share interactive visualization, and download high-quality publication-ready figures. scSVAS provides versatile utilities for managing, investigating, sharing, and publishing single-cell copy number variation profiles. We envision this online platform will expedite the biological understanding of cancer clonal evolution in single-cell resolution. All visualizations are publicly hosted at https://sc.deepomics.org.
A high content microscopy screening identifies new genes involved in cell width control inBacillus subtilis
Authors: Juillot Dimitri , Cornilleau Charlène , Deboosere Nathalie , Billaudeau Cyrille , Evouna-Mengue Parfait , Lejard Véronique , Brodin Priscille , Carballido-López Rut , Chastanet Arnaud
Published: June 2021

How cells control their shape and size is a fundamental question of biology. In most bacteria, cell shape is imposed by the peptidoglycan (PG) polymeric meshwork that surrounds the cell. Thus, bacterial cell morphogenesis results from the coordinated action of the proteins assembling and degrading the PG shell. Remarkably, during steady-state growth, most bacteria maintain a defined shape along generations, suggesting that error-proof mechanisms tightly control the process. In the rod-shaped model for Gram-positive bacteriaBacillus subtilis, the average cell length varies as a function of the growth rate but the cell diameter remains constant throughout the cell cycle and across growth conditions. Here, in an attempt to shed light on the cellular circuits controlling bacterial cell width, we developed a screen to identify genetic determinants of cell width inB. subtilis. Using high-content screening (HCS) fluorescence microscopy and semi-automated measurement of single-cell dimensions, we screened a library of ~ 4000 single knockout mutants. We identified 13 mutations significantly altering cell diameter, in genes that belong to several functional groups. In particular, our results indicate that metabolism plays a major role in cell width control inB. subtilis.
In vitro culture of freshly isolated Trypanosoma brucei brucei bloodstream forms results in gene copy-number changes
Authors: Mulindwa Julius , Ssentamu Geofrey , Matovu Enock , Marucha Kevin Kamanyi , Aresta-Branco Francisco , Helbig Claudia , Clayton Christine
Published: June 2021

Most researchers who study unicellular eukaryotes work with an extremely limited number of laboratory-adapted isolates that were obtained from the field decades ago, but the effects of passage in laboratory rodents, and adaptation to in vitro culture, have been little studied. For example, the vast majority of studies of Trypanosoma brucei biology have concentrated on just two strains, Lister 427 and EATRO1125, which were taken from the field over half a century ago and have since have undergone innumerable passages in rodents and culture. We here describe two new Trypanosoma brucei brucei strains. MAK65 and MAK98, which have undergone only 3 rodent passages since isolation from Ugandan cattle. High-coverage sequencing revealed that adaptation of the parasites to culture was accompanied by changes in gene copy numbers. T. brucei has so far been considered to be uniformly diploid, but we also found trisomy of chromosome 5 not only in one Lister 427 culture, but also in the MAK98 field isolate. Trisomy of chromosome 6, and increased copies of other chromosome segments, were also seen in established cultured lines. The two new T. brucei strains should be useful to researchers interested in trypanosome differentiation and pathogenicity. Initial results suggested that the two strains have differing infection patterns in rodents. MAK65 is uniformly diploid and grew more reproducibly in bloodstream-form culture than MAK98.
Changes In Ploidy Affect Vascular Allometry And Hydraulic Function In Trees
Authors: Barceló-Anguiano M , Holbrook NM , Hormaza JI , Losada JM
Published: June 2021

The enucleated vascular elements of the xylem and the phloem offer an excellent system to test the effect of ploidy on plant function because variation in vascular geometry has a direct influence on transport efficiency. However, evaluations of conduit sizes in polyploid plants have remained elusive, most remarkably in woody species.

We used a combination of molecular, physiological, and microscopy techniques to model the hydraulic resistance between source and sinks in tetraploid and diploid mango trees.

Tetraploids exhibited larger chloroplasts, mesophyll cells, and stomatal guard cells, resulting in higher leaf elastic modulus and lower dehydration rates despite the high water potentials of both ploidies in the field. Both the xylem and the phloem displayed a scaling of conduits with ploidy, revealing attenuated hydraulic resistance in tetraploids.

Conspicuous wall hygroscopic moieties in the cells involved in processes of transpiration and transport advocates a role in volumetric adjustments due to turgor change in polyploids, which, together with the enlargement of organelles, cells, and tissues that are critical for water and photo assimilate transport at long distances, imply major physiological novelties of polyploidy.
Biological, Molecular and Phiysiological
Characterization of Four Soybean mosaic
virus Isolates Present in Argentine Soybean
Crops
Authors: Maugeri Suarez M , Rodríguez M , Bejerman N , Laguna I. G , Rodríguez Pardina P
Published: June 2021

Soybean mosaic
virus (SMV) causes systemic
infections in soybean plants, leading to chlorotic
mosaic and producing significant yield losses. The
virus is widely distributed in all soybean
production areas in the world. In Argentina, three
geographical isolates were identified: Marcos
Juárez (MJ), Manfredi (M), and North Western
Argentina (NOA), and another isolate named “Planta
Vinosa” (PV), which causes severe necrosis
symptoms in some cultivars. Here, the biological,
molecular and physiological characterization of
these isolates was performed for the first time.
Three of the four isolates showed a low genetic
divergence in the evaluated genes (P1, CI and CP).
Although SMV-NOA and SMV-PV had high homology at
the sequence level, they showed wide differences
in pathogenicity, seed mottling and the ability of
transmission by seeds or aphids, as well as in
physiological effects. SMV-NOA caused early
alterations (before symptom appearance, BS) in
ΦPSII and MDA content in leaves with respect to
the other isolates. After the appearance of
macroscopic symptoms (late symptoms, LS), SMV-M
caused a significant increase in the content of
MDA, total soluble sugars, and starch with respect
to the other isolates. Thus, early alterations of
ΦPSII and soluble sugars might have an impact on
late viral symptoms. Likewise, SMV-MJ developed
more severe symptoms in the susceptible Davis
cultivar than in DM 4800. Therefore, our results
show differences in genome, biological properties
and physiological effects among SMV isolates as
well as different interactions of SMV-MJ with two
soybean cultivars.
Systems analysis reveals ageing-related perturbations in retinoids and sex hormones in Alzheimer’s and Parkinson’s diseases
Authors: Lam Simon , Hartmann Nils , Benfeitas Rui , Zhang Cheng , Arif Muhammad , Turkez Hasan , Uhlén Mathias , Englert Christoph , Knight Robert , Mardinoglu Adil
Published: June 2021

Neurodegenerative diseases (NDDs), including Alzheimer’s (AD) and Parkinson’s diseases (PD), are complex heterogeneous diseases with highly variable patient responses to treatment. Due to the growing evidence for ageing-related clinical and pathological commonalities between AD and PD, these diseases have recently been studied in tandem. In this study, we analyse transcriptomic data from AD and PD patients, and stratify these patients into three subclasses with distinct gene expression and metabolic profiles. Through integrating transcriptomic data with a genome-scale metabolic model and validating our findings by network exploration and co-analysis using a zebrafish ageing model, we identify retinoids as a key ageing-related feature in all subclasses of AD and PD. We also demonstrate that the dysregulation of androgen metabolism by three different independent mechanisms is a source of heterogeneity in AD and PD. Taken together, our work highlights the need for stratification of AD/PD patients and development of personalised and precision medicine approaches based on the detailed characterisation of these subclasses.
Mapping RNA-binding proteins in human B cells and T cells upon differentiation
Authors: Zandhuis Nordin D. , Nicolet Benoit P. , Wolkers Monika C.
Published: June 2021

B cells and T cells are key players in the defence against infections and malignancies. To exert their function, B cells and T cells differentiate into effector and memory cells. Tight regulation of these differentiation processes is key to prevent their malfunction, which can result in life-threatening disease. Lymphocyte differentiation relies on the appropriate timing and dosage of regulatory molecules, and post-transcriptional gene regulation (PTR) is a key player herein. PTR includes the regulation through RNA-binding proteins (RBPs), which control the fate of RNA and its translation into proteins. To date, a comprehensive RBP expression map throughout lymphocyte differentiation is lacking. Using transcriptome and proteome analyses, we here provide an RBP expression map for human B cells and T cells. We observed that even though the overall RBP expression is conserved, the relative RBP expression is distinct between B cells and T cells. Differentiation into effector and memory cells alters the RBP expression, resulting into preferential expression of different classes of RBPs. For instance, whereas naïve T cells express high levels of translation-regulating RBPs, effector T cells preferentially express RBPs that modulate mRNA stability. Lastly, we found that cytotoxic CD8+and CD4+T cells express a common RBP repertoire. Combined, our study reveals a cell type-specific and differentiation-dependent RBP expression landscape in human lymphocytes, which will help unravel the role of RBPs in lymphocyte function.
RNA polymerase II is recruited to DNA double-strand breaks for dilncRNA transcription inDrosophila
Authors: Böttcher Romy , Schmidts Ines , Nitschko Volker , Duric Petar , Förstemann Klaus
Published: June 2021

DNA double-strand breaks are among the most toxic lesions that can occur in a genome and their faithful repair is thus of great importance. Recent findings have uncovered local transcription that initiates at the break and forms a non-coding transcript, called damage-induced long non-coding RNA (dilncRNA), which helps to coordinate the DNA transactions necessary for repair. We provide nascent RNA sequencing-based evidence that RNA polymerase II transcribes the dilncRNA inDrosophilaand that this is more efficient for DNA breaks in an intron-containing gene, consistent with the higher damage-induced siRNA levels downstream of an intron. The spliceosome thus stimulates recruitment of RNA polymerase II to the break, rather than merely promoting the annealing of sense and antisense RNA to form the siRNA precursor. In contrast, RNA polymerase III nascent RNA libraries did not contain reads corresponding to the cleaved loci and selective inhibition of RNA polymerase III did not reduce the yield of damage-induced siRNAs. Finally, the damage-induced siRNA density was unchanged downstream of a T8 sequence, which terminates RNA polymerase III transcription. We thus found no evidence for a participation of RNA polymerase III in dilncRNA transcription in cultured Drosophila cells.
Remote cortical perturbation dynamically changes the network solutions to given tactile inputs in neocortical neurons
Authors: Etemadi Leila , Enander Jonas M.D. , Jörntell Henrik
Published: June 2021

The neocortex is a widely interconnected neuronal network. All such networks have a connectivity structure, which limits the possible combinations of neuronal activations across it. In this sense, the network can be said to contain solutions, i.e., for each given external input the cortex may yield a specific combination of neuronal activations/output. If the cortex has a variety of states, a given input could result in a range of possible outputs. There will also be a vast range of outputs that are not possible due to the network structure. Here we use intracellular recordings in SI neurons to show that remote intracortical electrical perturbation can impact such constraints on the responses to given tactile input patterns. Whereas each given tactile input pattern induced a wide set of preferred response states, when combined with cortical perturbation they induced response states that did not otherwise occur. The findings indicate that the physiological network structure can dynamically change as the state of any given cortical region changes, thereby enabling a very rich, multifactorial, perceptual capability.
The long arm of childhood socioeconomic deprivation on mid- to later-life cognitive trajectories: A cross-cohort analysis
Authors: Tsang Ruby S. M. , Gallacher John E. , Bauermeister Sarah
Published: June 2021

INTRODUCTION

Earlier studies of the effects of childhood socioeconomic status (SES) on later life cognitive function consistently report a social gradient in later life cognitive function. Evidence for their effects on cognitive decline is, however, less clear.

METHODS

The sample consists of 5,324 participants in the Whitehall II Study, 8,572 in the Health and Retirement Study, and 1,413 in the Kame Project, who completed self-report questionnaires on their early-life experiences and underwent repeated cognitive assessments. We characterised cognitive trajectories using latent class mixed models, and explored associations between childhood SES and latent class membership using logistic regressions.

RESULTS

We identified distinct trajectories classes for all cognitive measures examined. Childhood socioeconomic deprivation was associated with an increased likelihood of being in a lower trajectory class.

DISCUSSION

Our findings support the notions that cognitive ageing is a heterogeneous process and early-life circumstances may have lasting effects on cognition across the life-course.

Research in context

Systematic review: We reviewed the literature on childhood socioeconomic status (SES) as a predictor for cognitive decline in mid- to later-life using PubMed. Studies generally reported lower childhood SES is associated with poorer baseline cognition, but not a faster rate of decline. These studies generally focused on the mean rate of decline in the population; no study to date has explored associations between childhood SES and different cognitive trajectories. Relevant studies have been appropriately cited.

Interpretation: Our findings suggest that cognitive trajectories differ between individuals and across cognitive domains. Individuals of lower childhood SES were more likely to be in a lower cognitive trajectory class, which may or may not involve more rapid decline.

Future directions: Future studies should include more cognitive outcomes and longer follow-ups, as well as investigate the impact of social mobility to further improve our understanding on how early-life circumstances influence cognitive decline.
Molecular dissection of pro-fibrotic signaling identifies the mechanism underlying IL11-driven fibrosis gene translation, reveals non-specific effects of STAT3 and suggests a new mechanism of action for nintedanib
Authors: Widjaja Anissa A. , Viswanathan Sivakumar , Jinrui Dong , Singh Brijesh K. , Tan Jessie , Ting Joyce Goh Wei , Lamb David , Shekeran Shamini G , George Benjamin L , Schafer Sebastian , Carling David , Adami Eleonora , Cook Stuart A.
Published: June 2021

In fibroblasts, TGFβ1 stimulates IL11 upregulation that leads to an autocrine loop of IL11-dependent pro-fibrotic protein translation. The signalling pathways downstream of IL11 are contentious and both STAT3 and ERK have been implicated. Here we show that TGFβ1- or IL11-induced ERK activation is consistently associated with fibrogenesis whereas STAT3 phosphorylation (pSTAT3) is unrelated to fibroblast activation. Surprisingly, recombinant human IL11, which has been used extensively in mouse experiments to infer STAT3 activity downstream of IL11, non-specifically increases pSTAT3 in Il11ra1 null mouse fibroblasts. Pharmacologic inhibition of STAT3 prevents TGFβ1-induced fibrogenesis but this effect was found to reflect fibroblast dysfunction due to severe proteotoxic ER stress. In contrast, inhibition of MEK/ERK prevented fibrosis in the absence of ER stress. TGFβ1-stimulated ERK/mTOR/P70RSK-driven protein translation was IL11-dependent and selectivity for pro-fibrotic protein synthesis was ascribed to an EPRS-related mechanism. In TGFβ1-stimulated fibroblasts, the anti-fibrotic drug nintedanib caused dose-dependent ER stress, reduced pSTAT/pERK and inhibited pro-fibrotic protein translation, similarly to generic STAT3 inhibitors or ER stressors. Pirfenidone, while anti-fibrotic, had no effect on ER stress whereas anti-IL11 inhibited the ERK/mTOR axis while reducing ER stress. These studies discount a specific role for STAT3 in pro-fibrotic signaling, suggest a novel mechanism of action for nintedanib and prioritise further the IL11 pathway as a therapeutic target for fibrosis.
An ancient antimicrobial protein co-opted by a fungal plant pathogen for in planta mycobiome manipulation
Authors: Snelders Nick C. , Petti Gabriella C. , van den Berg Grardy C. M. , Seidl Michael F. , Thomma Bart P.H.J.
Published: June 2021

Microbes typically secrete a plethora of molecules to promote niche colonization. Soil-dwelling microbes are well-known producers of antimicrobials that are exploited to outcompete microbial co-inhabitants. Also plant pathogenic microbes secrete a diversity of molecules into their environment for niche establishment. Upon plant colonization, microbial pathogens secrete so-called effector proteins that promote disease development. While such effectors are typically considered to exclusively act through direct host manipulation, we recently reported that the soil-borne fungal xylem-colonizing vascular wilt pathogen Verticillium dahliae exploits effector proteins with antibacterial properties to promote host colonization through the manipulation of beneficial host microbiota. Since fungal evolution preceded land plant evolution, we now speculate that a subset of the pathogen effectors involved in host microbiota manipulation evolved from ancient antimicrobial proteins of terrestrial fungal ancestors that served in microbial competition prior to the evolution of plant pathogenicity. Here, we show that V. dahliae has co-opted an ancient antimicrobial protein as effector, named VdAMP3, for mycobiome manipulation in planta. We show that VdAMP3 is specifically expressed to ward off fungal niche competitors during resting structure formation in senescing mesophyll tissues. Our findings indicate that effector-mediated microbiome manipulation by plant pathogenic microbes extends beyond bacteria and also concerns eukaryotic members of the plant microbiome. Finally, we demonstrate that fungal pathogens can exploit plant microbiome-manipulating effectors in a life-stage specific manner, and that a subset of these effectors has evolved from ancient antimicrobial proteins of fungal ancestors that likely originally functioned in manipulation of terrestrial biota.

SIGNIFICANCE STATEMENT

Microbes secrete a diversity of molecules into their environment to mediate niche colonization. During host ingress, plant pathogenic microbes secrete effector proteins that facilitate disease development, many of which deregulate host immune responses. We recently demonstrated that plant pathogens additionally exploit effectors with antibacterial activities to manipulate beneficial plant microbiota to promote host colonization. Here, we show that the fungal pathogen Verticillium dahliae has co-opted an ancient antimicrobial protein, that likely served in microbial competition in terrestrial environments before land plants existed, as effector for the manipulation of fungal competitors during host colonization. Thus, we demonstrate that pathogen effector repertoires comprise antifungal proteins, and speculate such effectors could be exploited for the development of novel antimycotics.
Dimensional reduction of phenotypes from 53,000 mouse models reveals a diverse landscape of gene function
Authors: Konopka Tomasz , Vestito Letizia , Smedley Damian
Published: June 2021

Animal models have long been used to study gene function and the impact of genetic mutations on phenotype. Through the research efforts of thousands of research groups, systematic curation of published literature, and high-throughput phenotyping screens, the collective body of knowledge for the mouse now covers the majority of protein-coding genes. We here collected data for over 53,000 mouse models with mutations in over 15,000 genomic markers and characterized by more than 254,000 annotations using more than 9,000 distinct ontology terms. We investigated dimensional reduction and embedding techniques as means to facilitate access to this diverse and high-dimensional information. Our analyses provide the first visual maps of the landscape of mouse phenotypic diversity. We also summarize some of the difficulties in producing and interpreting embeddings of sparse phenotypic data. In particular, we show that data preprocessing, filtering, and encoding have as much impact on the final embeddings as the process of dimensional reduction. Nonetheless, techniques developed in the context of dimensional reduction create opportunities for explorative analysis of this large pool of public data, including for searching for mouse models suited to study human diseases.
Adaptive diversification in the cellular circadian behavior of Arabidopsis leaf- and root-derived cells
Authors: Nakamura Shunji , Oyama Tokitaka
Published: June 2021

The plant circadian system is based on self-sustained cellular oscillations and is utilized to adapt to daily and seasonal environmental changes. The cellular circadian clocks in the above- and belowground plant organs are subjected to diverse local environments. Individual cellular clocks are affected by other cells/tissues in plants, and the intrinsic properties of cellular clocks remain to be elucidated. In this study, we showed the circadian properties of leaf- and root-derived cells of a CCA1::LUC Arabidopsis transgenic plant and demonstrated that the cells in total isolation from other cells harbor a genuine circadian clock. Quantitative and statistical analyses for individual cellular bioluminescence rhythms revealed a difference in amplitude and precision of light/dark entrainment between the two cell-types, suggesting that leaf-derived cells have a clock with a stronger persistence against fluctuating environments. Circadian systems in the leaves and roots are diversified to adapt to their local environments at the cellular level.