bluuebunny/crossref_metadata_2025 huggingface dataset:
Population genomics and pathotypic evaluation of the bacterial leaf blight pathogen of rice reveals rapid evolutionary dynamics of a plant pathogen
Authors: Zheng Jinshui , Song Zhiwei , Zheng Dehong , Hu Huifeng , Liu Hongxia , Zhao Yancun , Sun Ming , Ruan Lifang , Liu Fengquan
Published: July 2019

Xanthomonas oryzaepv.oryzae(Xoo) causes bacterial blight disease, which reduces crop yield by up to 50% in rice production. Despite its substantial threat on food production worldwide, knowledge about its population structure, virulence diversity and the relationship between them is limited. We used whole-genome sequencing to explore the diversity and evolution ofXooduring the past 30 years in the main rice-planting areas of China. Six separate lineages were revealed by phylogenomic analysis, with CX-5 and CX-6 predominating in the population for decades. The recent sporadic outbreaks were respectively caused byXooderived from these lineages especially the two major ones. The lineage and sub-lineage distribution of isolates strongly correlated to their geographical origin, which was found to be mainly determined by the planting of the two major rice subspecies,indicaandjaponica. Large-scale virulence testing was conducted to evaluate the diversity of pathogenicity forXoo.We found rapid virulence dynamics against rice, and its determinant factors including genetic background ofXoo, rice resistance genes and the planting environment of rice. Genetic background was investigated deeply by comparative genomics, which indicates that transposition events contributing the most to evolution of theXoogenome and the rapid diversification of virulence. This study provided a good model to understand the evolution and dynamics of plant pathogens in the context of interaction with their hosts which are influenced by both geographical conditions and farming practices.
Quantitative intravital imaging ofPlasmodium falciparumsporozoites: A novel platform to test malaria intervention strategies
Authors: Hopp Christine S. , Kanatani Sachie , Archer Nathan K. , Miller Robert J. , Liu Haiyun , Chiou Kevin , Miller Lloyd S. , Sinnis Photini
Published: July 2019

Malaria infection starts with the injection of motilePlasmodiumsporozoites into the host’s skin during a mosquito bite. Previous studies using the rodent malaria model indicate that the dermal inoculation site may be where sporozoites are most vulnerable to antibodies, yet, functionalin vivoassays with human malaria parasites are lacking. Here, we present the first characterization ofP. falciparumsporozoites in the skin, comparing their motility to two rodent malaria species and investigating whether the environment of its natural host influencesP. falciparumsporozoite motility using a human skin xenograft model. The combined data suggest that in contrast to the liver and blood stages, the skin is not a species-specific barrier forPlasmodium. We observe thatP. falciparumsporozoites inoculated into mouse skin move with similar speed, displacement and duration, and enter blood vessels in similar numbers as the rodent parasites. Thus, interventions targetingP. falciparumsporozoite migration can be tested in the murine dermis. Importantly, to streamline quantification of sporozoite motility, we developed a toolbox allowing for automated detection and tracking of sporozoites in intravital microscopy videos. This establishes a platform to test vaccine candidates, immunization protocols, monoclonal antibodies and drug candidates for their impact on human malaria sporozoitesin vivo. Screening of intervention strategies forin vivoefficacy againstPfsporozoites using this new platform will have the potential to validate targets prior to expensive clinical trials.
The polyphagous plant pathogenic fungusBotrytis cinereaencompasses host-specialized and generalist populations
Authors: Mercier Alex , Carpentier Florence , Duplaix Clémentine , Auger Annie , Pradier Jean-Marc , Viaud Muriel , Gladieux Pierre , Walker Anne-Sophie
Published: July 2019

The host plant is often the main variable explaining population structure in fungal plant pathogens, because specialization contributes to reduce gene flow between populations associated with different hosts. Previous population genetic analysis revealed that French populations of the grey mould pathogenBotrytis cinereawere structured by hosts tomato and grapevine, suggesting host specialization in this highly polyphagous pathogen. However, these findings raised questions about the magnitude of this specialization and the possibility of specialization to other hosts. Here we report specialization ofB. cinereapopulations to tomato and grapevine hosts but not to other tested plants. Population genetic analysis revealed two pathogen clusters associated with tomato and grapevine, while the other clusters co-occurred on hydrangea, strawberry and bramble. Measurements of quantitative pathogenicity were consistent with host specialization of populations found on tomato, and to a lesser extent, populations found on grapevine. Pathogen populations from hydrangea and strawberry appeared to be generalist, while populations from bramble may be weakly specialized. Our results suggest that the polyphagousB. cinereais more accurately described as a collection of generalist and specialist individuals in populations. This work opens new perspectives for grey mold management, while suggesting spatial optimization of crop organization within agricultural landscapes.
Two-photon Imaging with Silicon Photomultipliers
Authors: Modi Mehrab , Turner Glenn C , Podgorski Kaspar
Published: July 2019

Silicon photomultipliers (SiPMs) are a class of inexpensive and robust single-pixel detectors with applications similar to photomultiplier tubes (PMTs). We performed side-by-side comparisons of recently-developed SiPMs and a GaAsP PMT for two-photon fluorescence imaging of neural activity. Despite higher dark counts, which limit their performance at low photon rates (<1μs), SiPMs matched the signal-to-noise ratio of the GaAsP PMT at photon rates encountered in typical calcium imaging experiments due to their much lower pulse height variability. At higher photon rates and dynamic ranges encountered during high-speed two-photon voltage imaging, SiPMs significantly outperformed the GaAsP PMT.
Perturbation-based mapping of natural frequencies with direct intracranial stimulation of the human brain
Authors: Amengual Julià L , Stengel Chloé , Moreau Tristan , Adam Claude , Chavez Mario , Valero-Cabré Antoni
Published: July 2019

Theoretical and experimental evidence suggest that the induction of oscillatory activity by an external rhythmic source on a specific brain area is maximally efficient if the input pattern matches its so-called ‘natural’ frequency, defined as the predominant neural rhythm at which the activity of this area tends to fluctuate spontaneously. Based on this principle, single pulse Transcranial Magnetic Stimulation (TMS) coupled to scalp electroencephalography (EEG) has provided evidence of frequency-specific power increases within a unique ‘natural’ frequency band, considered common to the whole lobe.

In an attempt to gain deeper insight into this phenomenon and set the basis for a finer-grained atlas of ‘natural’ frequencies, here we analyzed intracranial EEG (iEEG) signals modulated by single pulses of direct electrical brain stimulation in human patients implanted with depth multielectrodes. Our analyses revealed changes in local EEG activity emerging from local oscillators and contributing to a complex distribution of frequency-specific ‘natural’ rhythmic responses throughout cortical regions. Moreover, challenging the notion of ‘natural’ oscillations featuring a predominant frequency band characteristic for an entire lobe, our data support a rich diversity of spectral fingerprints (narrowband, vs. broadband or multiband) with single or multiple frequency peaks, often encompassing contiguous frequency bands, operating at a very local scale.

Our findings contribute novel insights on which specific brain areas could be more likely to be synchronized at a given frequencies band and their preferred coupling frequencies, features that could ultimately inform on their structural and functional organization. Our results may also increase our mechanistic understanding of invasive and noninvasive brain stimulation and promote further developments of these approaches for the manipulation of brain oscillations subtending normal and impaired cognition.
Combined single-cell and spatial transcriptomics reveals the molecular, cellular and spatial bone marrow niche organization
Authors: Baccin Chiara , Al-Sabah Jude , Velten Lars , Helbling Patrick M. , Grünschläger Florian , Hernández-Malmierca Pablo , Nombela-Arrieta César , Steinmetz Lars M. , Trumpp Andreas , Haas Simon
Published: July 2019

The bone marrow (BM) constitutes the primary site for life-long blood production and skeletal regeneration. However, its cellular composition and the spatial organization into distinct ‘niches’ remains controversial. Here, we combine single-cell and spatially resolved transcriptomics to systematically map the molecular and cellular composition of the endosteal, sinusoidal, and arteriolar BM niches. This allowed us to transcriptionally profile all major BM resident cell types, determine their localization, and clarify the cellular and spatial sources of key growth factors and cytokines. Our data demonstrate that previously unrecognized Cxcl12-abundant reticular (CAR) cell subsets (i.e. Adipo- and Osteo-CAR cells) differentially localize to sinusoidal or arteriolar surfaces, locally act as ‘professional cytokine secreting cells’, and thereby establish distinct peri-vascular micro-niches. Importantly, we also demonstrate that the 3-dimensional organization of the BM can be accurately inferred from single-cell gene expression data using the newly developed RNA-Magnet algorithm. Together, our study reveals the cellular and spatial organization of BM niches, and offers a novel strategy to dissect the complex organization of whole organs in a systematic manner.

One Sentence Summary

Integration of single-cell and spatial transcriptomics reveals the molecular, cellular and spatial organization of bone marrow niches
A novel mosaic tetracycline resistance gene tet(S/M) detected in a multidrug-resistant pneumococcal CC230 lineage that underwent capsular switching in South Africa
Authors: Lo Stephanie W. , Gladstone Rebecca A. , van Tonder Andries J. , du Plessis Mignon , Cornick Jennifer E. , Hawkins Paulina A. , Madhi Shabir A. , Nzenze Susan A. , Kandasamy Rama , Ravikumar KL , Elmdaghri Naima , Kwambana-Adams Brenda , Grassi Almeida Samanta Cristine , Skoczynska Anna , Egorova Ekaterina , Titov Leonid , Saha Samir K. , Paragi Metka , Everett Dean B. , Antonio Martin , Klugman Keith P. , Li Yuan , Metcalf Benjamin J , Beall Bernard , McGee Lesley , Breiman Robert F. , Bentley Stephen D. , von Gottberg Anne ,   on behalf of The Global Pneumococcal Sequencing Consortium
Published: July 2019

Synopsis

Objective

We reported a novel tetracycline-resistant gene in Streptococcus pneumoniae and investigated its temporal spread in relation to nationwide clinical interventions.

Methods

We whole genome sequenced 12,254 pneumococcal isolates from twenty-nine countries on an Illumina HiSeq Sequencer. Serotypes, sequence types and antibiotic resistance were inferred from genomes. Phylogeny was built based on single-nucleotide variants. Temporal changes of spread were reconstructed using a birth-death model.

Results

We identified tet(S/M) in 131 pneumococcal isolates, 97 (74%) caused invasive pneumococcal diseases among young children (59% HIV-positive, where HIV status was available) in South Africa. A majority of tet(S/M)-positive isolates (129/131) belong to clonal complex (CC)230. A global phylogeny of CC230 (n=389) revealed that tet(S/M)-positive isolates formed a sub-lineage that exhibited multidrug-resistance. Using the genomic data and a birth-death model, we detected an unrecognised outbreak of this sub-lineage in South Africa between 2000 and 2004 with an expected secondary infections (R) of ~2.5. R declined to ~1.0 in 2005 and <1.0 in 2012. The declining epidemic coincided and could be related to the nationwide implementation of anti-retroviral treatment (ART) for HIV-infected individuals in 2004 and PCVs in late 2000s. Capsular switching from vaccine serotype 14 to non-vaccine serotype 23A was observed within the sub-lineage.

Conclusions

The prevalence of tet(S/M) in pneumococci was low and its dissemination was due to an unrecognised outbreak of CC230 in South Africa prior to ART and PCVs. However, capsular switching in this multidrug-resistant sub-lineage highlighted its potential to continue to cause disease in the post-PCV13 era.
Positive allosteric modulation of metabotropic glutamate receptor 5 modulates Akt and GSK3β signaling in vivo
Authors: Johnson Kari A. , Conn P. Jeffrey
Published: July 2019

Background

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) have behavioral effects predictive of antipsychotic activity in experimental models such as amphetamine-induced hyperlocomotion (AHL). However, the signaling mechanisms that contribute to the antipsychotic-like properties of mGlu5 PAMs are not well understood.

Methods

Because the Akt/GSK3β pathway has been implicated in schizophrenia and is modulated by known antipsychotic drugs, we evaluated the effects of systemic administration of two mGlu5 PAMs on Akt and GSK3β signaling using western blot analysis in both naïve and amphetamine-treated adult male rats.

Results

In the dorsal striatum, the mGlu5-selective PAM VU0092273 (30 mg/kg) significantly increased Akt phosphorylation at residues associated with enhanced kinase activity, Thr308 and Ser473. Inhibitory phosphorylation of GSK3β at Ser9 was also increased. Similar effects were observed with a second mGlu5 PAM, VU0360172 (56.6 mg/kg). VU0092273 increased Akt phosphorylation levels in amphetamine-treated rats. Effects on Akt/GSK3β signaling were not limited to the striatum, as VU0092273 also increased Akt/GSK3β phosphorylation in the medial prefrontal cortex.

Conclusions

These findings suggest that mGlu5 PAMs that have antipsychotic-like efficacy in rats affect signaling pathways that are modulated by known antipsychotics, and raise the possibility that inhibition of GSK3β might contribute to the antipsychotic-like effects of mGlu5 PAMs.
MultIscale MultiObjective Systems Analysis (MIMOSA): an advanced metabolic modeling framework for complex systems
Authors: Gardner Joseph J. , Hodge Bri-Mathias S. , Boyle Nanette R.
Published: July 2019

In natural environments, cells live in complex communities and experience a high degree of heterogeneity internally and in the environment. Unfortunately, most of the metabolic modeling approaches that are currently used assume ideal conditions and that each cell is identical, limiting their application to pure cultures in well-mixed vessels. Here we describe our development of MultIscale MultiObjective Systems Analysis (MIMOSA), a metabolic modeling approach that can track individual cells in both space and time, track the diffusion of nutrients and light and the interaction of cells with each other and the environment. As a proof-of concept study, we used MIMOSA to model the growth ofTrichodesmium erythraeum, a filamentous diazotrophic cyanobacterium which has cells with two distinct metabolic modes. The use of MIMOSA significantly improves our ability to predictively model metabolic changes and phenotype in more complex cell cultures.
The localization of chitin synthase mediates the patterned deposition of chitin in developing Drosophila bristles
Authors: Adler Paul N.
Published: July 2019

The insect exoskeleton is a complex structure that is a key for the life style of this very successful group of animals. It contains proteins, lipids and the N-acetyl glucosamine polymer chitin. Chitin is synthesized by the enzyme chitin synthase. In most body regions, chitin fibrils are found in a stack of parallel arrays that can be detected by transmission electron microscopy. Each array is rotated with respect to the layers above and below. In sensory bristles, chitin primarily accumulates in bands parallel to the proximal/distal axis of the bristle. These bands are visible by confocal microscopy providing experimental advantages. We have used this cell type and an edited chitin synthase gene to establish that the bands of chitin are closely associated with stripes of chitin synthase, arguing the localization of chitin synthase plays an important role in mediating the patterned deposition of chitin. This is reminiscent of what has been seen for chitin and chitin synthase in fungi and between cellulose and cellulose synthase in plants. Several genes are known to be essential for proper chitin deposition. We found one of these,Rab11is required for the insertion of chitin synthase into the plasma membrane and a second,duskylikeis required for plasma membrane chitin synthase to localize properly into stripes. We also established that the actin cytoskeleton is required for the proper localization of chitin synthase and chitin in developing sensory bristles.
Evidence that pleiotropic alleles underlie adaptive divergence between natural populations
Authors: Thompson Ken A.
Published: July 2019

The alleles used for adaptation can pleiotropically affect traits under stabilizing selection, and compensatory alleles can be favoured by selection to counteract such deleterious pleiotropy. Such compensatory alleles can segregate in interpopulation hybrids, causing segregation variance for traits where parents have the same phenotype. If adaptation typically involves pleiotropy and compensation, then the segregation variance for traits under stabilizing selection is expected to increase with the magnitude of adaptive phenotypic divergence between parents. This prediction has not been tested empirically, and I gathered data from experimental hybridization studies to evaluate it. I found that pairs of parents which are more phenotypically divergent beget hybrids with more segregation variance in traits where the parents do not differ. This result suggests that adaptive divergence between pairs of natural populations proceeds via pleiotropy and compensation, and that potentially deleterious transgressive segregation variance accumulates systematically as populations diverge.
A genome-wide CRISPR screen identifies ZCCHC14 as a host factor required for hepatitis B surface antigen production
Authors: Hyrina Anastasia , Jones Christopher , Chen Darlene , Clarkson Scott , Cochran Nadire , Feucht Paul , Hoffman Gregory , Lindeman Alicia , Russ Carsten , Sigoillot Frederic , Uehara Kyoko , Xie Lili , Ganem Don , Holdorf Meghan
Published: July 2019

GRAPHICAL ABSTRACT

A hallmark of chronic hepatitis B virus (CHB) infection is the presence of high circulating levels of non-infectious small lipid HBV surface antigen (HBsAg) vesicles. Although rare, sustained HBsAg loss is the idealized endpoint of any CHB therapy. A novel small molecule RG7834 has been previously reported to inhibit HBsAg expression by targeting terminal nucleotidyltransferase protein 4A and 4B (TENT4A and TENT4B). In this study, we describe a genome-wide CRISPR screen to identify other potential novel host factors required for HBsAg expression and to gain further insights into the mechanism of RG7834. We report more than 60 genes involved in regulating HBsAg and identified novel factors involved in RG7834 activity, including a zinc finger CCHC-type containing 14 (ZCCHC14) protein. We show that ZCCHC14, together with TENT4A/B, stabilizes HBsAg expression through HBV RNA tailing, providing a potential new therapeutic target to achieve functional cure in CHB patients.
Automated Cytogenetic Biodosimetry at Population-Scale
Authors: Rogan PK , Lu R , Mucaki E , Ali S , Shirley B , Li Y , Wilkins R , Norton F , Sevriukova O , Pham D , Ainsbury E , Moquat J , Cooke R , Peerlaproulx T , Waller E , Knoll JHM
Published: July 2019

Introduction

The dicentric chromosome (DC) assay accurately quantifies exposure to radiation, however manual and semi-automated assignment of DCs has limited its use for a potential large-scale radiation incident. The Automated Dicentric Chromosome Identifier and Dose Estimator Chromosome (ADCI) software automates unattended DC detection and determines radiation exposures, fulfilling IAEA criteria for triage biodosimetry. We present high performance ADCI (ADCI-HT), with the requisite throughput to stratify exposures of populations in large scale radiation events.

Methods

ADCI-HT streamlines dose estimation by optimal scheduling of DC detection, given that the numbers of samples and metaphase cell images in each sample vary. A supercomputer analyzes these data in parallel, with each processor handling a single image at a time. Processor resources are managed hierarchically to maximize a constant stream of sample and image analysis. Metaphase data from populations of individuals with clinically relevant radiation exposures after simulated large nuclear incidents were analyzed. Sample counts were derived from US Census data. Analysis times and exposures were quantified for 15 different scenarios.

Results

Processing of metaphase images from 1,744 samples (500 images each) used 16,384 CPUs and was completed in 1hr 11min 23sec, with radiation dose of all samples determined in 32 sec with 1,024 CPUs. Processing of 40,000 samples with varying numbers of metaphase cells, 10 different exposures from 5 different biodosimetry labs met IAEA accuracy criteria (dose estimate differences were < 0.5 Gy; median = 0.07) and was completed in ~25 hours. Population-scale metaphase image datasets within radiation contours of nuclear incidents were defined by exposure levels (either >1 Gy or >2 Gy). The time needed to analyze samples of all individuals receiving exposures from a high yield airborne nuclear device ranged from 0.6-7.4 days, depending on the population density.

Conclusion

ADCI-HT delivers timely and accurate dose estimates in a simulated population-scale radiation incident.
Delineation of the First Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency
Authors: Beck David B. , Petracovici Ana , He Chongsheng , Moore Hannah W. , Louie Raymond J. , Ansar Muhammad , Douzgou Sofia , Sithambaram Sivagamy , Cottrell Trudie , Santos-Cortez Regie Lyn P. , Prijoles Eloise J. , Bend Renee , Keren Boris , Mignot Cyril , Nougues Marie-Christine , Õunap Katrin , Reimand Tiia , Pajusalu Sander , Zahid Muhammad , Nadeem Saqib Muhammad Arif , Buratti Julien , Seaby Eleanor G , McWalter Kirsty , Telegrafi Aida , Baldridge Dustin , Shinawi Marwan , Leal Suzanne M. , Schaefer G. Bradley , Stevenson Roger E. , Banka Siddharth , Bonasio Roberto , Fahrner Jill A.
Published: July 2019

Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation of DNA (5mC) is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has been delineated. Here, we describe in detail the first Mendelian disorder caused by disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. Here we identify and characterize 11 cases of human TET3 deficiency in 8 families with the common phenotypic features of intellectual disability/global developmental delay, hypotonia, autistic traits, movement disorders, growth abnormalities, and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues with all but one occurring within the catalytic domain and most displaying hypomorphic function in a catalytic activity assay. TET3 deficiency shows substantial phenotypic overlap with other Mendelian disorders of the epigenetic machinery, including intellectual disability and growth abnormalities, underscoring shared disease mechanisms.
Systematic revision and redefinition of the genus Scirrotherium Edmund and Theodor, 1997 (Cingulata, Pampatheriidae): Implications for the origin of pampatheriids and the evolution of the South American lineage including Holmesina
Authors: Jiménez-Lara Kevin
Published: July 2019

The intrageneric relationships of the pampatheriid genus Scirrotherium and its affinities with supposedly related genera, i.e., Kraglievichia and Holmesina, are revised through parsimony phylogenetic analyses and new comparative morphological descriptions. For this work, unpublished material of pampatheriids (numerous osteoderms, one partial skull and a few postcranial bones) from Neogene formations of Colombia was analyzed. The results show that Scirrotherium is paraphyletic if we include all its referred species, i.e., Scirrotherium hondaensis, S. carinatum and S. antelucanus. The species S. carinatum is closer to Kraglievichia paranensis than to S. hondaensis or S. antelucanus, therefore the new name K. carinatum comb. nov. is proposed. The relationship among S. hondaensis and S. antelucanus could not be resolved, so these species should be designated in aphyly. In spite of failing to recover S. hondaensis and S. antelucanus as one single clade, here is preferred to maintain the generic name Scirrotherium in both species based on diagnostic evidence. New emended diagnoses for Scirrotherium, S. hondaensis and Kraglievichia are provided. The genus Holmesina was found to be monophyletic and positioned as the sister clade of Scirrotherium + Kraglievichia. The evolutionary and biogeographic implications of the new phylogeny and taxonomic re-arrangements are discussed. A possible geographic origin of the family Pampatheriidae and Scirrotherium in low latitudes of South America as early as Early Miocene times is claimed. The South American ancestor or sister taxon of Holmesina is predicted to be morphologically more similar to Scirrotherium than to Kraglievichia.
Categorical representation from sound and sight in the ventral occipito-temporal cortex of sighted and blind
Authors: Mattioni Stefania , Rezk Mohamed , Battal Ceren , Bottini Roberto , Cuculiza Mendoza Karen E. , Oosterhof Nikolaas N. , Collignon Olivier
Published: July 2019

Is vision necessary for the development of the categorical organization of the Ventral Occipito-Temporal Cortex (VOTC)? We used fMRI to characterize VOTC responses to eight categories presented acoustically in sighted and early blind individuals, and visually in a separate sighted group. We observed that VOTC reliably encodes sound categories in sighted and blind people using a representational structure and connectivity partially similar to the one found in vision. Sound categories were, however, more reliably encoded in the blind than the sighted group, using a representational format closer to the one found in vision. Crucially, VOTC in blind represents the categorical membership of sounds rather than their acoustic features. Our results suggest that sounds trigger categorical responses in the VOTC of congenitally blind and sighted people that partially match the topography and functional profile of the visual response, despite qualitative nuances in the categorical organization of VOTC between modalities and groups.
The negative adipogenesis regulator DLK1 is transcriptionally regulated by TIS7 (IFRD1) and translationally by its orthologue SKMc15 (IFRD2)
Authors: Vietor Ilja , Cikes Domagoj , Piironen Kati , Vasakou Theodora , Heimdörfer David , Gstir Ronald , Erlacher Matthias David , Tancevski Ivan , Eller Philipp , Demetz Egon , Hess Michael , Kuhn Volker , Degenhart Gerald , Rozman Jan , Klingenspor Martin , Hrabe de Angelis Martin , Valovka Taras , Huber Lukas A.
Published: July 2019

Delta-like homolog 1 (DLK1), an inhibitor of adipogenesis, controls the cell fate of adipocyte progenitors. Here we identify two independent regulatory mechanisms, transcriptional and translational, by which TIS7 (IFRD1) and its orthologue SKMc15 (IFRD2) regulate DLK1 levels. Mice deficient in both TIS7 and SKMc15 (dKO) had severely reduced adipose tissue and were resistant to high fat diet-induced obesity. Wnt signaling, a negative regulator of adipocyte differentiation was significantly up regulated in dKO mice. Elevated levels of the Wnt/β-catenin target protein Dlk-1 inhibited the expression of adipogenesis regulators PPARγ and C/EBPα, and fatty acid transporter CD36. Although both, TIS7 and SKMc15, contributed to this phenotype, they utilized two different mechanisms. TIS7 acted by controlling Wnt signaling and thereby transcriptional regulation of Dlk-1. On the other hand, here we provide distinctive experimental evidence that SKMc15 acts as a general translational inhibitor significantly affecting DLK-1 protein levels. Our study provides data describing novel mechanisms of DLK1 regulation in adipocyte differentiation involving TIS7 and SKMc15.

SYNOPSIS

This study uncovered that IFRD1 (TIS7) and its orthologue IFRD2 (SKMc15) are two essential regulators of adipogenesis. These proteins are highly similar on the sequence level, yet they regulate adipocyte differentiation using different but complementary mechanisms. Our main findings are:

IFRD1 (TIS7) and IFRD2 (SKMc15) knockout mice are resistant against diet-induced obesity

IFRD1 (TIS7) and IFRD2 (SKMc15) are critical for proper nutritional fat uptake and adipogenesis

IFRD1 (TIS7) controls adipogenesis via Wnt/β-catenin-dependent transcriptional regulation of adipocyte-specific genes

IFRD2 (SKMc15) regulates adipocyte-specific genes acting as a novel general translational inhibitor
Detecting genotype-population interaction effects by ancestry principal components
Authors: Yu Chenglong , Ni Guiyan , van der Werf Julius , Lee S. Hong
Published: July 2019

Heterogeneity in the phenotypic mean and variance across populations is often observed for complex traits. One way to understand heterogeneous phenotypes lies in uncovering heterogeneity in genetic effects. Previous studies on genetic heterogeneity across populations were typically based on discrete groups of population stratified by different countries or cohorts, which ignored the difference of population characteristics for the individuals within each group and resulted in loss of information. Here we introduce a novel concept of genotype-by-population (G×P) interaction where population is defined by the first and second ancestry principal components (PCs), which are less likely to be confounded with country/cohort-specific factors. We applied a reaction norm model fitting each of 70 complex traits with significant SNP-heritability and the PCs as covariates to examine G×P interactions across diverse populations including white British and other white Europeans from the UK Biobank (N = 22,229). Our results demonstrated a significant population genetic heterogeneity for behavioural traits such as age first had sexual intercourse and qualifications. Our approach may shed light on the latent genetic architecture of complex traits that underlies the modulation of genetic effects across different populations.
Mitochondrial dysfunction impairs human neuronal development and reduces neuronal network activity and synchronicity
Authors: Klein Gunnewiek T.M. , Van Hugte E. J. H. , Frega M. , Guardia G. Solé , Foreman K.B. , Panneman D. , Mossink B. , Linda K. , Keller J.M. , Schubert D. , Cassiman D. , Morava E. , Rodenburg R. , Perales-Clemente E. , Nelson T.J. , Kasri N. Nadif , Kozicz T.
Published: July 2019

Epilepsy, intellectual and cortical sensory deficits and psychiatric manifestations are among the most frequent manifestations of mitochondrial diseases. Yet, how mitochondrial dysfunction affects neural structure and function remains largely elusive. This is mostly due to the lack of a properin vitrotranslational neuronal model system(s) with impaired energy metabolism. Leveraging the induced pluripotent stem cell technology, from a cohort of patients with the common pathogenic m.3243A>G variant of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), we differentiated excitatory cortical neurons (iNeurons) with normal (low heteroplasmy) and impaired (high heteroplasmy) mitochondrial function on an isogenic nuclear DNA background. iNeurons with high levels of heteroplasmy exhibited mitochondrial dysfunction, delayed neural maturation, reduced dendritic complexity and fewer functional excitatory synapses. Micro-electrode array recordings of neuronal networks with high heteroplasmy displayed reduced network activity and decreased synchronous network bursting. The impaired neural energy metabolism of iNeurons compromising the structural and functional integrity of neurons and neural networks, could be the primary driver of increased susceptibility to neuropsychiatric manifestations of mitochondrial disease.
Importance of Matrix-dimensionality in Regulating the Bone Marrow Hematopoietic Cells Pool
Authors: Zhang P. , Zhang C. , Han J. , Gao J. , Zhao W. , Yang H.
Published: July 2019

In bone marrow, hematopoietic stem cells (HSCs) and multiple hematopoietic progenitor cells (HPCs) cooperate to differentiate and replenish blood and immune cells. It has long been recognized bone marrow niche parameters interact with hematopoietic stem and progenitor cells (HSPCs) and additional work is required to study niche physical signals controlling cell behavior. Here we presented that important biophysical signals, stiffness and dimensionality, regulating expansion of bone marrow HSPCs. Mice bone marrow derived progenitor cells were cultured in collagen I hydrogel in vitro. We found stiffer 3D matrix promoted the expansion of lineage negative (Lin−) progenitor cells and Lin−Sca-1+c-kit+ (LSK) HSPCs compared to softer hydrogel. Compared with cells cultured in 2D environment, 3D embedded construct had significant advantage on HSPCs expansion, accompanied by increases on myeloid and lymphoid lineage fractions. Bright changes on gene expression were subsequently discovered. According to these data, we concluded that culture matrix dimensionality is an important factor to regulate the behavior of subpopulations in hematopoietic cell pool, which should be considered in attempts to illuminate HSCs fate decision in vitro.

Statement of Significance

We would like to submit the enclosed manuscript entitled "Importance of Niche-dimensionality in Regulating the Bone Marrow Hematopoietic Cells Pool", which we wish to be considered for publication in Biophysical Journal. Studies about the interaction between HSCs and factors provided by their microenvironment is largely focus on pure perspective of biology. But biophysical factors affecting HSC fate and behavior needs to be further explore. Herein we found ex vivo culture dimensionality affected HSPC expansion. Cell surface marker detection and mRNA expression analysis predicted the changes on myeloid and lymphoid lineage fractions. We hope niche physical signals which we identified will be considered to design HSC biomimetic niches in clinical applications. And we believe that our study will make it interesting to general readers. We deeply appreciate your consideration of our manuscript, and we look forward to receiving comments from the reviewers.
NGO accountability: retrospective and prospective academic contributions
Authors: Agyemang Gloria , O’Dwyer Brendan , Unerman Jeffrey
Published: July 2019

Purpose

The purpose of this paper is to offer a retrospective and prospective analysis of the themes explored in the 2006Accounting, Auditing and Accountability Journalspecial issue on non-governmental organisation (NGO) accountability.

Design/methodology/approach

The paper is a reflective review essay.

Findings

The paper outlines how a number of themes in the 2006 special issue addressing downward accountability, hierarchical accountability and management control have been subsequently developed in a selection of papers from the accounting literature. The development of these themes leads to several suggestions for future research in NGO accountability.

Originality/value

The paper offers a systematic, original perspective on recent developments in certain areas of the field of NGO accountability.
Telecommunication access business model options in Maluku and Papua, the less-favored business regions in Indonesia
Authors: Oktarini Lydia , Kawano Hirotaka
Published: July 2019

Purpose

This paper aims to provide feasible business model options that benefit all stakeholders; the government, the investor and especially the inhabitants in Maluku and Papua, the less-favored business regions in Indonesia.

Design/methodology/approach

Three feasible business model options result from ICT for development literature, current role of the government, other models and investment scheme review, statistical analysis, technology analysis and investment simulations.

Findings

This paper proposes three different feasible business model options. The infrastructure subsidy model, which combines 20 per cent private investment and 80 per cent government subsidy, is the most feasible business model based on investment simulations. This model which combines 20 per cent private investment and 80 per cent government subsidy provides stronger determination of Indonesian Government for serving rural and remote people. The revenue subsidy and the mixed project subsidy are alternative models that may provide more attractive schemes from the standpoint of investors.

Research limitations/implications

However, current paper has limitation which is subject to enhance for better analysis in future research such as implementation of the in-depth assessment of risk management system to deal with all exposed risks.

Practical implications

This paper provides that setting up a complete telecommunication access infrastructures in eastern Indonesia is feasible under new proposed models.

Social implications

The new proposed models provide stronger determination of Indonesian Government for serving rural and remote people and minimizing the digital divide in eastern area.

Originality/value

Under the new proposed models, the role and capacity of the government is adjusted. The government should dominate and be less dependent on private investment. Also, the government should shift from triggering service penetration into developing a complete infrastructure set up.
Incentive structures in multi-partner project teams
Authors: Han Jiaojie , Rapoport Amnon , Fong Patrick S.W.
Published: July 2019

Purpose

The purpose of this paper is to investigate the impact of incentive contracts in multi-partner project teams (MPPTs) on the agents’ effort expenditure and project performance, analyze how the agents allocate their efforts between production and cooperation and offer suggestions for project managers on how to design incentive contracts.

Design/methodology/approach

The paper proposes a model of MPPT in which agents are inequity-averse and their effort expenditures are exogenously bounded. An extensive numerical example is presented in online Appendix 2 to illustrate the theoretical results.

Findings

The paper suggests that if the potential benefit of the agents’ cooperation in MPPT is high or if both agents exhibit inequity aversion and the efforts’ marginal costs are low, then group-based incentive contracts outperform individual-based incentive contracts. It also shows that the impact of the incentive contract on the agents’ effort expenditure and project team performance is correlated with several critical project attributes.

Originality/value

Fulfilling a need to study the design of incentive structures in MPPTs, the paper complements the existing literature in three ways. First, in contrast to single-partner project teams, it considers projects with multiple partners where cooperation between them enhances the project outcome. Second, rather than focusing on individual production problems, it considers multi-task projects with constrained efforts that must be allocated between production and cooperation. Third, it analyzes the effects of changes in the project attributes, incentive intensities and information transparency on the effectiveness of the contract.
Impact of heat generation/absorption on the unsteady magnetohydrodynamic stagnation point flow and heat transfer of nanofluids
Authors: Jusoh Rahimah , Nazar Roslinda , Pop Ioan
Published: July 2019

Purpose

The purpose of this study is to describe the unsteady three-dimensional magnetohydrodynamic stagnation point flow of nanofluids with heat generation/absorption.

Design/methodology/approach

The comprehensive numerical simulations in this study accommodate a physical insight into the heat transfer and flow problem. The use of finite difference method through the bvp4c function in Matlab provides the numerical results and graphical illustrations for the heat transfer rate and shear stress.

Findings

Dual solutions are discovered in this study. Thus, stability analysis is implemented and the first solution complies the stability behavior. Silver nanoparticles dominate the highest thermal conductivity. Accretion of the rate of heat transfer is obtained with an increment in the magnitude of heat absorption, suction parameter and nanoparticle volume fraction. A stronger magnetic field and larger unsteadiness parameter contribute to the increase of the surface shear stress.

Practical implications

Many practical fluid mechanics problems involve the time-dependent element. Practically, an unsteady flow of nanofluid can be implemented in the micro-manufacturing, periodic heat exchanges process, nano drug delivery system and nuclear reactors.

Originality/value

In spite of numerous studies on the unsteady flow, none of the researchers combined the effect of heat generation/absorption and magnetic field in the nanofluid model. The behavior of the flow and heat transfer have been analyzed thoroughly with the variations in the unsteadiness parameter, heat source/sink and nanoparticle volume fraction. Moreover, the discovery of dual solutions in this model strengthens the novelty of this study. Subsequently, the implementation of stability analysis leads to a remarkable revelation where the first solution is found to be stable.
Drop-out in programming courses – prediction and prevention
Authors: Hawlitschek Anja , Köppen Veit , Dietrich André , Zug Sebastian
Published: July 2019

Purpose

An ideal learning analytics tool for programming exercises performs the role of a lecturer who monitors the code development, provides customized support and identifies students at risk to drop out. But a reliable prediction and prevention of drop-out is difficult, due to the huge problem space in programming tasks and variety of solutions and programming strategies. The purpose of this paper is to tackle this problem by, first, identifying activity patterns that indicate students at risk; and, second, finding reasons behind specific activity pattern, for identification of instructional interventions that prevent drop-out.

Design/methodology/approach

The authors combine two investigation strategies: first, learning analytic techniques (decision trees) are applied on features gathered from students, while completing programming exercises, in order to classify predictors for drop-outs. Second, the authors determine cognitive, motivational and demographic learner characteristics based on a questionnaire. Finally, both parts are related with a correlation analysis.

Findings

It was possible to identify generic variables that could predict early and later drop-outs. For students who drop out early, the most relevant variable is the delay time between availability of the assignment and the first login. The correlation analysis indicates a relation with prior programming experience in years and job occupation per week. For students who drop out later in the course, the number of errors within the first assignment is the most relevant predictor, which correlates with prior programming skills.

Originality/value

The findings indicate a relation between activity patterns and learner characteristics. Based on the results, the authors deduce instructional interventions to support students and to prevent drop-outs.
Management styles in a project environment: evidence from software industry in Oman
Authors: Chaudhry Muhammad Saqib , Raziq Muhammad Mustafa , Saeed Abubakr , Sajjad Aymen , Borini Felipe Mendes
Published: July 2019

Purpose

The purpose of this paper is to examine the management styles adopted by project managers in the software industry in Oman.

Design/methodology/approach

A sample of 208 project management professionals is drawn from the Omani software industry. Data analysis is based on factor analysis and analysis of variance techniques.

Findings

The results suggest that project managers in the Omani software industry mainly adopt three management styles: people oriented, task oriented and organization oriented. Furthermore, the management styles of project managers are affected by their experience and age, and the organizational structure.

Originality/value

The paper contributes to the literature by examining management styles adopted by managers in a temporary organization environment from an under-researched context, Oman.
Additive and interactive effects of pollination and biological pest control on crop yield
Authors: Gagic Vesna , Marcora Anna , Howie Lynita
Published: July 2019

Insect pollination and biological pest control simultaneously influence crop yield, but are often investigated individually. This can lead to under‐ or over‐estimation of the importance of individual services when they interact to affect yield. Recent, limited evidence from field studies showed contrasting results with both additive and non‐additive positive and negative effects.

To disentangle the mechanisms underlying these responses, we conducted a greenhouse experiment and a field study. We tested the potential and realized contribution of insect pollination to cotton boll retention and yield under various pest pressures and biocontrol levels.

We found both additive and interactive effects of insect pollination and biocontrol within a single crop system depending on the level of pest pressure. In the greenhouse experiment, pollination did not contribute to cotton boll retention and final yield at low pest pressure. At high pest abundances, boll retention and final yield were higher when pollinators were present. In the field study, pollination was sufficient to alter the negative effect of pests on boll retention. Thus, interactive effect between the two ecosystem services on boll retention was present at high pest pressure in the greenhouse and at natural levels of pest pressure in the field, but not at lower pest abundances in controlled conditions.

Although cotton plants partly compensated for bolls shedding by increasing their weight in the greenhouse experiment, this effect was not detected in the field study, likely due to higher environmental variation. Similarly, interactive effect of pollination and biocontrol on the final yield was present only in the greenhouse study.

Synthesis and applications. We conclude that the contrasting findings of additive versus non‐additive effects between ecosystem services may be due to the levels of services and disservices tested and environmental variation. Further, this study shows that even when an ecosystem service does not appear to limit crop yield, it can make a substantial contribution to yield and act as insurance when the other service is reduced. For achieving food and fibre security, it is essential that future studies test interactive effects between these ecosystem services in different systems and environmental conditions.