Miracle-dz/UniFAR-FTUs huggingface dataset:
Pediatric IgG4-related disease: a descriptive review

ABSTRACT Introduction IgG4-related disease (IgG4-RD) is an immune-mediated systemic fibroinflammatory condition characterized by serum IgG4 elevation and IgG4-positive plasma cell infiltration into various organs. It generally occurs in elderly males. Pediatric cases have been reported, albeit rarely, accordingly lack of recognition of such cases could delay therapeutic intervention leading to poorer outcomes. Areas covered The present review is a descriptive review of all published case reports, cohort studies, and reviews of pediatric IgG4-RD listed in PubMed. Characteristics of pediatric IgG4-RD were clarified, including sex, organ involvement, serological and histological findings, and treatment. We assessed how many published cases met current classification and comprehensive diagnostic criteria. Expert opinion The characteristics of pediatricIgG4-RD differed from adult IgG4-RD in terms of sex and involved organs. There was no clear male dominance in numbers of cases, and surface organ involvement such as ophthalmic diseases were more common in the pediatric IgG4-RD. Organ involvement tended to be indolent and unilateral, causing difficulty in definitively diagnosing pediatric IgG4-RD. Only about 20% of published cases met IgG4-RD classification or comprehensive diagnostic criteria. Physicians should be careful in diagnosing pediatric IgG4-RD after excluding mimickers. International collaboration toward high-quality evidence to support diagnosis and treatment of pediatric IgG4-RD is advised.
Intrabacterial lipid inclusion‐associated proteins: a core machinery conserved from saprophyte Actinobacteria to the human pathogen Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb), the aetiologic agent of tuberculosis (TB), stores triacylglycerol (TAG) in the form of intrabacterial lipid inclusions (ILI) to survive and chronically persist within its host. These highly energetic molecules represent a major source of carbon to support bacterial persistence and reactivation, thus playing a leading role in TB pathogenesis. However, despite its physiological and clinical relevance, ILI metabolism in Mtb remains poorly understood. Recent discoveries have suggested that several ILI‐associated proteins might be widely conserved across TAG‐producing prokaryotes, but still very little is known regarding the nature and the biological functions of these proteins. Herein, we performed an in silico analysis of three independent ILI‐associated proteomes previously reported to computationally define a potential core ILI‐associated proteome, referred to as ILIome. Our investigation revealed the presence of 70 orthologous proteins that were strictly conserved, thereby defining a minimal ILIome core. We further narrowed our analysis to proteins involved in lipid metabolism and discuss here their putative biological functions, along with their molecular interactions and dynamics at the surface of these bacterial organelles. We also highlight the experimental limitations of the original proteomic investigations and of the present bioinformatic analysis, while describing new technological approaches and presenting biological perspectives in the field. The in silico investigation presented here aims at providing useful datasets that could constitute a scientific resource of broad interest for the mycobacterial community, with the ultimate goal of enlightening ILI metabolism in prokaryotes with a special emphasis on Mtb pathogenesis.
Modelling interactions between fold–thrust belt deformation, foreland flexure and surface mass transport

Interactions between fold and thrust belt deformation, foreland flexure and surface mass transport are investigated using a newly developed mathematical model incorporating fully dynamic coupling between mechanics and surface processes. The mechanical model is two dimensional (plane strain) and includes an elasto‐visco‐plastic rheology. The evolving model is flexurally compensated using an elastic beam formulation. Erosion and deposition at the surface are treated in a simple manner using a linear diffusion equation. The model is solved with the finite element method using a Lagrangian scheme with marker particles. Because the model is particle based, it enables straightforward tracking of stratigraphy and exhumation paths and it can sustain very large strain. It is thus ideally suited to study deformation, erosion and sedimentation in fold–thrust belts and foreland basins.
Practical application of the linkage disequilibrium method for estimating contemporary effective population size: A review

The method to estimate contemporary effective population size (Ne) based on patterns of linkage disequilibrium (LD) at unlinked loci has been widely applied to natural and managed populations. The underlying model makes many simplifying assumptions, most of which have been evaluated in numerous studies published over the last two decades. Here, these performance evaluations are reviewed and summarized, with a focus on information that facilitates practical application to real populations in nature. Potential sources of bias that are discussed include calculation of r2 (a measure of LD), adjustments for sampling error, physical linkage, age structure, migration and spatial structure, mutation and selection, mating systems, changes in abundance, rare alleles, missing data, genotyping errors, data filtering choices and methods for combining multiple Ne estimates. Factors that affect precision are reviewed, including pseudoreplication that limits the information gained from large genomics datasets, constraints imposed by small samples of individuals, and the challenges in obtaining robust estimates for large populations. Topics that merit further research include the potential to weight r2 values by allele frequency, lump samples of individuals, use genotypic likelihoods rather than called genotypes, prune large LD values and apply the method to species practising partial monogamy.
In vitro reconstitution of herpes simplex virus 1 fusion identifies low pH as a fusion co-trigger

ABSTRACT Membrane fusion mediated by herpes simplex virus 1 (HSV-1) is a complex, multi-protein process that is receptor triggered and can occur both at the cell surface and in endosomes. To deconvolute this complexity, we reconstituted HSV-1 fusion with synthetic lipid vesicles in vitro. Using this simplified, controllable system, we discovered that HSV-1 fusion required not only a cognate host receptor but also low pH. On the target membrane side, efficient fusion required cholesterol, negatively charged lipids found in the endosomal membranes, and an optimal balance of lipid order and disorder. On the virion side, the four HSV-1 entry glycoproteins—gB, gD, gH, and gL—were sufficient for fusion. We propose that low pH is a biologically relevant co-trigger for HSV-1 fusion. The dependence of fusion on low pH and endosomal lipids could explain why HSV-1 enters most cell types by endocytosis. We hypothesize that under neutral pH conditions, other, yet undefined, cellular factors may serve as fusion co-triggers. The in vitro fusion system established here can be employed to systematically investigate HSV-1-mediated membrane fusion. IMPORTANCE HSV-1 causes lifelong, incurable infections and diseases ranging from mucocutaneous lesions to fatal encephalitis. Fusion of viral and host membranes is a critical step in HSV-1 infection of target cells that requires multiple factors on both the viral and host sides. Due to this complexity, many fundamental questions remain unanswered, such as the identity of the viral and host factors that are necessary and sufficient for HSV-1-mediated membrane fusion and the nature of the fusion trigger. Here, we developed a simplified in vitro fusion assay to examine the fusion requirements and identified low pH as a co-trigger for virus-mediated fusion in vitro. We hypothesize that low pH has a critical role in cell entry and, potentially, pathogenesis. HSV-1 causes lifelong, incurable infections and diseases ranging from mucocutaneous lesions to fatal encephalitis. Fusion of viral and host membranes is a critical step in HSV-1 infection of target cells that requires multiple factors on both the viral and host sides. Due to this complexity, many fundamental questions remain unanswered, such as the identity of the viral and host factors that are necessary and sufficient for HSV-1-mediated membrane fusion and the nature of the fusion trigger. Here, we developed a simplified in vitro fusion assay to examine the fusion requirements and identified low pH as a co-trigger for virus-mediated fusion in vitro. We hypothesize that low pH has a critical role in cell entry and, potentially, pathogenesis.
The changing role of ecohydrological science in guiding environmental flows

Abstract The term “environmental flows” is now widely used to reflect the hydrological regime required to sustain freshwater and estuarine ecosystems, and the human livelihoods and well-being that depend on them. The definition suggests a central role for ecohydrological science to help determine a required flow regime for a target ecosystem condition. Indeed, many countries have established laws and policies to implement environmental flows with the expectation that science can deliver the answers. This article provides an overview of recent developments and applications of environmental flows on six continents to explore the changing role of ecohydrological sciences, recognizing its limitations and the emerging needs of society, water resource managers and policy makers. Science has responded with new methods to link hydrology to ecosystem status, but these have also raised fundamental questions that go beyond ecohydrology, such as who decides on the target condition of the ecosystem? Some environmental flow methods are based on the natural flow paradigm, which assumes the desired regime is the natural “unmodified” condition. However, this may be unrealistic where flow regimes have been altered for many centuries and are likely to change with future climate change. Ecosystems are dynamic, so the adoption of environmental flows needs to have a similar dynamic basis. Furthermore, methodological developments have been made in two directions: first, broad-scale hydrological analysis of flow regimes (assuming ecological relevance of hydrograph components) and, second, analysis of ecological impacts of more than one stressor (e.g. flow, morphology, water quality). All methods retain a degree of uncertainty, which translates into risks, and raises questions regarding trust between scientists and the public. Communication between scientists, social scientists, practitioners, policy makers and the public is thus becoming as important as the quality of the science. Editor Z.W. Kundzewicz Citation Acreman, M.C. , Overton, I.C. , King, J., Wood, P., Cowx, I.G. , Dunbar, M.J., Kendy, E. , and Young, W. , 2014. The changing role of ecohydrological science in guiding environmental flows. Hydrological Sciences Journal, 59 (3–4), 433–450
Last Glacial Maximum CO2 and δ13C successfully reconciled

During the Last Glacial Maximum (LGM, ∼21,000 years ago) the cold climate was strongly tied to low atmospheric CO2 concentration (∼190 ppm). Although it is generally assumed that this low CO2 was due to an expansion of the oceanic carbon reservoir, simulating the glacial level has remained a challenge especially with the additional δ13C constraint. Indeed the LGM carbon cycle was also characterized by a modern‐like δ13C in the atmosphere and a higher surface to deep Atlantic δ13C gradient indicating probable changes in the thermohaline circulation. Here we show with a model of intermediate complexity, that adding three oceanic mechanisms: brine induced stratification, stratification‐dependant diffusion and iron fertilization to the standard glacial simulation (which includes sea level drop, temperature change, carbonate compensation and terrestrial carbon release) decreases CO2 down to the glacial value of ∼190 ppm and simultaneously matches glacial atmospheric and oceanic δ13C inferred from proxy data. LGM CO2 and δ13C can at last be successfully reconciled.
Refphase: Multi-sample phasing reveals haplotype-specific copy number heterogeneity

Most computational methods that infer somatic copy number alterations (SCNAs) from bulk sequencing of DNA analyse tumour samples individually. However, the sequencing of multiple tumour samples from a patient’s disease is an increasingly common practice. We introduce Refphase, an algorithm that leverages this multi-sampling approach to infer haplotype-specific copy numbers through multi-sample phasing. We demonstrate Refphase’s ability to infer haplotype-specific SCNAs and characterise their intra-tumour heterogeneity, to uncover previously undetected allelic imbalance in low purity samples, and to identify parallel evolution in the context of whole genome doubling in a pan-cancer cohort of 336 samples from 99 tumours.
Resident regulatory T cells reflect the immune history of individual lymph nodes

Regulatory T cells (Tregs) are present in lymphoid and nonlymphoid tissues where they restrict immune activation, prevent autoimmunity, and regulate inflammation. Tregs in nonlymphoid tissues are typically resident, whereas those in lymph nodes (LNs) are considered to recirculate. However, Tregs in LNs are not a homogenous population, and circulation kinetics of different Treg subsets are poorly characterized. Furthermore, whether Tregs can acquire memory T cell properties and persist for extended periods after their activation in LNs is unclear. Here, we used in situ labeling with a stabilized photoconvertible protein to uncover turnover rates of Tregs in LNs in vivo. We found that, whereas most Tregs in LNs recirculate, 10 to 20% are memory-like resident cells that remain in their respective LNs for weeks to months. Single-cell RNA sequencing revealed that LN-resident cells are a functionally and ontogenetically heterogeneous population and share the same core residency gene signature with conventional CD4+ and CD8+ T cells. Resident cells in LNs did not actively proliferate and did not require continuous T cell receptor (TCR) signaling for their residency. However, resident and circulating Tregs had distinct TCR repertoires, and each LN contained exclusive clonal subpopulations of resident Tregs. Our results demonstrate that, similar to conventional T cells, Tregs can form resident memory-like populations in LNs after adaptive immune responses. Specific and local suppression of immune responses by resident Tregs in draining LNs might provide previously unidentified therapeutic opportunities for the treatment of local chronic inflammatory conditions. Description Resident memory-like regulatory T cells locally record adaptive immune responses in each lymph node.
SET7/9-mediated methylation affects oncogenic functions of histone demethylase JMJD2A

The histone demethylase JMJD2A/KDM4A facilitates prostate cancer development, yet how JMJD2A function is regulated has remained elusive. Here, we demonstrate that SET7/9-mediated methylation on 6 lysine residues modulated JMJD2A. Joint mutation of these lysine residues suppressed JMJD2A’s ability to stimulate the MMP1 matrix metallopeptidase promoter upon recruitment by the ETV1 transcription factor. Mutation of just 3 methylation sites (K505, K506, and K507) to arginine residues (3xR mutation) was sufficient to maximally reduce JMJD2A transcriptional activity and also decreased its binding to ETV1. Introduction of the 3xR mutation into DU145 prostate cancer cells reduced in vitro growth and invasion and also severely compromised tumorigenesis. Consistently, the 3xR genotype caused transcriptome changes related to cell proliferation and invasion pathways, including downregulation of MMP1 and the NPM3 nucleophosmin/nucleoplasmin gene. NPM3 downregulation phenocopied and its overexpression rescued, to a large degree, the 3xR mutation in DU145 cells, suggesting that NPM3 was a seminal downstream effector of methylated JMJD2A. Moreover, we found that NPM3 was overexpressed in prostate cancer and might be indicative of disease aggressiveness. SET7/9-mediated lysine methylation of JMJD2A may aggravate prostate tumorigenesis in a manner dependent on NPM3, implying that the SET7/9→JMJD2A→NPM3 axis could be targeted for therapy.
Consistent predictors of microbial community composition across spatial scales in grasslands reveal low context‐dependency

Environmental circumstances shaping soil microbial communities have been studied extensively. However, due to disparate study designs, it has been difficult to resolve whether a globally consistent set of predictors exists, or context‐dependency prevails. Here, we used a network of 18 grassland sites (11 of those containing regional plant productivity gradients) to examine (i) if similar abiotic or biotic factors predict both large‐scale (across sites) and regional‐scale (within sites) patterns in bacterial and fungal community composition, and (ii) if microbial community composition differs consistently at two levels of regional plant productivity (low vs. high). Our results revealed that bacteria were associated with particular soil properties (such as base saturation) and both bacteria and fungi were associated with plant community composition across sites and within the majority of sites. Moreover, a discernible microbial community signal emerged, clearly distinguishing high and low‐productivity soils across different grasslands independent of their location in the world. Hence, regional productivity differences may be typified by characteristic soil microbial communities across the grassland biome. These results could encourage future research aiming to predict the general effects of global changes on soil microbial community composition in grasslands and to discriminate fertile from infertile systems using generally applicable microbial indicators.
The Upper Permian of Western Europe — A Palynological Approach to Chronostratigraphy

Abstract In Western Europe palynology can be applied successfully in regional correlation of Permian successions. However, palynological literature shows that there is still a strong tendency to correlate palynological data strictly with conventional schemes of chronostratigraphical classification used in the areas of investigation. Palynological data so far available cannot be reconciled with the essentially lithostratigraphical nineteenth-century framework of current West-European classifications. An alternative concept, with special reference to the stratigraphical and geographical extent of the Upper Permian in Western Europe, emphasizes that palynology may provide the primary biostratigraphical criteria for a reappraisal of the Thuringian Stage. This stage, typified by the development of the classic Zechstein deposits, could well be regarded as a practical working unit for the classification and correlation of the latest Permian successions from all over Europe.
Metabolic dysregulation and gut dysbiosis linked to hyperandrogenism in female mice

Abstract Introduction Polycystic ovary syndrome (PCOS) is a common endocrine pathology in women. In addition to infertility, women with PCOS have metabolic dysregulation which predisposes them to Type 2 diabetes, cardiovascular disease and non‐alcoholic fatty liver disease. Moreover, women with PCOS have changes in their gut microbial community that may be indicative of dysbiosis. While hyperandrogenism is associated with both the development of metabolic dysfunction and gut dysbiosis in females, the mechanisms involved are not well understood. Methods We used dihydrotestosterone (DHT) and ovariectomy (OVX) mouse models coupled with metabolic assessments and 16S rRNA gene sequencing to explore the contributions of hyperandrogenism and oestrogen deficiency to the development of insulin resistance and gut microbial dysbiosis in pubertal female mice. Results We demonstrated that, while DHT treatment or OVX alone were insufficient to induce insulin resistance during the pubertal‐to‐adult transition, combining OVX with DHT resulted in insulin resistance similar to that observed in letrozole‐treated mice with elevated testosterone and decreased oestrogen levels. In addition, our results showed that OVX and DHT in combination resulted in a distinct shift in the gut microbiome compared to DHT or OVX alone, suggesting that the substantial metabolic dysregulation occurring in the OVX + DHT model was accompanied by unique changes in the abundances of gut bacteria including S24‐7, Rikenellaceae and Mucispirillum schaedleri. Conclusions While hyperandrogenism plays an important role in the development of metabolic dysregulation in female mice, our results indicate that investigation into additional factors influencing insulin resistance and the gut microbiome during the pubertal‐to‐adult transition could provide additional insight into the pathophysiology of PCOS.
Feasibility testing of an interprofessional education intervention to support collaborative practice in home care for older stroke survivors with multiple chronic conditions

ABSTRACT This mixed-methods study examined the feasibility of implementing a new six-month, theory-based, interprofessional education intervention, and explored its effects and impact on collaborative practice among home care providers caring for older adult stroke survivors (≥65) with multiple chronic conditions. The evaluation utilized a qualitative descriptive and one group repeated measures design which included participant questionnaires, focus groups and field notes. Participants included 37 home care providers (registered nurses, physiotherapists, occupational therapists, personal support workers, care coordinators, and their supervisors) in Ontario, Canada. The intervention was feasible and acceptable to home care providers. Perceived benefits included improved communication and collaboration within teams, enhanced role understanding, increased learning with and from each other, and increased appreciation of all team members’ expertise. From 3 to 6 months post initial IPE training, there was a statistically significant improvement in three domains of collaborative practice as measured by the Collaborative Practice Assessment Tool (communication/information exchange; community linkage and coordination of care; decision-making and conflict management) and one domain of collaborative practice, as measured by the 19-item Team Climate Inventory (task orientation). Implications for implementing interprofessional education in home care practice settings are described. Further testing in other populations and settings is warranted.