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Tuberculosis is a significant public health concern resulting in the death of over 1 million individuals each year worldwide. While treatment options and vaccines exist, a substantial number of infections still remain untreated or are caused by treatment resistant strains. Therefore, it is important to identify mechanisms that contribute to risk and prognosis of tuberculosis as this may provide tools to understand disease mechanisms and provide novel treatment options for those with severe infection. Our goal was to identify genetic risk factors that contribute to the risk of tuberculosis and to understand biological mechanisms and causality behind the risk of tuberculosis. A total of 1,895 individuals in the FinnGen study had ICD-based tuberculosis diagnosis. GWAS analysis identified genetic variants with statistically significant association with tuberculosis at the Human leukocyte antigen (HLA) region (pINPP5A. Fine mapping the HLA-association provided evidence for one protective haplotype tagged by HLA DQB1*05:01 (p=1.82E-06, OR = 0.81 [CI 95 % 0.74-0.88]), and predisposing alleles tagged by HLA DRB1*13:02 (p=0.00011, OR = 1.35 [CI 95% 1.16-1.57]). Furthermore, genetic correlation analysis showed association with earlier reported risk factors including smoking (pINPP5A associate with the risk of tuberculosis. In addition, lifestyle risk factors such as smoking contribute to the risk of developing tuberculosis.

Niche-derived factors regulate tissue stem cells, but apart from the mechanosensory pathways, the effect of niche geometry is not well understood. We used organoids and bioengineered tissue culture platforms to demonstrate that the conical shape of Lgr5 + small intestinal stem cells (ISCs) facilitate their self-renewal and function. Inhibition of non-muscle myosin II (NM II)–driven apical constriction altered ISC shape and reduced niche curvature and stem cell capacity. Niche curvature is decreased in aged mice, suggesting that suboptimal interactions between old ISCs and their niche develop with age. We show that activation of NM IIC or physical restriction to young topology improves in vitro regeneration by old epithelium. We propose that the increase in lateral surface area of ISCs induced by apical constriction promotes interactions between neighboring cells, and the curved topology of the intestinal niche has evolved to maximize signaling between ISCs and neighboring cells.

Plant pathogens encounter pre-existing and induced defense compounds when they invade the host. Pathogen ATP-binding cassette (ABC) and major facilitator superfamily (MFS) transporters can provide protection during infection through efflux removal of plant defense compounds from the cell. In the current work, we identified a total of 973 transporter genes, including 232 MFS and 39 ABC transporters, in the genome of the southern corn leaf blight pathogen Cochliobolus heterostrophus. We compared these genes with a recently published transcriptomic data set from C. heterostrophus exposed to the phenolic maize defense compound ferulic acid (FA) and identified four transporter gene families that were significantly (P

Various strains of the mycoparasitic fungal species Clonostachys rosea are used commercially as biological control agents for the control of fungal plant diseases in agricultural crop production. Further improvements of the use and efficacy of C. rosea in biocontrol require a mechanistic understanding of the factors that determines the outcome of the interaction between C. rosea and plant pathogenic fungi. Here, we determined the genome sequences of 11 Clonostachys strains, representing five species in Clonostachys subgenus Bionectria, and performed a comparative genomic analysis with the aim to identify gene families evolving under selection for gene gains or losses. Several gene families predicted to encode proteins involved in biosynthesis of secondary metabolites, including polyketide synthases, nonribosomal peptide syntethases and cytochrome P450s, evolved under selection for gene gains (p ≤ .05) in the Bionectria subgenus lineage. This was accompanied with gene copy number increases (p ≤ .05) in ATP‐binding cassette (ABC) transporters and major facilitator superfamily (MFS) transporters predicted to contribute to drug efflux. Most Clonostachys species were also characterized by high numbers of auxiliary activity (AA) family 9 lytic polysaccharide monooxygenases, AA3 glucose–methanol–choline oxidoreductases and additional carbohydrate‐active enzyme gene families with putative activity (or binding) towards xylan and rhamnose/pectin substrates. Particular features of the C. rosea genome included expansions (p ≤ .05) of the ABC‐B4 multidrug resistance transporters, the ABC‐C5 multidrug resistance‐related transporters and the 2.A.1.3 drug:H + antiporter‐2 MFS drug resistance transporters. The ABC‐G1 pleiotropic drug resistance transporter gene abcG6 in C. rosea was induced (p ≤ .009) by exposure to the antifungal Fusarium mycotoxin zearalenone (1121‐fold) and various fungicides. Deletion of abcG6 resulted in mutants with reduced (p

Biological control is a promising approach to reduce plant diseases caused by nematodes to ensure high productivity in agricultural production. Large‐scale analyses of genetic variation in fungal species used for biocontrol can generate knowledge regarding interaction mechanisms that can improve efficacy of biocontrol applications. In this study, we performed a genome‐wide association study (GWAS) for in vitro antagonism against the root lesion nematode Pratylenchus penetrans in 53 previously genome re‐sequenced strains of the biocontrol fungus Clonostachys rosea. Nematode mortality in C. rosea potato dextrose broth (PDB) culture filtrates was highly variable and showed continuous variation (p

Congenital heart defects (CHD) are structural defects of the heart affecting approximately 1% of newborns. CHDs exhibit a complex inheritance pattern. While genetic factors are known to play an important role in the development of CHD, relatively few variants have been discovered so far and very few genome-wide association studies (GWAS) have been conducted. We performed a GWAS of general CHD and five CHD subgroups in FinnGen followed by functional fine-mapping through eQTL analysis in the GTEx database, and target validation in human induced pluripotent stem cell - derived cardiomyocytes (hiPS-CM) from CHD patients. We discovered that the MYL4-KPNB1 locus (rs11570508, beta = 0.24, P = 1.2×10−11) was associated with the general CHD group. An additional four variants were significantly associated with the different CHD subgroups. Two of these, rs1342740627 associated with left ventricular outflow tract obstruction defects and rs1293973611 associated with septal defects, were Finnish population enriched. The variant rs11570508 associated with the expression of MYL4 (normalized expression score (NES) = 0.1, P = 0.0017, in the atrial appendage of the heart) and KPNB1 (NES = -0.037, P = 0.039, in the left ventricle of the heart). Furthermore, lower expression levels of both genes were observed in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) from CHD patients compared to healthy controls. Together, the results demonstrate KPNB1 and MYL4 as in a potential genetic risk loci associated with the development of CHD.

Study Objective Insomnia has been linked to acute and chronic pain conditions; however, it is unclear whether such relationships are causal. Recently, a large number of genetic variants have been discovered for both insomnia and pain through genome-wide association studies (GWASs) providing a unique opportunity to examine the evidence for causal relationships through the use of the Mendelian randomization paradigm. Methods To elucidate the causality between insomnia and pain, we performed bidirectional Mendelian randomization analysis in FinnGen, where clinically diagnosed ICD-10 categories of pain had been evaluated. In addition, we used measures of self-reported insomnia symptoms. We used endpoints for pain in the FinnGen Release 5 (R5) (N = 218,379), and a non-overlapping sample for insomnia (UK Biobank (UKBB) and 23andMe, N = 1,331,010 or UKBB alone N = 453,379). We assessed the robustness of results through conventional Mendelian randomization sensitivity analyses. Results Genetic liability to insomnia symptoms increased the odds of reporting pain (odds ratio (OR) [95% confidence interval (CI)] = 1.47 [1.38–1.58], p = 4.12 × 10−28). Manifested pain had a small effect on increased risk for insomnia (OR [95% CI] = 1.04 [1.01–1.07], p < 0.05). Results were consistent in sensitivity analyses. Conclusions Our findings support a bidirectional causal relationship between insomnia and pain. These data support a further clinical investigation into the utility of insomnia treatment as a strategy for pain management and vice versa.

Paneth cell niche promotes the function of intestinal stem cells (ISCs) during reduced food intake, but how ISC activity can be boosted when availability of resources is simultaneously reduced remains unknown. Here, we show that the increase in ISC function upon dietary restriction (DR) is dependent on the mitochondrial alanine transaminase Gpt2 in Paneth cells. Metabolic tracing of Alanine directly showed that during DR, the Paneth cell niche catabolizes increased amounts of alanine to produce lactate, which is transported to ISCs to fuel their TCA cycle. Correspondingly, inhibition of lactate import to stem cells abolished the DR induced capacity of Paneth cells to support ISC function. DR resulted in deacetylation of Gpt2 in a Sirtuin3 dependent manner, providing a possible mechanism for Gpt2 regulation. Taken together, our results reveal an important role of the metabolic niche in tissue adaptation, where alanine utilization by the Paneth cells supports stem cells during nutritional challenges.

ObjectiveTo investigate if obstructive sleep apnoea (OSA) is an independent risk factor for severe COVID-19. To examine whether the risk for contracting COVID-19 is elevated among OSA patients.Design and settingRegistry based retrospective case-control study using Finnish nationwide health registries and the FinnGen Study cohort.ParticipantsInformation regarding OSA diagnosis and COVID-19 infection was extracted from the FinnGen study (N=260,405) with a total of 305 patients who had a recorded PCR-validated COVID-19 infection including 26 (8.5%) individuals who were also OSA patients. Severe COVID-19 (N=83; 27.2%) was defined as an infection requiring hospitalization. Among the hospitalized individuals there were 16 (19.3%) with OSA diagnosis. In addition, we also included in our analysis previously reported risk factors for both severe COVID-19 or risk factors and comorbidities for OSA from FinnGen.Main outcome measuresOSA diagnosis, information concerning COVID-19 infection such as hospitalization, were derived from Finnish National Hospital Discharge Registry, Causes of Death Registry and the National Infectious Diseases Registry.ResultsWe show that OSA is a risk factor for COVID-19 hospitalization independent from age, sex, body mass index (BMI), hypertension, diabetes, coronary heart disease (CHD), asthma and chronic obstructive pulmonary disease (COPD), (p-unadjusted=1.04×10−4, OR-adjusted=5.24 [95%CI 1.33 to 23.43], p-adjusted=0.022). OSA was not associated with the risk of contracting COVID-19 (p=0.49).ConclusionWhile an OSA patient’s risk of contracting COVID-19 is the same as non-OSA individuals, the OSA patients have a five-fold risk to be hospitalized when affected by COVID-19 than non-OSA individuals. Our findings suggest that, in assessment of patients with suspected or confirmed COVID-19 infection, OSA needs to be recognized as one of the comorbidity risk factors for developing a severe form of the disease.

Forest declines caused by climate disturbance, insect pests and microbial pathogens threaten the global landscape, and tree diseases are increasingly attributed to the emergent properties of complex ecological interactions between the host, microbiota and insects. To address this hypothesis, we combined reductionist approaches (single and polyspecies bacterial cultures) with emergentist approaches (bacterial inoculations in an oak infection model with the addition of insect larvae) to unravel the gene expression landscape and symptom severity of host–microbiota–insect interactions in the acute oak decline (AOD) pathosystem. AOD is a complex decline disease characterized by predisposing abiotic factors, inner bark lesions driven by a bacterial pathobiome, and larval galleries of the bark-boring beetle Agrilus biguttatus . We identified expression of key pathogenicity genes in Brenneria goodwinii , the dominant member of the AOD pathobiome, tissue-specific gene expression profiles, cooperation with other bacterial pathobiome members in sugar catabolism, and demonstrated amplification of pathogenic gene expression in the presence of Agrilus larvae. This study highlights the emergent properties of complex host–pathobiota–insect interactions that underlie the pathology of diseases that threaten global forest biomes.

Lysin motif (LysM) modules are approximately 50 amino acids long and bind to peptidoglycan, chitin and its derivatives. Certain LysM proteins in plant pathogenic and entomopathogenic fungi are shown to scavenge chitin oligosaccharides and thereby dampen host defense reactions. Other LysM proteins can protect the fungal cell wall against hydrolytic enzymes. In this study, we investigated the biological function of LysM proteins in the mycoparasitic fungus Clonostachys rosea. The C. rosea genome contained three genes coding for LysM-containing proteins and gene expression analysis revealed that lysm1 and lysm2 were induced during mycoparasitic interaction with Fusarium graminearum and during colonization of wheat roots. Lysm1 was suppressed in germinating conidia, while lysm2 was induced during growth in chitin or peptidoglycan-containing medium. Deletion of lysm1 and lysm2 resulted in mutants with increased levels of conidiation and conidial germination, but reduced ability to control plant diseases caused by F. graminearum and Botrytis cinerea. The Δlysm2 strain showed a distinct, accelerated mycelial disintegration phenotype accompanied by reduced biomass production and hyphal protection against hydrolytic enzymes including chitinases, suggesting a role of LYSM2 in hyphal protection against chitinases. The Δlysm2 and Δlysm1Δlysm2 strains displayed reduced ability to colonize wheat roots, while only Δlysm1Δlysm2 failed to suppress expression of the wheat defense response genes PR1 and PR4. Based on our data, we propose a role of LYSM1 as a regulator of fungal development and of LYSM2 in cell wall protection against endogenous hydrolytic enzymes, while both are required to suppress plant defense responses. Our findings expand the understanding of the role of LysM proteins in fungal-fungal interactions and biocontrol.

There is an increasing importance for using biocontrol agents in combating plant diseases sustainably and in the long term. As large scale genomic sequencing becomes economically viable, the impact of single nucleotide polymorphisms (SNPs) on biocontrol-associated phenotypes can be easily studied across entire genomes of fungal populations. Here, we improved a previously reported genome assembly of the biocontrol fungus Clonostachys rosea strain IK726 using the PacBio sequencing platform, which resulted in a total genome size of 70.7 Mbp and 21,246 predicted genes. We further performed whole-genome re-sequencing of 52 additional C. rosea strains isolated globally using Illumina sequencing technology, in order to perform genome-wide association studies in conditions relevant for biocontrol activity. One such condition is the ability to grow at lower temperatures commonly encountered in cryic or frigid soils in temperate regions, as these will be prevalent for protecting growing crops in temperate climates. Growth rates at 10°C on potato dextrose agar of the 53 sequenced strains of C. rosea were measured and ranged between 0.066 and 0.413 mm/day. Performing a genome wide association study, a total of 1,478 SNP markers were significantly associated with the trait and located in 227 scaffolds, within or close to (< 1000 bp distance) 265 different genes. The predicted gene products included several chaperone proteins, membrane transporters, lipases, and proteins involved in chitin metabolism with possible roles in cold tolerance. The data reported in this study provides a foundation for future investigations into the genetic basis for cold tolerance in fungi, with important implications for biocontrol.

Background Britain’s native oak species are currently under threat from acute oak decline (AOD), a decline-disease where stem bleeds overlying necrotic lesions in the inner bark and larval galleries of the bark-boring beetle, Agrilus biguttatus, represent the primary symptoms. It is known that complex interactions between the plant host and its microbiome, i.e. the holobiont, significantly influence the health status of the plant. In AOD, necrotic lesions are caused by a microbiome shift to a pathobiome consisting predominantly of Brenneria goodwinii, Gibbsiella quercinecans, Rahnella victoriana and potentially other bacteria. However, the specific mechanistic processes of the microbiota causing tissue necrosis, and the host response, have not been established and represent a barrier to understanding and managing this decline. Results We profiled the metagenome, metatranscriptome and metaproteome of inner bark tissue from AOD symptomatic and non-symptomatic trees to characterise microbiota-host interactions. Active bacterial virulence factors such as plant cell wall-degrading enzymes, reactive oxygen species defence and flagella in AOD lesions, along with host defence responses including reactive oxygen species, cell wall modification and defence regulators were identified. B. goodwinii dominated the lesion microbiome, with significant expression of virulence factors such as the phytopathogen effector avrE. A smaller proportion of microbiome activity was attributed to G. quercinecans and R. victoriana. In addition, we describe for the first time the potential role of two previously uncharacterised Gram-positive bacteria predicted from metagenomic binning and identified as active in the AOD lesion metatranscriptome and metaproteome, implicating them in lesion formation. Conclusions This multi-omic study provides novel functional insights into microbiota-host interactions in AOD, a complex arboreal decline disease where polymicrobial-host interactions result in lesion formation on tree stems. We present the first descriptions of holobiont function in oak health and disease, specifically, the relative lesion activity of B. goodwinii, G. quercinecans, Rahnella victoriana and other bacteria. Thus, the research presented here provides evidence of some of the mechanisms used by members of the lesion microbiome and a template for future multi-omic research into holobiont characterisation, plant polymicrobial diseases and pathogen defence in trees. Electronic supplementary material The online version of this article (10.1186/s40168-018-0408-5) contains supplementary material, which is available to authorized users.

Decline-diseases are complex and becoming increasingly problematic to tree health globally. Acute Oak Decline (AOD) is characterized by necrotic stem lesions and galleries of the bark-boring beetle, Agrilus biguttatus, and represents a serious threat to oak. Although multiple novel bacterial species and Agrilus galleries are associated with AOD lesions, the causative agent(s) are unknown. The AOD pathosystem therefore provides an ideal model for a systems-based research approach to address our hypothesis that AOD lesions are caused by a polymicrobial complex. Here we show that three bacterial species, Brenneria goodwinii, Gibbsiella quercinecans and Rahnella victoriana, are consistently abundant in the lesion microbiome and possess virulence genes used by canonical phytopathogens that are expressed in AOD lesions. Individual and polyspecies inoculations on oak logs and trees demonstrated that B. goodwinii and G. quercinecans cause tissue necrosis and, in combination with A. biguttatus, produce the diagnostic symptoms of AOD. We have proved a polybacterial cause of AOD lesions, providing new insights into polymicrobial interactions and tree disease. This work presents a novel conceptual and methodological template for adapting Koch’s postulates to address the role of microbial communities in disease.

Cuticular defects trigger a battery of reactions including enhanced reactive oxygen species (ROS) production and resistance to necrotrophic pathogens. However, the source of ROS generated by such impaired cuticles has remained elusive. Here, we report the characterization of Arabidopsis thaliana ohyl mutant, a Peroxidase 57 (PER57) - overexpressing line that demonstrates enhanced defense responses that result both from increased accumulation of ROS and permeability of the leaf cuticle. The ohyl mutant was identified in a screen of A. thaliana seedlings for oligogalacturonides (OGs) insensitive/hypersensitive mutants that exhibit altered growth retardation in response to exogenous OGs. Mutants impaired in OG sensitivity were analyzed for disease resistance/susceptibility to the necrotrophic phytopathogens Botrytis cinerea and Pectobacterium carotovorum. In the ohyl line, the hypersensitivity to OGs was associated with resistance to the tested pathogens. This PER57 overexpressing line exhibited a significantly more permeable leaf cuticle than wild-type plants and this phenotype could be recapitulated by overexpressing other class III peroxidases. Such peroxidase overexpression was accompanied by the suppressed expression of cutin biosynthesis genes and the enhanced expression of genes associated with OG-signaling. Application of ABA completely removed ROS, restored the expression of genes associated with cuticle biosynthesis and led to decreased permeability of the leaf cuticle, and finally, abolished immunity to B. cinerea. Our work demonstrates that increased peroxidase activity increases permeability of the leaf cuticle. The loss of cuticle integrity primes plant defenses to necrotrophic pathogens via the activation of DAMP-responses.

Background Oligogalacturonides (OGs) are important components of damage-associated molecular pattern (DAMP) signaling and influence growth regulation in plants. Recent studies have focused on the impact of long OGs (degree of polymerization (DP) from 10–15), demonstrating the induction of plant defense signaling resulting in enhanced defenses to necrotrophic pathogens. To clarify the role of trimers (trimeric OGs, DP3) in DAMP signaling and their impact on plant growth regulation, we performed a transcriptomic analysis through the RNA sequencing of Arabidopsis thaliana exposed to trimers. Results The transcriptomic data from trimer-treated Arabidopsis seedlings indicate a clear activation of genes involved in defense signaling, phytohormone signaling and a down-regulation of genes involved in processes related to growth regulation and development. This is further accompanied with improved defenses against necrotrophic pathogens triggered by the trimer treatment, indicating that short OGs have a clear impact on plant responses, similar to those described for long OGs. Conclusions Our results demonstrate that trimers are indeed active elicitors of plant defenses. This is clearly indicated by the up-regulation of genes associated with plant defense signaling, accompanied with improved defenses against necrotrophic pathogens. Moreover, trimers simultaneously trigger a clear down-regulation of genes and gene sets associated with growth and development, leading to stunted seedling growth in Arabidopsis. Keywords Plant signaling Arabidopsis thaliana Oligogalacturonides OG Trimers Transcriptomics Defense induction Growth inhibition Disease resistance Pectobacterium carotovorum Botrytis cinerea

ExpA (GacA) is a global response regulator that controls the expression of major virulence genes, such as those encoding plant cell wall-degrading enzymes (PCWDEs) in the model soft rot phytopathogen Pectobacterium wasabiae SCC3193. Several studies with pectobacteria as well as related phytopathogenic gammaproteobacteria, such as Dickeya and Pseudomonas , suggest that the control of virulence by ExpA and its homologues is executed partly by modulating the activity of RsmA, an RNA-binding posttranscriptional regulator. To elucidate the extent of the overlap between the ExpA and RsmA regulons in P. wasabiae , we characterized both regulons by microarray analysis. To do this, we compared the transcriptomes of the wild-type strain, an expA mutant, an rsmA mutant, and an expA rsmA double mutant. The microarray data for selected virulence-related genes were confirmed through quantitative reverse transcription (qRT-PCR). Subsequently, assays were performed to link the observed transcriptome differences to changes in bacterial phenotypes such as growth, motility, PCWDE production, and virulence in planta . An extensive overlap between the ExpA and RsmA regulons was observed, suggesting that a substantial portion of ExpA regulation appears to be mediated through RsmA. However, a number of genes involved in the electron transport chain and oligogalacturonide metabolism, among other processes, were identified as being regulated by ExpA independently of RsmA. These results suggest that ExpA may only partially impact fitness and virulence via RsmA.

A general prediction for aging placental mammals is that they should show a decline in reproductive value, and reproductive effort is therefore predicted to increase with age. To test this, we monitored known-age radio-collared females of a large ungulate, the moose (Alces alces), in a Swedish population. Female moose showed senescence in reproduction (i.e., litter size) from about 12 yr of age. Further evidence of senescence was a decrease in parental care during summer (expressed as increased offspring mortality) with the mother's age. Moreover, aging females facing a declining reproductive value increased their reproductive effort by giving birth to heavier offspring regardless of litter size. A logistic regression model showed that older moose have to give birth to heavier offspring to achieve the same offspring summer survival as that for offspring of younger mothers. This suggests that females increase their reproductive effort (by increasing offspring mass) as they get older. Furthermore, the rather intense harvest in our population may select for an increased reproductive effort in terms of litter size, which furthermore may select for an earlier onset of senescence in reproductive characters and mortality.

The posttranscriptional regulator RsmA controls the production of plant cell wall degrading enzymes (PCWDE) and cell motility in the Pectobacterium genus of plant pathogens. In this study the physiological role of gene regulation by RsmA is under investigation. Disruption of rsmA gene of the Pectobacterium wasabiae strain, SCC3193 resulted in 3-fold decrease in growth rate and increased virulence. The comparison of mRNA levels of the rsmA(-) mutant and wild-type using a genome-wide microarray showed, that genes responsible for successful infection, i.e. virulence factors, motility, butanediol fermentation, various secretion systems etc. were up-regulated in the rsmA(-) strain. The rsmA(-) strain exhibited a higher propensity to swarm and produce PCWDE compared to the wild-type strain. Virulence experiments in potato tubers demonstrated that in spite of its more efficient tissue maceration, the rsmA(-) strain's ability to survive within the host is reduced and the infection site is taken over by resident bacteria. Taken together, in the absence of RsmA, cells revert to a constitutively infective phenotype characterized by expression of virulence factors and swarming. We hypothesize that lack of control over these costly energetic processes results in decreased growth rate and fitness. In addition, our findings suggest a relationship between swarming and virulence in plant pathogens.