bluuebunny/crossref_metadata_2025 huggingface dataset:
CenH3-independent kinetochore assembly in Lepidoptera requires CENP-T
Authors: Cortes-Silva N , Ulmer J , Kiuchi T , Hsieh E , Cornilleau G , Ladid I , Dingli F , Loew D , Katsuma S , Drinnenberg IA
Published: November 2019

Accurate chromosome segregation requires assembly of the multiprotein kinetochore complex at centromeres. In most eukaryotes, kinetochore assembly is primed by the histone H3 variant CenH3, which physically interacts with components of the inner kinetochore constitutive-centromere-associated-network (CCAN). Unexpected to its critical function, previous work identified that select eukaryotic lineages, including several insects, have lost CenH3, while having retained homologs of the CCAN. These findings imply alternative CCAN assembly pathways in these organisms that function in CenH3-independent manners. Here, we study the composition and assembly of CenH3-deficient kinetochores of Lepidoptera (butterflies and moths). We show that lepidopteran kinetochores consist of previously identified CCAN homologs as well as additional components including a divergent CENP-T homolog, which are required for accurate mitotic progression. Our study focuses on CENP-T that we find both necessary and sufficient to recruit the Mis12 outer kinetochore complex. In addition, CRISPR-mediated gene editing inBombyx moriestablishes an essential function of CENP-Tin vivo. Finally, the retention of CENP-T homologs in other independently-derived CenH3-deficient insects indicates a conserved mechanism of kinetochore assembly between these lineages. Our study provides the first functional insights into CCAN-based kinetochore assembly pathways that function independently of CenH3, thus contributing to the emerging picture of an unexpected plasticity to build a kinetochore.
Inhibiting the prostaglandin transporter PGT induces non-canonical thermogenesis at thermoneutrality
Authors: Pai Victor J , Lu Run , Wu Licheng , Macia Marina Garcia , Koba Wade R , Chi Yuling , Singh Rajat , Schwartz Gary J , Schuster Victor L
Published: November 2019

ABSTRACT / SUMMARY

Prostaglandins play fundamental roles in adipose tissue function. While prostaglandin F2α inhibits adipogenesis, prostaglandin E2 promotes adipose beiging. PGF2α and PGE2 are both inactivated through uptake by the plasma membrane transporter (PGT). We hypothesized that inhibiting PGT would increase PGF2α and PGE2 levels, thereby reducing white fat expansion and inducing beiging. Consistent with this hypothesis, inhibiting PGT in mice on high fat diet via genetic knockout or pharmacological blockade reduced body fat stores and induced thermogenesis at thermoneutrality. Inguinal white adipose tissue (iWAT) of these mice exhibited robust UCP1-independent thermogenesis characterized by mitochondrial expansion, coupling of O2 consumption to ATP synthesis, and induction of the creatine pathway. Enhanced coupled respiration persisted in PGT-KO iWAT adipocytes in a creatine shuttle-dependent manner. Thus, inhibiting PGT increases mitochondrial biogenesis and coupled respiration—each supported by the creatine pathway in a system lacking UCP1 expression—revealing PGT as a promising drug target against obesity.
Heme synthesis inhibition blocks angiogenesis via mitochondrial dysfunction
Authors: Shetty Trupti , Sishtla Kamakshi , Park Bomina , Repass Matthew J. , Corson Timothy W.
Published: November 2019

The relationship between heme metabolism and angiogenesis is poorly understood. The final synthesis of heme occurs in mitochondria, where ferrochelatase (FECH) inserts Fe2+ into protoporphyrin IX to produce proto-heme IX. We previously showed that FECH inhibition is antiangiogenic in human retinal microvascular endothelial cells (HRECs) and in animal models of ocular neovascularization. In the present study, we sought to understand the mechanism of how FECH and thus heme is involved in endothelial cell function. Mitochondria in endothelial cells had several defects in function after heme inhibition. FECH loss changed the shape and mass of mitochondria and led to significant oxidative stress. Oxidative phosphorylation and mitochondrial Complex IV were decreased in HRECs and in murine retina ex vivo after heme depletion. Supplementation with heme partially rescued phenotypes of FECH blockade. These findings provide an unexpected link between mitochondrial heme metabolism and angiogenesis.

Abstract Figure

Highlights

Heme synthesis inhibition changes mitochondrial morphology in endothelial cells

Loss of heme causes a buildup of mitochondrial ROS and depolarized membrane potential

Endothelial cells have defective oxidative phosphorylation and glycolysis on loss of heme

Mitochondrial damage is caused by loss of functional heme-containing Complex IV and partially restored by exogenous heme
Interaction of two strongly divergent archaellins stabilizes the structure of theHalorubrumarchaellum
Authors: Pyatibratov Mikhail G. , Syutkin Alexey S. , Quax Tessa E.F. , Melnik Tatjana N. , Papke R. Thane , Gogarten Johann Peter , Kireev Igor I. , Surin Alexey K. , Beznosov Sergei N. , Galeva Anna V. , Fedorov Oleg V.
Published: November 2019

The archaellum is a unique motility structure that has only functional similarity to its bacterial counterpart, the flagellum. Archaellar filaments consist of thousands of copies of the protein protomer archaellin. Most euryarchaeal genomes encode multiple homologous archaellins. The role of these multiple archaellin genes remains unclear. Halophilic archaea from the genusHalorubrumpossess two archaellin genes,flaB1andflaB2. Amino acid sequences of the corresponding protein products are extraordinarily diverged (identity of ∼ 40%). To clarify roles for each archaellin, we compared archaella from two naturalHalorubrum lacusprofundistrains: the DL18 strain, which possesses both archaellin genes, and the type strain ACAM 34 whose genome contains theflaB2gene only. Both strains synthesize functional archaella; however, the DL18 strain, where both archaellins are present in comparable amounts, is more motile. In addition, we expressed these differentHrr. lacusprofundiarchaellins in aHaloferax volcaniistrain from which the endogenous archaellin genes were deleted. ThreeHfx. volcaniistrains expressingHrr. lacusprofundiarchaellinsflaB1,flaB2orflaB1-flaB2produced archaellum filaments consisting of only one (FlaB1 or FlaB2) or both (FlaB1/B2) archaellins. All three recombinantHfx. volcaniistrains were motile, although there were profound differences in the efficiency of motility. The recombinant filaments resemble the natural filaments ofHrr. lacusprofundi. Electron microscopy showed that FlaB1 FlaB2-archaella look like typical supercoiled filaments, while with the shape of the FlaB1- and FlaB2-archaella is more variable. Both native and recombinant FlaB1 FlaB2-filaments have greater thermal stability and are more resistant to low salinity stress than single-component filaments. This shows that thermal stability of archaellins depends on the presence of both archaellin types, indicating a close interaction between these subunits in the supramolecular structure. Functional helicalHrr. lacusprofundiarchaella can be composed of either single archaellin: FlaB2 or FlaB1; however, the two divergent archaellin subunits in combination provide additional stabilization to the archaellum structure and thus adaptation to a wider range of external conditions. A comparative genomic analysis of archaellins suggests that the described combination of divergent archaellins is not restricted toHrr. lacusprofundi,but is occurring also in organisms from other haloarchaeal genera.
A Systems Approach Identifies Enhancer of Zeste Homolog 2 (EZH2) as a Protective Factor in Epilepsy
Authors: Khan Nadia , Schoenike Barry , Basu Trina , Grabenstatter Heidi , Rodriguez Genesis , Sindic Caleb , Johnson Margaret , Wallace Eli , Maganti Rama , Dingledine Raymond , Roopra Avtar
Published: November 2019

Complex neurological conditions can give rise to large scale transcriptomic changes that drive disease progression. It is likely that alterations in one or a few transcription factors or cofactors underlie these transcriptomic alterations. Identifying the driving transcription factors/cofactors is a non-trivial problem and a limiting step in the understanding of neurological disorders. Epilepsy has a prevalence of 1% and is the fourth most common neurological disorder. While a number of anti-seizure drugs exist to treat seizures symptomatically, none is curative or preventive. This reflects a lack of understanding of disease progression. We used a novel systems approach to mine transcriptome profiles of rodent and human epileptic brain samples to identify regulators of transcriptional networks in the epileptic brain. We find that Enhancer of Zeste Homolog 2 (EZH2) regulates differentially expressed genes in epilepsy across multiple rodent models of acquired epilepsy. EZH2 undergoes a prolonged upregulation in the epileptic brain. A transient inhibition of EZH2 immediately after seizure induction robustly increases spontaneous seizure burden weeks later. Thus, EZH2 upregulation is a protective response mounted after a seizure. These findings are the first to characterize a role for EZH2 in opposing epileptogenesis and debut a bioinformatic approach to identify nuclear drivers of complex transcriptional changes in disease.

Author Summary

Epilepsy is the fourth most common neurological disorder and has been described since the time of Hippocrates. Despite this, no treatments exist to stop epilepsy progression. This is fundamentally due to the complex nature of the disease. Epilepsy is associated with hundreds if not thousands of gene expression changes in the brain that are likely driven by a few key master regulators called transcription factors and cofactors. Finding the aberrantly acting factors is a complex problem that currently lacks a satisfactory solution. We used a novel datamining tool to define key master regulators of gene expression changes across multiple epilepsy models and patient samples. We find that a nuclear enzyme, EZH2, regulates a large number of genes in the rodent and patient epileptic brain and that it’s function is protective. Thus, inhibiting EZH2 greatly exacerbates seizure burden. This is the first report of a novel datamining tool to define drivers of large-scale gene changes and is also the first report of EZH2 induction as an endogenous protective response in the epilepsy.
Horizontal gene transfer drives the evolution of dependencies in bacteria
Authors: Goyal Akshit
Published: November 2019

Many naturally-occurring bacteria lead a lifestyle of metabolic dependency, i.e., they depend on others for crucial resources. We do not understand what factors drive bacteria towards this lifestyle, and how. Here, we systematically show that horizontal gene transfer (HGT) plays a crucial role in the evolution of dependencies in bacteria. Across 835 bacterial species, we map gene gain-loss dynamics on a deep evolutionary tree, and assess the impact of HGT and gene loss on bacterial metabolic networks. Our analyses suggest that genes acquired by HGT can affect which genes are later lost. Dependency evolution is contingent on earlier HGT because of two reasons. First, we find that HGT typically adds new catabolic routes to bacterial metabolic networks. This increases the chance of new metabolic interactions between bacteria, which is a prerequisite for dependency evolution. Second, we show that gaining new routes can promote the loss of specific ancestral routes (a mechanism we call “coupled gains and losses”, CGLs). Phylogenetic patterns indicate that both types of dependencies — those mediated by CGLs and those purely by gene loss — are equally likely. Our results highlight HGT as an important driver of metabolic dependency evolution in bacteria.
Geometry and evolution of the ecological niche in plant-associated microbes
Authors: Chaloner Thomas M. , Gurr Sarah J. , Bebber Daniel P.
Published: November 2019

The ecological niche of a species can be conceptualized as a volume in multidimensional space, where each dimension describes an abiotic condition or biotic resource. The shape and size of this volume strongly determines interactions among species and influences their global distribution, but the geometry of the niche is poorly understood. Here, we analyse temperature response functions and host plant ranges for hundreds of fungi and oomycetes. We demonstrate that niche specialization is independent on abiotic and biotic axes, that host interactions restrict fundamental niche breadth to form the realized niche, and that both abiotic and biotic niches show limited phylogenetic constraint. Such niche adaptability makes plant pathogens a formidable threat to agriculture and forestry.
Dynamic DNA-based information storage
Authors: Lin Kevin N. , Keung Albert J. , Tuck James M.
Published: November 2019

Technological leaps are often driven by key innovations that transform the underlying architectures of systems. Current DNA storage systems largely rely on polymerase chain reaction, which broadly informs how information is encoded, databases are organized, and files are accessed. Here we show that a hybrid ‘toehold’ DNA structure can unlock a fundamentally different, dynamic DNA-based information storage system architecture with broad advantages. This innovation increases theoretical storage densities and capacities by eliminating non-specific DNA-DNA interactions common in PCR and increasing the encodable sequence space. It also provides a physical handle with which to implement a range of in-storage file operations. Finally, it reads files non-destructively by harnessing the natural role of transcription in accessing information from DNA. This simple but powerful toehold structure lays the foundation for an information storage architecture with versatile capabilities.
The Manifold Actions of Signaling Peptides on Subcellular Dynamics of a Receptor Specify Stomatal Cell Fate
Authors: Qi Xingyun , Maes Michal , Zeng Scott , Torii Keiko U
Published: November 2019

Receptor endocytosis is important for signal activation and transduction. However, how a receptor interprets conflicting signals to adjust cellular output is not clearly understood. During plant development, the family of EPIDERMAL PATTERNING FACTOR (EPF) peptides fine-tunes stomatal patterning through ERECTA-family receptor kinases. Using genetic, cell biological, and pharmacological approaches, we report here that ERECTA-LIKE1 (ERL1), the major receptor restricting stomatal differentiation, undergoes dynamic subcellular behaviors in response to different signal inputs. ERL1 is constitutively recycled, whereas its activation by EPF1 peptide induces rapid internalization to multivesicular bodies (MVB). In contrast, the dominant-negative ERL1 resides predominantly in plasma membrane. The co-receptor, TOO MANY MOUTHS (TMM), is essential for EPF1-induced ERL1 internalization but dispensable for EPFL6-induced ERL1 internalization. The peptide antagonist of EPF1, Stomagen/EPFL9, triggers retention of ERL1 in the endoplasmic reticulum. Our study elucidates that multiple related yet unique peptides specify cell fate by deploying the differential subcellular dynamics of a single receptor.
Dynamic Genome Evolution and Blueprint of Complex Virocell Metabolism in Globally-Distributed Giant Viruses
Authors: Moniruzzaman Mohammad , Martinez-Gutierrez Carolina A. , Weinheimer Alaina R. , Aylward Frank O.
Published: November 2019

The discovery of giant viruses with large genomes has transformed our understanding of the limits of viral complexity in the biosphere, and subsequent research in model virus-host systems has advanced our knowledge of intricate mechanisms used by these viruses to take over host cells during infection. The extent of the metabolic diversity encoded by these viruses in the environment is less well-understood, however, and their potential impact on global biogeochemical cycles remains unclear. To address this, we generated 501 metagenome-assembled genomes (MAGs) of NCLDVs from diverse environments around the globe and analyzed their encoded functional diversity and potential for reprogramming host physiology. We found that 476 (95%) of the MAGs belonged to the Mimiviridae and Phycodnaviridae families, and of these we recovered 96% from aquatic environments, highlighting the diversity of these viral families in global freshwater and marine systems. MAGs encoded diverse genes predicted to be involved in nutrient uptake and processing, light harvesting, central nitrogen metabolism, and the manipulation of cell death, underscoring the complex interplay between these viruses and their hosts. Surprisingly, numerous genomes encoded genes involved in glycolysis, gluconeogenesis, and the TCA cycle, including one genome with a 70%-complete glycolytic pathway, suggesting that many of these viruses can even reprogram fundamental aspects of their host’s central carbon metabolism. Phylogenetic trees of NCLDV metabolic genes together with their cellular homologs revealed distinct clustering of viral sequences into divergent clades, indicating these metabolic genes are virus-specific and were acquired in the distant past. Our findings reveal that diverse NCLDV genomes encode complex, cell-like metabolic capabilities with evolutionary histories that are largely independent of cellular life, strongly implicating them as distinct drivers of biogeochemical cycles in their own right.
Nightmares share strong genetic risk with sleep and psychiatric disorders
Authors: Ollila Hanna M , Sinnott-Armstrong Nasa , Kantojärvi Katri , Palviainen Teemu , Pandit Anita , Rong Robin , Kristiansson Kati , Sandman Nils , Valli Katja , Hublin Christer , Kaprio Jaakko , Saxena Richa , Paunio Tiina
Published: November 2019

Nightmares are vivid, extended and extremely dysphoric dreams that awaken the dreamer. Twin studies indicate that nightmare frequency has a heritability between 36 and 51% providing evidence for genetic factors underlying predisposition to nightmares. Furthermore, while cross-sectional epidemiological findings suggest that heavy alcohol usage, traumatic experiences and psychiatric diseases associate with nightmares, the causal relationships between these conditions and nightmares have remained unknown. To examine the biological mechanisms behind nightmares, we performed a genome-wide association study in 28,596 individuals from Finland and the United States. We identified individual genetic variants that predispose to nightmares near MYOF (rs701873, p=2.18e-8) and PTPRJ (rs11039471,p=3.7e-8), a gene previously associated with sleep duration. We found a strong genetic correlation between the frequency of nightmares and traits related to personality and psychiatric disorders; neuroticism (rg=0.59, p=8e-7), post-traumatic stress disorder (PTSD) (rg=0.58, p=0.004) as well as major depressive disorder (rg=0.68, p=7e-4), and sleep traits; and daytime sleepiness (rg=0.62, p=1e-6) and insomnia (rg=0.50, p=1.87e-5). Analysis of directionality using mendelian randomization showed a significant effect from feelings of fed-up (p=0.001), nervous (p=0.004) and miserableness (p=0.0045) to nightmares with no evidence of pleiotropy and no evidence of nightmares predisposing to psychiatric or psychological problems. Our findings suggest that nightmares are caused by unique genetic risk factors, and here we identify the first individual genetic associations. In addition, a substantial effect on nightmares is conveyed through underlying psychological and sleep problems, with psychological problems being causal for nightmares.
Ultradian regulation of rest and activity bouts in mice
Authors: Ananthasubramaniam Bharath , Meijer Johanna H.
Published: November 2019

The suprachiasmatic nucleus (SCN), which serves as the central pacemaker in mammals, regulates the 24-hour rhythm in behavioral activity. However, it is currently unclear whether and how bouts of activity and rest are regulated within the 24-hour cycle (i.e., over ultradian time scales). Therefore, we used passive infrared sensors to measure behavior in mice housed under either a light-dark (LD) cycle or continuous darkness (DD). We found that a probabilistic Markov model captures the ultradian changes in the behavioral state over a 24-hour cycle. In this model, the animal’s behavioral state in the next time interval is determined solely by the animal’s current behavioral state and by the “toss” of a proverbial “biased coin”. We found that the bias of this “coin” is regulated by light input and by the phase of the clock. Moreover, the bias of this “coin” for an animal is related to the average length of rest and activity bouts in that animal. In LD conditions, the average length of rest bouts was greater during the day compared to during the night, whereas the average length of activity bouts was greater during the night compared to during the day. Importantly, we also found that day-night changes in the rest bout lengths were significantly greater than day-night changes in the activity bout lengths. Finally, in DD conditions, the activity and rest bouts also differed between subjective night and subjective day, albeit to a lesser extent compared to LD conditions. The persistent differences in bout length over the circadian cycle following loss of the external LD cycle indicate that the central pacemaker plays a role in regulating rest and activity bouts on an ultradian time scale.
Marker-Trait Complete Analysis
Authors: Zhou Yi-Hui , Gallins Paul , Wright Fred
Published: November 2019

1

A recurring problem in genomics involves testing association of one or more traits of interest to multiple genomic features. Feature-trait squared correlations r2 are commonly-used statistics, sensitive to trend associations. It is often of interest to perform testing across collections {r2} over markers and/or traits using both maxima and sums. However, both trait-trait correlations and marker-marker correlations may be strong and must be considered. The primary tools for multiple testing suffer from various shortcomings, including p-value inaccuracies due to asymptotic methods that may not be applicable. Moreover, there is a lack of general tools for fast screening and follow-up of regions of interest.To address these difficulties, we propose the MTCA approach, for Marker-Trait Complete Analysis. MTCA encompasses a large number of existing approaches, and provides accurate p-values over markers and traits for maxima and sums of r2 statistics. MTCA uses the conditional inference implicit in permutation as a motivational frame-work, but provides an option for fast screening with two novel tools: (i) a multivariate-normal approximation for the max statistic, and (ii) the concept of eigenvalue-conditional moments for the sum statistic. We provide examples for gene-based association testing of a continuous phenotype and cis-eQTL analysis, but MTCA can be applied in a much wider variety of settings and platforms.
Poisson balanced spiking networks
Authors: Rullán Buxó Camille E. , Pillow Jonathan W.
Published: November 2019

An important problem in computational neuroscience is to understand how networks of spiking neurons can carry out various computations underlying behavior. Balanced spiking networks (BSNs) provide a powerful framework for implementing arbitrary linear dynamical systems in networks of integrate-and-fire neurons (Boerlin et al. [1]). However, the classic BSN model requires near-instantaneous transmission of spikes between neurons, which is biologically implausible. Introducing realistic synaptic delays leads to an pathological regime known as “ping-ponging”, in which different populations spike maximally in alternating time bins, causing network output to overshoot the target solution. Here we document this phenomenon and provide a novel solution: we show that a network can have realistic synaptic delays while maintaining accuracy and stability if neurons are endowed with conditionally Poisson firing. Formally, we propose two alternate formulations of Poisson balanced spiking networks: (1) a “local” framework, which replaces the hard integrate-and-fire spiking rule within each neuron by a “soft” threshold function, such that firing probability grows as a smooth nonlinear function of membrane potential; and (2) a “population” framework, which reformulates the BSN objective function in terms of expected spike counts over the entire population. We show that both approaches offer improved robustness, allowing for accurate implementation of network dynamics with realistic synaptic delays between neurons. Moreover, both models produce positive correlations between similarly tuned neurons, a feature of real neural populations that is not found in the original BSN. This work unifies balanced spiking networks with Poisson generalized linear models and suggests several promising avenues for future research.
Physiological and molecular responses of a newly evolved auxotroph of Chlamydomonas to B12 deprivation
Authors: Bunbury Freddy , Helliwell Katherine E , Mehrshahi Payam , Davey Matthew P , Salmon Deborah , Holzer Andre , Smirnoff Nicholas , Smith Alison G
Published: November 2019

The corrinoid B12 is synthesised only by prokaryotes yet is widely required by eukaryotes as an enzyme cofactor. Microalgae have evolved B12 dependence on multiple occasions and we previously demonstrated that experimental evolution of the non-requiring alga Chlamydomonas reinhardtii in media supplemented with B12 generated a B12-dependent mutant (hereafter metE7). This clone provides a unique opportunity to study the physiology of a nascent B12 auxotroph. Our analyses demonstrate that B12 deprivation of metE7 disrupted C1 metabolism, caused an accumulation of starch and triacylglycerides and a decrease in photosynthetic pigments, proteins and free amino acids. B12 deprivation also caused a substantial increase in reactive oxygen species (ROS), which preceded rapid cell death. Surprisingly, survival could be improved without compromising growth by simultaneously depriving the cells of nitrogen, suggesting a type of cross protection. Significantly, we found further improvements in survival under B12 limitation and an increase in B12 use-efficiency after metE7 underwent a further period of experimental evolution, this time in coculture with a B12-producing bacterium. Therefore, although an early B12-dependent alga would likely be poorly adapted to B12 deprivation, association with B12-producers can ensure long-term survival whilst also providing the environment to evolve mechanisms to better tolerate B12 limitation.
Aurora B-dependent Ndc80 Degradation Regulates Kinetochore Composition in Meiosis
Authors: Chen Jingxun , Liao Andrew , Powers Emily N , Liao Hanna , Kohlstaedt Lori A , Evans Rena , Holly Ryan M , Kim Jenny Kim , Jovanovic Marko , Ünal Elçin
Published: November 2019

The kinetochore complex is a conserved machinery that connects chromosomes to spindle microtubules. During meiosis, the kinetochore is restructured to accommodate a specialized chromosome segregation pattern. In budding yeast, meiotic kinetochore remodeling is mediated by the temporal changes in the abundance of a single subunit called Ndc80. We have previously described the regulatory events that control the timely synthesis of Ndc80. Here, we report that Ndc80 turnover is also tightly regulated in meiosis: Ndc80 degradation is active in meiotic prophase, but not in metaphase I. Ndc80 degradation depends on the ubiquitin ligase APCAma1and is mediated by the proteasome. Importantly, Aurora B-dependent Ndc80 phosphorylation, a mark that has been previously implicated in correcting erroneous microtubule–kinetochore attachments, is essential for Ndc80 degradation in a microtubule-independent manner. The N-terminus of Ndc80, including a 27-residue sequence and Aurora B phosphorylation sites, is both necessary and sufficient for kinetochore protein degradation. Finally, defects in Ndc80 turnover predispose meiotic cells to chromosome mis-segregation. Our study elucidates the mechanism by which meiotic cells modulate their kinetochore composition through regulated Ndc80 degradation, and demonstrates that Aurora B-dependent regulation of kinetochores extends beyond altering microtubule attachments.
Mass spectrometry analysis of mouse hematopoietic stem cells and their progenitors reveals differential expression within and between proteome and transcriptome throughout adult and aged hematopoiesis
Authors: Zaro Balyn W. , Noh Joseph J. , Mascetti Victoria L. , Demeter Janos , George Benson M. , Zukowska Monika , Gulati Gunsagar S. , Sinha Rahul , Morganti Rachel M. , Banuelos Allison M. , Zhang Allison , Jackson Peter K. , Weissman Irving L.
Published: November 2019

Hematopoietic stem cells (HSCs) are responsible for the generation of blood and immune cells throughout life. They have the unique ability to self-renew and generate more HSCs or differentiate into a progenitor cell in response to cell-intrinsic and -extrinsic stimuli. The balance of HSC fate commitment is critical for a healthy blood supply. Imbalances during hematopoiesis, which are frequent in aging, can result in hematological malignancies and pre-malignancies as well as increase risk of atherosclerosis. Given the importance of HSCs and their progenitors, they have been extensively characterized in genomic and transcriptomic studies. However, an understanding of protein expression within the HSC compartment and more broadly throughout hematopoiesis remains poorly understood, and it has been widely reported that the correlation between mRNA and proteins is more complicated than previously thought. Previous mouse mass spectrometry studies have focused either specifically on stem and the first early progenitor or broadly across mixed populations of stem and progenitor cells, which do not allow for cell-type specific protein resolution across stages of differentiation. Mass cytometry has been employed to characterize transcription factor expression in human HSCs and progenitors but does not apply an unbiased discovery approach. New mass spectrometry technology now allows for deep proteomic coverage with no more than 200 ng of sample input. We report here a proteomics resource characterizing protein expression in mouse adult and aged HSCs, multipotent progenitors and oligopotent progenitors, 12 cell types in total. We validated differential expression by flow cytometry analysis and immunofluorescence staining. Additionally, we investigated the relationship between mRNA and protein levels of individual genes in HSCs compared to progenitors through RNA sequencing studies and identified two proteins that appear to be uniquely regulated in the HSC compartment, Cpin1 and Adnp. In summary, this resource provides proteomic coverage of adult and aged hematopoietic stem cells and their progenitors and reveals changes in protein abundance between cell types, with potential future implications in understanding mechanisms for stem-cell maintenance, niche interactions and fate determination.
Impact of admixture and ancestry on eQTL analysis and GWAS colocalization in GTEx
Authors: Gay Nicole R. , Gloudemans Michael , Antonio Margaret L. , Balliu Brunilda , Park YoSon , Martin Alicia R. , Musharoff Shaila , Rao Abhiram , Aguet François , Barbeira Alvaro , Bonazzola Rodrigo , Hormozdiari Farhad ,   GTEx Consortium, Ardlie Kristin G. , Brown Christopher D. , Im Hae Kyung , Lappalainen Tuuli , Wen Xiaoquan , Montgomery Stephen B.
Published: November 2019

Background

Population structure among study subjects may confound genetic association studies, and lack of proper correction can lead to spurious findings. The Genotype-Tissue Expression (GTEx) project largely contains individuals of European ancestry, but the final release (v8) also includes up to 15% of individuals of non-European ancestry. Assessing ancestry-based adjustments in GTEx provides an opportunity to improve portability of this research across populations and to further measure the impact of population structure on GWAS colocalization.

Results

Here, we identify a subset of 117 individuals in GTEx (v8) with a high degree of population admixture and estimate genome-wide local ancestry. We perform genome-wide cis-eQTL mapping using admixed samples in six tissues, adjusted by either global or local ancestry. Consistent with previous work, we observe improved power with local ancestry adjustment. At loci where the two adjustments produce different lead variants, we observe only 0.8% of tests with GWAS colocalization posterior probabilities that change by 10% or more. Notably, both adjustments produce similar numbers of significant colocalizations. Finally, we identify a small subset of GTEx v8 eQTL-associated variants highly correlated with local ancestry (R2 > 0.7), providing a resource to enhance functional follow-up.

Conclusions

We provide a local ancestry map for admixed individuals in the final GTEx release and describe the impact of ancestry and admixture on gene expression, eQTLs, and GWAS colocalization. While the majority of results are concordant between local and global ancestry-based adjustments, we identify distinct advantages and disadvantages to each approach.
Population genetic models of GERP scores suggest pervasive turnover of constrained sites across mammalian evolution
Authors: Huber Christian D. , Kim Bernard Y. , Lohmueller Kirk E.
Published: November 2019

Comparative genomic approaches have been used to identify sites where mutations are under purifying selection and of functional consequence by searching for sequences that are conserved across distantly related species. However, the performance of these approaches has not been rigorously evaluated under population genetic models. Further, short-lived functional elements may not leave a footprint of sequence conservation across many species. Here, we use simulations to study how one measure of conservation, the GERP score, relates to the strength of selection (Nes). We show that the GERP score is related to the strength of purifying selection. However, changes in selection coefficients or functional elements over time (i.e. functional turnover) can strongly affect the GERP distribution, leading to unexpected relationships between GERP andNes. Further, we show that for functional elements that have a high turnover rate, the optimal tree size is not necessarily the largest possible tree, and more turnover reduces the optimal tree size. Finally, we use the distribution of GERP scores across the human genome to compare models with and without turnover of sites where mutations under purifying selection. We show that mutations in 4.51% of the noncoding human genome are under purifying selection and that most of this sequence has likely experienced changes in selection coefficients throughout mammalian evolution.
Key ecological parameters of immotile versus locomotive life Фундаментальные экологические параметры неподвижной и передвигающейся жизни
Authors: Gorshkov V. G. , Makarieva A. M.
Published: November 2019

Principles of stable ecosystem organization are considered together with the role of abundant space, matter and energy in its maintenance. Life features the dichotomy of immotile (sessile, sedentary) organisms like plants, fungi, bacteria, on the one hand, versus organisms capable of active locomotion (animals) on the other. The immotile life can form a continuous live cover on the Earth’s surface. Since all available space is occupied, the immotile life does not experience an affluence of matter, energy and space itself. It turns out that this lack of abundance permits organization, on the basis of immotile organisms, of a stable ecosystem with a steady biomass. This live biomass comprises time-invariable genetic information about how to keep the environment in a stable state by controlling the degree of openness of nutrient cycles. Crucially, depending on their body size, energy and matter consumption by large animals exceed the area-specific fluxes of net primary production and its consumption in the immotile ecosystem by up to three orders of magnitude. The implication is that the herbivorous animals can meet their energy demands if and only if they move and destroy the live biomass of the immotile ecosystem. In consequence, if the immotile heterotrophs are replaced by locomotive heterotrophs, the ecosystem biomass experiences huge fluctuations and the ecosystem loses its capacity to maintain its favorable environment. From available theoretical and empirical evidence we conclude that life’s organization remains stable if the share of consumption by large animals is strictly limited, not exceeding about one per cent of ecosystem net primary production.
Isolation and screening of heavy metal resistant ammonia oxidizing bacteria from soil and waste dump: a potential candidates for bioremediation of heavy metals
Authors: Nyoyoko Veronica Fabian , Anyanwu Chukwudi U
Published: November 2019

The study was undertaken to examine the response of ammonia oxidizing bacteria to different heavy metal salt in an elevated concentration. Surface soil samples at depth of 0-15 cm were collected at random from Akwa Ibom State University in Akwa Ibom State, soil sample from University of Nigeria, Nsukka and from solid waste disposal site in Uyo, Akwa Ibom State. The response of heavy metal salt on Ammonia Oxidizing bacteria(AOB) isolated from soil samples were investigated by supplementing different heavy metal salts namely, copper(Cu),nickel (Ni), lead (Pb) and cadmium (Cd) at four loading rates(100,200,500,1000 µg/ml) in mineral salt broth with Ammonia Oxidizing Bacteria (AOB) isolate. The cultures were incubated for 7 days. Growth of AOB was measured by withdrawing samples from the medium every 24 hours and absorbance of the turbidity measured at 600 nanometre using spectrophotometer. All bacteria showed high tendency to decrease optical density while increasing metal concentration in the medium. Tolerance for the metal ions was dependent on concentration, time and the isolate tested. All the Ammonia oxidizing bacterial (AOB) showed a high level of tolerance for the metals tested, and exhibited good growth at all metal salt concentrations tested. These make the nitrifying bacteria attractive potential candidates for further investigations regarding their ability to remove metals from contaminated soil.

IMPORTANCE

The aim of this study is tolerance of ammonia oxidizing bacteria growth to heavy metal. Nitrifying bacteria remain a good option for bioremediation of soil and waste dump, since it is regarded as eco-friendly and efficient in biosorption of heavy metal. The study is significant to the field of environmental microbiology by adding to knowledge in bioremediation.
Structural insights into interaction mechanisms of alternative piperazine-urea YEATS domain binders in MLLT1
Authors: Ni Xiaomin , Heidenreich David , Christott Thomas , Bennett James , Moustakim Moses , Brennan Paul E. , Fedorov Oleg , Knapp Stefan , Chaikuad Apirat
Published: November 2019

YEATS-domain-containing MLLT1 is an acetyl/acyl-lysine reader domain, which is structurally distinct from well-studied bromodomains and has been strongly associated in development of cancer. Here, we characterized piperazine-urea derivatives as an acetyl/acyl-lysine mimetic moiety for MLLT1. Crystal structures revealed distinct interaction mechanisms of this chemotype compared to the recently described benzimidazole-amide based inhibitors, exploiting different binding pockets within the protein. Thus, the piperazine-urea scaffold offers an alternative strategy for targeting the YEATS domain family.
The evolution of multicellular complexity: the role of relatedness and environmental constraints
Authors: Fisher RM , Shik JZ , Boomsma JJ
Published: November 2019

A major challenge in evolutionary biology has been to explain the variation in multicellularity across the many independently evolved multicellular lineages, from slime moulds to humans. Social evolution theory has highlighted the key role of relatedness in determining multicellular complexity and obligateness, however there is a need to extend this to a broader perspective incorporating the role of the environment. In this paper, we formally test Bonner’s 1998 hypothesis that the environment is crucial in determining the course of multicellular evolution, with aggregative multicellularity evolving more frequently on land and clonal multicellularity more frequently in water. Using a combination of scaling theory and phylogenetic comparative analyses, we describe multicellular organisational complexity across 139 species spanning 14 independent transitions to multicellularity and investigate the role of the environment in determining multicellular group formation and in imposing constraints on multicellular evolution. Our results, showing that the physical environment has impacted the way in which multicellular groups form, could shed light on the role of the environment for other major evolutionary transitions.
Meta-analysis of Scandinavian Schizophrenia Exomes
Authors: Lescai Francesco , Grove Jakob , Satterstrom F. Kyle , Rees Elliott , Bybjerg-Grauholm Jonas , Als Thomas Damm , Kalinowski Jaroslaw , Halager Anders , Singh Tarjinder , Li Qibin , Wang Jun , Walters James T R , Owen Michael J , O’Donovan Michael C , Nordentoft Merete , Mortensen Preben Bo , Hougaard David M , Werge Thomas , Mors Ole , Neale Benjamin M , Daly Mark J , Børglum Anders D
Published: November 2019

Rare genetic variants may play a prominent role in schizophrenia. We report on the to date largest whole exome sequencing study of schizophrenia case-control samples from related populations and combine with other available sequence data, analysing in total 34,084 individuals (14,302 cases). Three genes showed significant association at FDR < 0.10 (SETD1A, TAF13 and MKI67) and gene-set analyses highlighted the involvement of the synaptome and excitatory neurons, and demonstrated shared architecture with high-functioning autism.
A Simplest Bioinformatics Pipeline for Whole Transcriptome Sequencing: Overview of the Processing and Steps from Raw Data to Downstream Analysis
Authors: Gupta Ayam , Gupta Sonal , Jatawa Suresh Kumar , Kumar Ashwani , Suravajhala Prashanth
Published: November 2019

Recent advances in next generation sequencing (NGS) technologies have heralded the genomic research. From the good-old inferring differentially expressed genes (DEG) using microarray to the current adage NGS-based whole transcriptome or RNA-Seq pipelines, there have been advances and improvements. With several bioinformatics pipelines for analysing RNA-Seq on rise, inferring the candidate DEGs prove to be a cumbersome approach as one may have to reach consensus among all the pipelines. To Check this, we have benchmarked the well known cufflinks-cuffdiff pipeline on a set of datasets and outline it in the form of a protocol where researchers interested in performing whole transcriptome shotgun sequencing and it’s downstream analysis can better disseminate the analysis using their datasets.
MicrobioLink: An integrated computational pipeline to infer functional effects of microbiome-host interactions
Authors: Andrighetti Tahila , Bohar Balazs , Lemke Ney , Sudhakar Padhmanand , Korcsmaros Tamas
Published: November 2019

Microbiome-host interactions play significant roles in health and in various diseases including auto-immune disorders. Uncovering these inter-kingdom cross-talks propels our understanding of disease pathogenesis, and provides useful leads on potential therapeutic targets. Despite the biological significance of microbe-host interactions, there is a big gap in understanding the downstream effects of these interactions on host processes. Computational methods are expected to fill this gap by generating, integrating and prioritizing predictions - as experimental detection remains challenging due to feasibility issues. Here, we present MicrobioLink, a computational pipeline to integrate predicted interactions between microbial and host proteins together with host molecular networks. Using the concept of network diffusion, MicrobioLink can analyse how microbial proteins in a certain context are influencing cellular processes by modulating gene or protein expression. We demonstrated the applicability of the pipeline using a case study. We used gut metaproteomic data from Crohn’s disease patients and healthy controls to uncover the mechanisms by which the microbial proteins can modulate host genes which belong to biological processes implicated in disease pathogenesis. MicrobioLink, which is agnostic of the microbial protein sources (bacterial, viral etc), is freely available on GitHub (https://github.com/korcsmarosgroup/HMIpipeline).
MOFA+: a probabilistic framework for comprehensive integration of structured single-cell data
Authors: Argelaguet Ricard , Arnol Damien , Bredikhin Danila , Deloro Yonatan , Velten Britta , Marioni John C , Stegle Oliver
Published: November 2019

Technological advances have enabled the joint analysis of multiple molecular layers at single cell resolution. At the same time, increased experimental throughput has facilitated the study of larger numbers of experimental conditions. While methods for analysing single-cell data that model the resulting structure of either of these dimensions are beginning to emerge, current methods do not account for complex experimental designs that include both multiple views (modalities or assays) and groups (conditions or experiments). Here we present Multi-Omics Factor Analysis v2 (MOFA+), a statistical framework for the comprehensive and scalable integration of structured single cell multi-modal data. MOFA+ builds upon a Bayesian Factor Analysis framework combined with fast GPU-accelerated stochastic variational inference. Similar to existing factor models, MOFA+ allows for interpreting variation in single-cell datasets by pooling information across cells and features to reconstruct a low-dimensional representation of the data. Uniquely, the model supports flexible group-level sparsity constraints that allow joint modelling of variation across multiple groups and views.

To illustrate MOFA+, we applied it to single-cell data sets of different scales and designs, demonstrating practical advantages when analyzing datasets with complex group and/or view structure. In a multi-omics analysis of mouse gastrulation this joint modelling reveals coordinated changes between gene expression and epigenetic variation associated with cell fate commitment.
Isolation and molecular identification of pectinase producing Aspergillus species from different soil samples of Bhubaneswar regions
Authors: Satapathy Sonali , Behera Pabitra Mohan , Tanty Dhananjay Kumar , Srivastava Shweta , Thatoi Hrudayanath , Dixit Anshuman , Sahoo Santi Lata
Published: November 2019

With the significant improvement of human civilization there is a spur in the urban, rural and industrial development, which has a profound effect on the surrounding natural environment. Increased utilization of natural resources is often associated with accumulation of waste materials whose management is crucial for sustainable development of life. Availability of different microorganisms in the soil facilitates the degradation of wastes through their potential enzymatic activities. Pectinase seems to be one of the important enzymes produced by a wide variety of microorganisms contained in the soil. It is mainly involved in maceration and rotting of plant extracts and debris by hydrolysis of 1,4-alpha glycosidic bonds of de-esterified pectate of plant call wall. In this paper we report molecular identification of some pectinase producing Aspergillus species selected from soil samples of five different zones of Bhubaneswar city using molecular biology and computational techniques. Among fifteen fungal isolates studied from these five zones Aspergillus parvisclerotigenus was potent for pectinase production next to Aspergillus niger in form of halozone of 0.6 mm. It’s 28S rDNA sequence also had some significant identity (>90%) with different subspecies of Aspergillus. We hope that our findings will helpful in genetic manipulation for improvement of fungal strains of isolates. Again large scale use of the improved Aspergillus strains can degrade plant biomass & diverse industrial wastes which will reduce environmental pollution of capital urban like Bhubaneswar.