bluuebunny/crossref_metadata_2025 huggingface dataset:
GPR55 deficiency is associated with increased adiposity and impaired insulin signaling in peripheral metabolic tissues
Authors: Lipina Christopher , Walsh Sarah K. , Mitchell Sharon E. , Speakman John R. , Wainwright Cherry L. , Hundal Harinder S.
Published: August 2018

Emerging evidence indicates that G‐protein coupled receptor 55 (GPR55), a nonclassic receptor of the endocannabinoid system that is activated by L‐α‐lysophosphatidylinositol and various cannabinoid ligands, may regulate endocrine function and energy metabolism. We examined how GPR55 deficiency and modulation affects insulin signaling in skeletal muscle, adipose tissue, and liver alongside expression analysis of proteins implicated in insulin action and energy metabolism. We show that GPR55‐null mice display decreased insulin sensitivity in these tissues, as evidenced by reduced phosphorylation of PKB/Akt and its downstream targets, concomitant with increased adiposity and reduced physical activity relative to wild‐type counterparts. Impaired tissue insulin sensitivity coincided with reduced insulin receptor substrate‐1 abundance in skeletal muscle, whereas in liver and epididymal fat it was associated with increased expression of the 3‐phosphoinoistide lipid phosphatase, phosphatase and tensin homolog. In contrast, GPR55 activation enhanced insulin signaling in cultured skeletal muscle cells, adipocytes, and hepatocytes; this response was negated by receptor antagonists and GPR55 gene silencing in L6 myotubes. Sustained GPR55 antagonism in 3T3‐L1 adipocytes enhanced expression of proteins implicated in lipogenesis and promoted triglyceride accumulation. Our findings identify GPR55 as a positive regulator of insulin action and adipogenesis and as a potential therapeutic target for countering obesity‐induced metabolic dysfunction and insulin resistance.—Lipina, C., Walsh, S. K., Mitchell, S. E., Speakman, J. R., Wainwright, C. L., Hundal, H. S. GPR55 deficiency is associated with increased adiposity and impaired insulin signaling in peripheral metabolic tissues. FASEB J. 33, 1299–1312 (2019). www.fasebj.org
Sunitinib induces early histomolecular changes in a subset of renal cancer cells that contribute to resistance
Authors: Lichner Zsuzsanna , Saleeb Rola , Butz Henriett , Ding Qiang , Nofech-Mozes Roy , Riad Sara , Farag Mina , Varkouhi Amir K. , dos Santos Claudia C. , Kapus András , Yousef George M.
Published: August 2018

Sunitinib is the standard‐of‐care, first‐line treatment for advanced renal cell carcinoma (RCC). Characteristics of treatment‐resistant RCC have been described; however, complex tumor adaptation mechanisms obstruct the identification of significant operators in resistance. We hypothesized that resistance is a late manifestation of early, treatment‐induced histomolecular alterations; therefore, studying early drug response may identify drivers of resistance. We describe an epithelioid RCC growth pattern in RCC xenografts, which emerges in sunitinib‐sensitive tumors and is augmented during resistance. This growth modality is molecularly and morphologically related to the RCC spheroids that advance during in vitro treatment. Based on time‐lapse microscopy, mRNA and microRNA screening, and tumor behavior‐related characteristics, we propose that the spheroid and adherent RCC growth patterns differentially respond to sunitinib. Gene expression analysis indicated that sunitinib promoted spheroid formation, which provided a selective survival advantage under treatment. Functional studies confirm that E‐cadherin is a key contributor to the survival of RCC cells under sunitinib treatment. In summary, we suggest that sunitinib‐resistant RCC cells exist in treatment‐sensitive tumors and are histologically identifiable.—Lichner, Z., Saleeb, R., Butz, H., Ding, Q., Nofech‐Mozes, R., Riad, S., Farag, M., Varkouhi, A. K., dosSantos, C. C., Kapus, A., Yousef, G. M. Sunitinib induces early histomolecular changes in a subset of renal cancer cells that contribute to resistance. FASEB J. 33, 1347–1359 (2019). www.fasebj.org
An update on autoantibodies in scleroderma
Authors: Mecoli Christopher A. , Casciola-Rosen Livia
Published: August 2018

Purpose of review

New research continues to provide important insights into the utility of antibody specificities. This review provides an update of recent findings, and the important insights they provide into disease mechanism.

Recent findings

A growing number of autoantibodies have been discovered in scleroderma patients with unique clinical associations. A subgroup of these antibodies may have functional consequences and contribute to disease pathogenesis, driving the vascular and fibrotic phenotype. Recent research into the relationship between malignancy and scleroderma onset provides important new insights into disease mechanism, and highlights the utility of autoantibodies as unique research probes.

Continued advances in the study of scleroderma antibody specificities has led to important insights into disease pathogenesis and clinical subgrouping. These advances include newly described specificities, functional antibodies and an emerging understanding of the cancer–scleroderma relationship.
Climatic factors and species range position predict sexually antagonistic selection across taxa
Authors: De Lisle Stephen P. , Goedert Debora , Reedy Aaron M. , Svensson Erik I.
Published: August 2018

Sex differences in selection are ubiquitous in sexually reproducing organisms. When the genetic basis of traits is shared between the sexes, such sexually antagonistic selection (SAS) creates a potential constraint on adaptive evolution. Theory and laboratory experiments suggest that environmental variation and the degree of local adaptation may all affect the frequency and intensity of SAS. Here, we capitalize on a large database of over 700 spatially or temporally replicated estimates of sex-specific phenotypic selection from wild populations, combined with data on microclimates and geographical range information. We performed a meta-analysis to test three predictions from SAS theory, that selection becomes more concordant between males and females: (1) in more stressful environments, (2) in more variable environments and (3) closer to the edge of the species' range. We find partial empirical support for all three predictions. Within-study analyses indicate SAS decreases in extreme environments, as indicated by a relationship with maximum temperature, minimum precipitation and evaporative potential (PET). Across studies, we found that the average level of SAS at high latitudes was lower, where environmental conditions are typically less stable. Finally, we found evidence for reduced SAS in populations that are far from the centre of their geographical range. However, and notably, we also found some evidence of reduced average strength of selection in these populations, which is in contrast to predictions from classical theoretical models on range limit evolution. Our results suggest that environmental lability and species range position predictably influence sex-specific selection and sexual antagonism in the wild.

This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences’.
Sex differences in local adaptation: what can we learn from reciprocal transplant experiments?
Authors: Svensson Erik I. , Goedert Debora , Gómez-Llano Miguel A. , Spagopoulou Foteini , Nava-Bolaños Angela , Booksmythe Isobel
Published: August 2018

Local adaptation is of fundamental interest to evolutionary biologists. Traditionally, local adaptation has been studied using reciprocal transplant experiments to quantify fitness differences between residents and immigrants in pairwise transplants between study populations. Previous studies have detected local adaptation in some cases, but others have shown lack of adaptation or even maladaptation. Recently, the importance of different fitness components, such as survival and fecundity, to local adaptation have been emphasized. Here, we address another neglected aspect in studies of local adaptation: sex differences. Given the ubiquity of sexual dimorphism in life histories and phenotypic traits, this neglect is surprising, but may be partly explained by differences in research traditions and terminology in the fields of local adaptation and sexual selection. Studies that investigate differences in mating success between resident and immigrants across populations tend to be framed in terms of reproductive and behavioural isolation, rather than local adaptation. We briefly review the published literature that bridges these areas and suggest that reciprocal transplant experiments could benefit from quantifying both male and female fitness components. Such a more integrative research approach could clarify the role of sex differences in the evolution of local adaptations.

This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences'.
The geography of sex: sexual conflict, environmental gradients and local loss of sex in facultatively parthenogenetic animals
Authors: Burke Nathan W. , Bonduriansky Russell
Published: August 2018

Obligately asexual organisms tend to occur at higher altitudes or latitudes and occupy larger ranges than their obligately sexual relatives—a phenomenon called geographical parthenogenesis. Some facultatively parthenogenetic organisms that reproduce both sexually and asexually also exhibit spatial variation in reproductive mode. Theory suggests that sexual conflict and mate limitation can determine the relative frequency of sex in facultative parthenogens, but the effect of these dynamics on spatial distributions is unknown. Here, we use individual-based models to investigate whether these dynamics can generate local differences in the reproductive mode in a facultatively parthenogenetic metapopulation occupying an environmental gradient. We find that selection for resistance and high fecundity creates positive epistasis in virgin females between a mutant allele for parthenogenesis and alleles for resistance, resulting in female-biased sex ratios and higher resistance and coercion towards the productive ‘core’ of the metapopulation. However, steeper environmental gradients, which lead to lower density and less mating at the ‘edge’, generate female bias without promoting coercion or resistance. Our analysis shows that local adaptation of facultatively parthenogenetic populations subject to sexual conflict and productivity gradients can generate striking spatial variation suggesting new patterns for empirical investigation. These findings could also help to explain the rarity of facultative parthenogenesis in animals.

This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences'.
Abandoning the ship using sex, dispersal or dormancy: multiple escape routes from challenging conditions
Authors: Gerber Nina , Kokko Hanna
Published: August 2018

Natural populations often experience environments that vary across space and over time, leading to spatio-temporal variation of the fitness of a genotype. If local conditions are poor, organisms can disperse in space (physical movement) or time (dormancy, diapause). Facultatively sexual organisms can switch between asexual and sexual reproduction, and thus have a third option available to deal with maladaptedness: they can engage in sexual reproduction in unfavourable conditions (an ‘abandon-ship’ response). Sexual reproduction in facultatively sexual organisms is often coupled with dispersal and/or dormancy, while bet-hedging theory at first sight predicts sex, dispersal and dormancy to covary negatively, as they represent different escape mechanisms that could substitute for each other. Here we briefly review the observed links between sex, dormancy and dispersal, and model the expected covariation patterns of dispersal, dormancy and the reproductive mode in the context of local adaptation to spatio-temporally fluctuating environments. The correlations between sex, dormancy and dispersal evolve differently within species versus across species. Various risk-spreading strategies are not completely interchangeable, as each has dynamic consequences that can feed back into the profitability of others. Our results shed light on the discrepancy between previous theoretical predictions on covarying risk-spreading traits and help explain why sex often associates with other means of escaping unfavourable situations.

This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences’.
Evolution of female choice under intralocus sexual conflict and genotype-by-environment interactions
Authors: Li Xiang-Yi , Holman Luke
Published: August 2018

In many species, females are hypothesized to obtain ‘good genes’ for their offspring by mating with males in good condition. However, female preferences might deplete genetic variance and make choice redundant. Additionally, high-condition males sometimes produce low-fitness offspring, for example because of environmental turnover and gene-by-environment interactions (GEIs) for fitness, or because fit males carry sexually antagonistic alleles causing them to produce unfit daughters. Here, we extend previous theory by investigating the evolution of female mate choice in a spatially explicit evolutionary simulation implementing both GEIs and intralocus sexual conflict (IASC), under sex-specific hard or soft selection. We show that IASC can weaken female preferences for high-condition males or even cause a preference for males in low condition, depending on the relative benefits of producing well-adapted sons versus daughters, which in turn depends on the relative hardness of selection on males and females. We discuss the relevance of our results to conservation genetics and empirical evolutionary biology.

This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences’.
Sex differences in dispersal syndrome are modulated by environment and evolution
Authors: Mishra Abhishek , Tung Sudipta , Shreenidhi P. M. , Aamir Sadiq Mohammed , Shree Sruti V. R. , Chakraborty Partha Pratim , Dey Sutirth
Published: August 2018

Dispersal syndromes (i.e. suites of phenotypic correlates of dispersal) are potentially important determinants of local adaptation in populations. Species that exhibit sexual dimorphism in their life history or behaviour may exhibit sex-specific differences in their dispersal syndromes. Unfortunately, there is little empirical evidence of sex differences in dispersal syndromes and how they respond to environmental change or dispersal evolution. We investigated these issues using two same-generation studies and a long-term (greater than 70 generations) selection experiment on laboratory populations of
Drosophila melanogaster
. There was a marked difference between the dispersal syndromes of males and females, the extent of which was modulated by nutrition availability. Moreover, dispersal evolution via spatial sorting reversed the direction of
dispersal
×
sex
interaction in one trait (desiccation resistance), while eliminating the sex difference in another trait (body size). Thus, we show that sex differences obtained through same-generation trait-associations (‘ecological dispersal syndromes’) are probably environment-dependent. Moreover, even under constant environments, they are not good predictors of the sex differences in ‘evolutionary dispersal syndrome’ (i.e. trait-associations shaped during dispersal evolution). Our findings have implications for local adaptation in the context of sex-biased dispersal and habitat-matching, as well as for the use of dispersal syndromes as a proxy of dispersal.

This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences’.
On the role of sex differences for evolution in heterogeneous and changing fitness landscapes: insights from pygmy grasshoppers
Authors: Forsman Anders
Published: August 2018

Much research has been devoted to study evolution of local adaptations by natural selection, and to explore the roles of neutral processes and developmental plasticity for patterns of diversity among individuals, populations and species. Some aspects, such as evolution of adaptive variation in phenotypic traits in stable environments, and the role of plasticity in predictable changing environments, are well understood. Other aspects, such as the role of sex differences for evolution in spatially heterogeneous and temporally changing environments and dynamic fitness landscapes, remain elusive. An increased understanding of evolution requires that sex differences in development, physiology, morphology, life-history and behaviours are more broadly considered. Studies of selection should take into consideration that the relationships linking phenotypes to fitness may vary not only according to environmental conditions but also differ between males and females. Such opposing selection, sex-by-environment interaction effects of selection and sex-specific developmental plasticity can have consequences for population differentiation, local adaptations and for the dynamics of polymorphisms. Integrating sex differences in analytical frameworks and population comparisons can therefore illuminate neglected evolutionary drivers and reconcile unexpected patterns. Here, I illustrate these issues using empirical examples from over 20 years of research on colour polymorphicTetrix subulataandTetrix undulatapygmy grasshoppers, and summarize findings from observational field studies, manipulation experiments, common garden breeding experiments and population genetics studies.

This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences’.
Modeling motor neuron resilience in ALS using stem cells
Authors: Allodi Ilary , Nijssen Jik , Benitez Julio Aguila , Schweingruber Christoph , Fuchs Andrea , Bonvicini Gillian , Cao Ming , Kiehn Ole , Hedlund Eva
Published: August 2018

Oculomotor neurons, which regulate eye movement, are resilient to degeneration in the lethal motor neuron disease amyotrophic lateral sclerosis (ALS). It would be highly advantageous if motor neuron resilience could be modeledin vitro. Towards this goal, we generated a high proportion of oculomotor neurons from mouse embryonic stem cells through temporal overexpression of Phox2a in neuronal progenitors. We demonstrate, using electrophysiology, immunocytochemistry and RNA sequencing, thatin vitrogenerated neurons arebona fideoculomotor neurons based on their cellular properties and similarity to theirin vivocounterpart in rodent and man. We also show thatin vitrogenerated oculomotor neurons display a robust activation of survival-promoting Akt signaling and are more resilient to the ALS-like toxicity of kainic acid than spinal motor neurons. Thus, we can generatebona fideoculomotor neuronsin vitrowhich display a resilience similar to that seenin vivo.
Reference Set ofMycobacterium tuberculosisClinical Strains: A tool for research and product development
Authors: Borrell Sonia , Trauner Andrej , Brites Daniela , Rigouts Leen , Loiseau Chloe , Coscolla Mireia , Niemann Stefan , Jong Bouke De , Yeboah-Manu Dorothy , Kato-Maeda Midori , Feldmann Julia , Reinhard Miriam , Beisel Christian , Gagneux Sebastien
Published: August 2018

TheMycobacterium tuberculosiscomplex (MTBC) causes tuberculosis (TB) in humans and various other mammals. The human-adapted members of the MTBC comprise seven phylogenetic lineages that differ in their geographical distribution. There is growing evidence that this phylogenetic diversity modulates the outcome of TB infection and disease. For decades, TB research and development has focused on the two canonical MTBC reference strains H37Rv and Erdman, both of which belong to Lineage 4. Relying on only a few laboratory-adapted strains can be misleading as study results might not be directly transferrable to clinical settings where patients are infected with a diverse array of strains, including drug-resistant variants. Here, we argue for the need to expand TB research and development by incorporating the phylogenetic diversity of the MTBC. To facilitate such work, we have assembled a group of 20 genetically well-characterized clinical strains representing the seven known human-adapted MTBC lineages. With the “MTBC clinical strains reference set” we aim to provide a standardized resource for the TB community. We hope it will enable more direct comparisons between studies that explore the physiology of MTBC beyond the lab strains used thus far. We anticipate that detailed phenotypic analyses of this reference strain set will increase our understanding of TB biology and assist in the development of new control tools that are universally effective.
α2-adrenergic signaling disrupts β cell BDNF-TrkB receptor tyrosine kinase signaling
Authors: Kalwat Michael A. , Huang Zhimin , Binns Derk D. , McGlynn Kathleen , Cobb Melanie H.
Published: August 2018

Adrenergic signaling is a well-known input into pancreatic islet function. Specifically, the insulin-secreting islet β cell expresses the Gi/o-linked α2-adrenergic receptor, which upon activation suppresses insulin secretion. The use of adrenergic agonist epinephrine at micromolar doses may have supraphysiological effects. We found that pretreating β cells with micromolar concentrations of epinephrine differentially inhibited activation of receptor tyrosine kinases. We chose TrkB as an example because of its relative sensitivity to the effects of epinephrine and due to its potential regulatory role in the β cell. Our characterization of brain-derived neurotrophic factor (BDNF)-TrkB signaling in MIN6 β cells showed that TrkB is activated by BDNF as expected, leading to canonical TrkB autophosphorylation and subsequent downstream signaling, as well as chronic effects on β cell growth. Micromolar, but not nanomolar, concentrations of epinephrine blocked BDNF-induced TrkB autophosphorylation and downstream mitogen-activated protein kinase pathway activation, suggesting an inhibitory phenomenon at the receptor level. We determined epinephrine-mediated inhibition of TrkB activation to be Gi/o-dependent using pertussis toxin, arguing against an off-target effect of high dose epinephrine. Published data suggested that inhibition of potassium channels or phosphoinositide-3-kinase signaling may abrogate the negative effects of epinephrine, however these did not rescue TrkB signaling in our experiments. Taken together, these results show that 1) TrkB kinase signaling occurs in β cells and 2) use of epinephrine in studies of insulin secretion requires careful consideration of concentration-dependent effects. BDNF-TrkB signaling in β cells may underlie pro-survival or growth signaling and warrants further study.
Human pancreatic islet 3D chromatin architecture provides insights into the genetics of type 2 diabetes
Authors: Miguel-Escalada Irene , Bonàs-Guarch Silvia , Cebola Inês , Joan Ponsa-Cobas , Mendieta-Esteban Julen , Rolando Delphine M.Y. , Javierre Biola M. , Atla Goutham , Farabella Irene , Morgan Claire C. , García-Hurtado Javier , Beucher Anthony , Morán Ignasi , Pasquali Lorenzo , Ramos Mireia , Appel Emil V.R. , Linneberg Allan , Gjesing Anette P. , Witte Daniel R. , Pedersen Oluf , Grarup Niels , Ravassard Philippe , Torrents David , Mercader Josep Maria , Piemonti Lorenzo , Berney Thierry , Koning de Eelco J.P. , Kerr-Conte Julie , Pattou François , Fedko Iryna O. , Prokopenko Inga , Hansen Torben , Marti-Renom Marc A. , Fraser Peter , Ferrer Jorge
Published: August 2018

Genetic studies promise to provide insight into the molecular mechanisms underlying type 2 diabetes (T2D). Variants associated with T2D are often located in tissue-specific enhancer regions (enhancer clusters, stretch enhancers or super-enhancers). So far, such domains have been defined through clustering of enhancers in linear genome maps rather than in 3D-space. Furthermore, their target genes are generally unknown. We have now created promoter capture Hi-C maps in human pancreatic islets. This linked diabetes-associated enhancers with their target genes, often located hundreds of kilobases away. It further revealed sets of islet enhancers, super-enhancers and active promoters that form 3D higher-order hubs, some of which show coordinated glucose-dependent activity. Hub genetic variants impact the heritability of insulin secretion, and help identify individuals in whom genetic variation of islet function is important for T2D. Human islet 3D chromatin architecture thus provides a framework for interpretation of T2D GWAS signals.
Pirfenidone attenuates lung fibrotic fibroblast-mediated fibrotic responses to transforming growth factor-β1
Authors: Jin Jin , Togo Shinsaku , Kadoya Kotaro , Tulafu Miniwan , Namba Yukiko , Iwai Moe , Watanabe Junko , Nagahama Kumi , Okabe Takahiro , Hidayat Moulid , Kodama Yuzo , Kitamura Hideya , Ogura Takashi , Kitamura Norikazu , Ikeo Kazuho , Sasaki Shinichi , Tominaga Shigeru , Takahashi Kazuhisa
Published: August 2018

Pirfenidone, an antifibrotic agent used for treatment of idiopathic pulmonary fibrosis (IPF), functions by inhibiting myofibroblast differentiation, which is involved in transforming growth factor (TGF)-β1-induced IPF pathogenesis. However, unlike normal lung fibroblasts, the relationship between pirfenidone responses of TGF-β1-induced human fibrotic lung fibroblasts and lung fibrosis is unknown. Here, we investigated the effect of pirfenidone on the functions of two new targets, collagen triple helix repeat containing protein 1 (CTHRC1) and four-and-a-half LIM domain protein 2 (FHL2), which included fibroblast activity, collagen gel contraction, and migration toward fibronectin. Compared to control lung fibroblasts, pirfenidone restored TGF-β1-stimulated fibroblast-mediated collagen gel contraction, migration, and CTHRC1 release in lung fibrotic fibroblasts. Furthermore, pirfenidone attenuated TGF-β1- and CTHRC1-induced fibroblast activity, bone morphogenic protein-4/Gremlin1 upregulation, and α-smooth muscle actin, fibronectin, and FHL2 downregulation, similar to that observed post-CTHRC1 inhibition. In contrast, FHL2 inhibition suppressed migration and fibronectin expression but did not downregulate CTHRC1. Overall, pirfenidone suppressed fibrotic fibroblast-mediated fibrotic processes via inverse regulation of CTHRC1-induced lung fibroblast activity. Thus, CTHRC1 can be used for predicting pirfenidone response and developing new therapeutic target for lung fibrosis.

Summary statement

Pirfenidone suppressed TGF-β1-mediated fibrotic processes in fibrotic lung fibroblasts by attenuating CTHRC1 expression, suggesting that CTHRC1 may be a novel therapeutic target for treating patients with lung fibrosis.
Quantifying local malignant adaptation in tissue-specific evolutionary trajectories by harnessing cancer’s repeatability at the genetic level
Authors: Tokutomi N , Moyret-Lalle C , Puisieux A , Sugano S , Martinez P
Published: August 2018

Cancer is a potentially lethal disease, in which patients with nearly identical genetic backgrounds can develop a similar pathology through distinct combinations of genetic alterations. We aimed to reconstruct the evolutionary process underlying tumour initiation, using the combination of convergence and discrepancies observed across 2,742 cancer genomes from 9 tumour types. We developed a framework using the repeatability of cancer development to score the local malignant adaptation (LMA) of genetic clones, as their potential to malignantly progress and invade their environment of origin. Using this framework, we found that pre-malignant skin and colorectal lesions appeared specifically adapted to their local environment, yet insufficiently for full cancerous transformation. We found that metastatic clones were more adapted to the site of origin than to the invaded tissue, suggesting that genetics may be more important for local progression than for the invasion of distant organs. In addition, we used network analyses to investigate evolutionary properties at the system-level, highlighting that different dynamics of malignant progression can be modelled by such a framework in tumour-type-specific fashion. We find that occurrence-based methods can be used to specifically recapitulate the process of cancer initiation and progression, as well as to evaluate the adaptation of genetic clones to given environments. The repeatability observed in the evolution of most tumour types could therefore be harnessed to better predict the trajectories likely to be taken by tumours and pre-neoplastic lesions in the future.
Cyclodextrin triggers MCOLN1-dependent endo-lysosome secretion in Niemann-Pick type C cells
Authors: Vacca Fabrizio , Vossio Stefania , Mercier Vincent , Moreau Dimitri , Johnson Shem , Montoya Jonathan Paz , Moniatte Marc , Gruenberg Jean
Published: August 2018

In specialized cell types, lysosome-related organelles support regulated secretory pathways, while in non-specialized cells, lysosomes can undergo fusion with the plasma membrane in response to a transient rise in cytosolic calcium. Recent evidence also indicates that lysosome secretion can be controlled transcriptionally and promote clearance in lysosome storage diseases. In addition, evidence is also accumulating that low concentrations of cyclodextrins reduce the cholesterol storage phenotype in cells and animals with the cholesterol storage disease Niemann-Pick type C, via an unknown mechanism. Here, we report that cyclodextrin triggers the secretion of the endo/lysosomal content in non-specialized cells, and that this mechanism is responsible for the decreased cholesterol overload in Niemann-Pick type C cells. We also find that that the secretion of the endo/lysosome content occurs via a mechanism dependent on the endosomal calcium channel MCOLN1, as well as FYCO1, the AP1 adaptor and its partner Gadkin. We conclude that endolysosomes in non-specialized cells can acquire secretory functions elicited by cyclodextrin, and that this pathway is responsible for the decrease in cholesterol storage in Niemann-Pick C cells.
Centromere repositioning induced by inner kinetochore impairment generates a meiosis barrier
Authors: Lu Min , He Xiangwei
Published: August 2018

Centromeres dictate the sites for kinetochore assembly on chromosomes, while their own position on each chromosome is determined epigenetically by a specific histone H3 variant CENP-A. For all eukaryotic species, the chromosomal position of each centromere is distinct and inherited with high fidelity, although the mechanisms underlying the epigenetic stability and its functional significance remain largely unknown. Here in the fission yeast Schizosaccharomyces pombe, we show that mutations in inner kinetochore components influence centromeric chromatin organization to various levels. In extreme cases, a single deletion of wip1, mhf1 and mhf2 (the conserved CENP-T-W-S-X complex subunits) or double deletions of cnp3 (a homologue of mammalian CENP-C) and fta6 (a pombe specific component) induce centromere repositioning - inactivation of the original centromere and formation of a neocentromere - in one of the three chromosomes at random. Neocentromeres tend to locate in pericentromeric heterochromatin regions, although heterochromatin is not required for centromere inactivation. Cells carrying a neocentromere are competent in mitosis and in meiosis of homozygotes. However, when these cells are crossed to cells carrying the original centromere, the progeny suffers severe lethality due to defects in meiotic chromosome segregation. These results recapitulate a meiosis barrier that could initiate genetic divergence between two populations with mismatched centromeres, documenting a potential role of the Evolutionary New Centromeres (ENCs) in speciation.

Significance Statement

In eukaryotes, centromeres are chromosomal regions where kinetochores are assembled and the positions of centromeres are accurately inherited. While the centromere and kinetochore assembly are extensively studied, the mechanisms that each centromere maintain its identity on chromosomes are still not well understood. In this study, we demonstrated that the inner kinetochore is required for the normal centromere identity as single depletion of the inner kinetochore CENP-T-W-S-X complex or double deletions of cnp3/CENP-C and fta6 induce centromere repositioning. We further showed cells carrying a neocentromere are reproductively isolated from the wildtype population carrying the original centromere. Taken together, these results suggest that induced centromere repositioning mimics the evolutionary new centromeres and is sufficient to cause reproductive isolation.
The role of land use types and water chemical properties in structuring the microbiomes of a connected lakes system
Authors: Marmen Sophi , Blank Lior , Al-Ashhab Ashraf , Malik Assaf , Ganzert Lars , Lalzar Maya , Grossart Hans-Peter , Sher Daniel
Published: August 2018

Lakes and other freshwater bodies are intimately connected to the surrounding land, yet to what extent land-use affects the quality of freshwater and the microbial communities living in various freshwater environments is largely unknown. We address this question through an analysis of the land use surrounding 46 inter-connected lakes located within 7 different drainage basins in northern Germany, and the microbiomes of these lakes during early summer. Lake microbiome structure was not determined by the specific drainage basin or by basin size, and bacterial distribution did not seem to be limited by distance. Instead, land use within the drainage basin could predict, to some extent, NO2+NO3 concentrations in the water, which (together with temperature, chlorophyll a and total phosphorus) affected water microbiome structure. Land use directly surrounding the water bodies, however, had little observable effects on water quality or the microbiome. Several microbial lineages, including environmentally important Cyanobacteria and Verrucomicrobia, were differentially partitioned between the lakes. As the amount of available data on land use (e.g. from remote sensing) increases, identifying relationships between land use, aquatic microbial communities and their effect on water quality will be important to better manage freshwater resources worldwide, e.g. by systemically identifying water bodies prone to ecological changes or the presence of harmful organisms.
Antimicrobial, Antioxidant and Anti-Inflammatory Activities of Proteins of Phaseoulus lunatus (Fabaceae) Baby Lima Beans Produced in Ecuador
Authors: Tamayo J. , Poveda T. , Paredes M. , Vásquez G. , Calero-Cáceres W.
Published: August 2018

Phaseoulus lunatus L., a variety of baby lima bean, which is produced in the coastal region of Ecuador, is a profitable crop of that country. Various cultivars of this common bean are considered a sources for nutraceutical compounds, such as bioactive peptides. To assess the potential biologic activities of protein isolates and hydrolysates of P. lunatus baby lima beans, this study evaluates the proteins antimicrobial, antioxidant and anti-inflammatory activities. Antioxidant activity was measured by the TBARS method. In-vitro anti-inflammatory activity was measured by the inhibition of denatured protein as well as a diffusion method, according with CLSI guidelines by antimicrobial activity. Both fractions (isolate and hydrolysates) showed anti-inflammatory and antioxidant activity. However, protein hydrolysates (pH 5) had a better performance than protein isolates. The same effect was observed in antimicrobial activity, when protein hydrolysates had a broad-spectrum antimicrobial activity against Gram-negative and Gram-positive bacteria. These preliminary studies suggest that P. lunatus baby lima beans could have a considerable biological activity for nutraceutical applications.
A serial dilution method for assessment of microplastic toxicity in suspension
Authors: Gerdes Zandra , Hermann Markus , Ogonowski Martin , Gorokhova Elena
Published: August 2018

The occurrence of microplastic (MP) in the environment is of global concern. MP risk assessment, however, is currently hampered by lacking ecotoxicological methods due to conceptual and practical problems with particle exposure. Natural particles of similar size as MP, e.g., clay and cellulose, occur abundantly in the environment. For MP risk assessment and regulation it must be established whether the addition of MP to these particles represents an additional hazard. We present a novel approach employing a serial dilution of MP and reference particles, in mixtures, which allows the differentiation of MP effects from other particulates. We demonstrate the applicability of the method using an immobilisation test with Daphnia magna exposed to polyethylene terephthalate (MP) and kaolin clay (reference material). In the concentration range of 0.1 to 10000 mg L-1 of total suspended solids (TSS), with MP contributing 0-100 %, the LC50 values for MP-kaolin mixtures were significantly lower compared to the pure kaolin suspension. MP particles were thus more harmful to daphnids than the reference material. The estimated threshold for %MP contribution above which higher mortality was observed was 1 % MP at 36 mg TSS L-1. This approach has a potential for standardisation of MP ecotoxicological testing as well as other particulate material of anthropogenic origin.
Detection of HPV16, HPV18, p16, and E6/E7 MRNA in Nasopharyngeal Cancer: A Systematic Review and Meta-Analysis
Authors: Machado Rosalie , Khaymovich Julian , Costantino Peter David , Tham Tristan
Published: August 2018

Introduction

Human Papilloma Virus (HPV) associated head and neck cancers, particularly oropharyngeal cancers (OPC), have a superior prognosis to HPV negative cancers. A literature review did not find any studies that analyzed HPV 16, HPV 18 DNA and p16 in the nasopharynx subsite, although it has been reported in the oropharynx. The detection of HPV DNA and p16 in the nasopharynx could have implications for the treatment of NPC. To date no one has reported the detection or concordance rates of HPV associated markers in nasopharyngeal carcinoma (NPC).

Methods

A literature search was undertaken on Medline, EMBASE, Scopus, and the Cochrane Library to identify studies that used PCR and ISH for detection of HPV DNA and p16 in the nasopharynx. We included studies published between 1992 and 2017 that reported the prognostic impact of HPV DNA and/or p16, treated HPV and p16 as categorical variables with at least 10 patients who tested for p16 and/or HPV16/HPV18 DNA in NPC, irrespective of HPV status. We then collected information from many parameters, and performed a meta-analysis to produce pooled prevalence estimates and explored sources of heterogeneity

Results

21 studies published between 1992 and 2017 were selected for meta-analysis, with sample sizes ranging from 10 to 1328. The total (random effects) pooled detection of any HPV marker in NPC patients was 19.7% (95% CI: 12.56 to 28.00). The total (random effects) pooled detection of p16 positivity in NPC patients was 23.98% (95% CI: 14.82 to 34.54). The total (random effects) pooled detection of HPV DNA in NPC patients, detected by ISH, was 14.43% (95% CI: 10.13 to 19.33) and for HPV DNA in NPC patients including E6/E7 was 18.13% (95% CI: 11.45 to 25.94). The total (random effects) pooled detection of HPV DNA in NPC patients was 18.13% (95% CI: 11.45 to 25.94). The total (random effects) pooled detection of EBV positivity in NPC patients was 76.21% (95% CI: 66.40 to 84.80). Heterogeneity was high for all of the results. The attributable fraction of p16+ and HPV DNA+ in NPC is 0.029. The attributable fraction of EBV positive and HPV – in NPC is 0.827. The attributable fraction of EBV negative and HPV – in NPC is 0.0639. The attributable fraction of EBV negative and HPV + in NPC is 0.085. The attributable fraction of EBV positive and HPV + in NPC is 0.023. The attributable fraction of HPV positive and mRNA+ in NPC was 0.115. The attributable fraction of p16 in NPC was 0.123.

Discussion

This is the first study that contributes to the concordance and detection rates of HPV related markers in NPC.

Limitations

Most of the studies included were of Asian extraction. Most of the papers also did not test for E6/E7 RNA and therefore we are unsure of the amount of active E6/E7 RNA in NPC.
Dynamic turnover of paused Pol II complexes at human promoters
Authors: Erickson Benjamin , Sheridan Ryan M. , Cortazar Michael , Bentley David L.
Published: August 2018

Paused RNA polymerase II (Pol II) that piles up near most human promoters is the target of mechanisms that control entry into productive elongation. Whether paused Pol II is a stable or dynamic target remains unresolved. We report that most 5′ paused Pol II throughout the genome is turned over within 2 min. This process is revealed under hypertonic conditions that prevent Pol II recruitment to promoters. This turnover requires cell viability but is not prevented by inhibiting transcription elongation, suggesting that it is mediated at the level of termination. When initiation was prevented by triptolide during recovery from high salt, a novel preinitiated state of Pol II lacking the pausing factor Spt5 accumulated at transcription start sites. We propose that Pol II occupancy near 5′ ends is governed by a cycle of ongoing assembly of preinitiated complexes that transition to pause sites followed by eviction from the DNA template. This model suggests that mechanisms regulating the transition to productive elongation at pause sites operate on a dynamic population of Pol II that is turning over at rates far higher than previously suspected. We suggest that a plausible alternative to elongation control via escape from a stable pause is by escape from premature termination.
A study on the asymmetric cylinder wall thickness difference discrimination by dolphins
Authors: Feng Wen , Zhang Yu , Wei Chong
Published: August 2018

Atlantic bottlenose dolphins (Tursiops truncatus) can effectively discriminate between water-filled cylinders with different wall thicknesses. The dolphins' performance may be particularly good when the cylinders are thinner. The dolphins' performance is also asymmetric, in that the discrimination accuracy is not equal when the target thickness increases and decreases by the same amount. Inspired by this, a finite element model is proposed here to mimic a dolphin actively transmitting sound to discriminate between targets using acoustic echoes. The waveforms and frequency spectra of acoustic echoes from a standard cylinder and comparison cylinders with wall thickness differences of ±0.3 mm were compared. The employed model simulations show good agreement with previous experimental measurements by Au and Pawloski [(1992). J. Compar. Physiol. A 170(1), 41–47]. Asymmetric arrival time shifts were found for the echo peaks and troughs with the same sequence numbers when the wall thicknesses were increased and decreased by the same amount. This asymmetry became more significant for echo peaks and troughs with higher sequence numbers. Apart from these asymmetric arrival time shifts of the acoustic echoes, the patterns of echo waveforms, the spatial distributions of sound pressures in the water, and the particle vibratory displacements in the cylinders were also found to vary with cylinder thickness. The physical origin of this asymmetric discrimination by the dolphins was explored using both geometric acoustics and wave acoustics. The asymmetry observed might be caused by the circumferential surface (Lamb) wave in the cylinder wall, which is a wave acoustics phenomenon that cannot be derived from geometric acoustics. The findings in this paper might be valuable not just for understanding the mechanism of the effect described, but also for helping the development of biomimetic intelligence for robust signal processing in underwater target discrimination.
Active-Site Conformational Fluctuations Promote the Enzymatic Activity of NDM-1
Authors: Zhang Hongmin , Ma Guixing , Zhu Yifan , Zeng Lingxiao , Ahmad Ashfaq , Wang Changzhi , Pang Bo , Fang Huiyan , Zhao Liqing , Hao Quan
Published: August 2018

β-Lactam antibiotics are the mainstay for the treatment of bacterial infections. However, elevated resistance to these antibiotics mediated by metallo-β-lactamases (MBLs) has become a global concern.
Nonthermal Plasma Jet Treatment Negatively Affects the Viability and Structure of Candida albicans SC5314 Biofilms
Authors: Handorf O. , Weihe T. , Bekeschus S. , Graf A. C. , Schnabel U. , Riedel K. , Ehlbeck J.
Published: August 2018

Microbial communities are an increasing problem in medicine but also in industry. Thus, an efficient and rapid removal of biofilms is becoming increasingly important. With the aid of the kINPen09, a radiofrequency plasma jet (RFPJ) instrument, decisive new findings on the effects of plasma onC. albicansbiofilms were obtained. This work showed that the inactivation of biofilms takes place mainly on the bottom, which in turn offers new possibilities for the removal of biofilms by other strategies, e.g., mechanical treatment. This result demonstrated that nonthermal atmospheric pressure plasma is well suited for biofilm decontamination.
Dextran Sulfate Sodium Colitis Facilitates Colonization with Shiga Toxin-Producing Escherichia coli: a Novel Murine Model for the Study of Shiga Toxicosis
Authors: Hall Gregory , Kurosawa Shinichiro , Stearns-Kurosawa D. J.
Published: August 2018

Shiga toxin-producing
Escherichia coli
(STEC) bacteria are globally important gastrointestinal pathogens causing hemorrhagic gastroenteritis with variable progression to potentially fatal Shiga toxicosis. Little is known about the potential effects of
E. coli-
derived Shiga-like toxins (STXs) on host gastrointestinal immune responses during infection, in part due to the lack of a reproducible immunocompetent-animal model of STEC infection without depleting the commensal microbiota.
Evolution of the U.S. Biological Select Agent Rathayibacter toxicus
Authors: Davis Edward W. , Tabima Javier F. , Weisberg Alexandra J. , Lopes Lucas Dantas , Wiseman Michele S. , Wiseman Michael S. , Pupko Tal , Belcher Michael S. , Sechler Aaron J. , Tancos Matt A. , Schroeder Brenda K. , Murray Timothy D. , Luster Douglas G. , Schneider William L. , Rogers Elizabeth E. , Andreote Fernando D. , Grünwald Niklaus J. , Putnam Melodie L. , Chang Jeff H.
Published: August 2018

Rathayibacter toxicus
is a toxin-producing species found in Australia and is often fatal to grazing animals. The threat of introduction of the species into the United States led to its inclusion in the Federal Select Agent Program, which makes
R. toxicus
a highly regulated species. This work provides novel insights into the evolution of
R. toxicus
.
R. toxicus
is the only species in the genus to have acquired a CRISPR adaptive immune system to protect against bacteriophages. Results suggest that coexistence with the bacteriophage NCPPB3778 led to the massive shrinkage of the
R. toxicus
genome, species divergence, and the maintenance of low genetic diversity in extant bacterial groups. This work contributes to an understanding of the evolution and ecology of an agriculturally important species of bacteria.