bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors Influencing Pediatric Cochlear Implant Outcomes: Carolina Sibling Study
Authors: Selleck Anne Morgan , Park Lisa R. , Brown Kevin D.
Published: August 2019

Objective:

To determine the correlation between speech perception performance between pediatric sibling pairs with severe to profound sensory hearing loss receiving cochlear implants, and in cases of discordance in performance, determine which variables negatively impacted performance.

Study Design:

Retrospective chart review.

Setting:

Tertiary academic referral center.

Subjects:

Eighty-nine pediatric subjects, 43 sibling groups, under the age of 18 with severe to profound sensory hearing loss who received a cochlear implant with a sibling who also received a cochlear implant.

Intervention:

Cochlear implantation.

Main Outcome Measures:

Speech perception scores, consonant-nucleus- consonant score.

Results:

A statistically significant correlation was found between speech perception performance of pediatric siblings. Depth of insertion is positively correlated with better speech perception in siblings with discordant results. There was no significant relationship with either electrode type, unilateral/bilateral status, or age of implantation.

Conclusion:

Pediatric siblings have a high correlation in speech perception outcomes following cochlear implantation, suggesting family environment plays a strong role. In circumstances in which outcomes between siblings are substantially different, greater depth of implant insertion is correlated with better consonant-nucleus- consonant word scores.
EGF-GH Axis in Rat Steatotic and Non-steatotic Liver Transplantation From Brain-dead Donors
Authors: Álvarez-Mercado Ana I. , Negrete-Sánchez Elsa , Gulfo José , Ávalos de León Cindy G. , Casillas-Ramírez Araní , Cornide-Petronio María Eugenia , Bujaldon Esther , Rotondo Floriana , Gracia-Sancho Jordi , Jiménez-Castro Mónica B. , Peralta Carmen
Published: August 2019

Background.

We evaluated the potential dysfunction caused by changes in growth hormone (GH) levels after brain death (BD), and the effects of modulating GH through exogenous epidermal growth factor (EGF) in steatotic and nonsteatotic grafts.

Methods.

Steatotic and nonsteatotic grafts from non-BD and BD rat donors were cold stored for 6 hours and transplanted to live rats. Administration of GH and EGF and their underlying mechanisms were characterized in recipients of steatotic and nonsteatotic grafts from BD donors maintained normotensive during the 6 hours before donation. Circulating and hepatic GH and EGF levels, hepatic damage, and regeneration parameters were evaluated. Recipient survival was monitored for 14 days. Somatostatin, ghrelin, and GH-releasing hormones that regulate GH secretion from the anterior pituitary were determined. The survival signaling pathway phosphoinositide-3-kinase/protein kinase B that regulates inflammation (suppressors of cytokine signaling, high-mobility group protein B1, oxidative stress, and neutrophil accumulation) was evaluated.

Results.

BD reduced circulating GH and increased GH levels only in steatotic livers. GH administration exacerbated adverse BD-associated effects in both types of graft. Exogenous EGF reduced GH in steatotic livers, thus activating cell proliferation and survival signaling pathways, ultimately reducing injury and inflammation. However, EGF increased GH in nonsteatotic grafts, which exacerbated damage. The benefits of EGF for steatotic grafts were associated with increased levels of somatostatin, a GH inhibitor, whereas the deleterious effect on nonsteatotic grafts was exerted through increased amounts of ghrelin, a GH stimulator.

Conclusions.

GH treatment is not appropriate in rat liver transplant from BD donors, whereas EGF (throughout GH inhibition) protects only in steatotic grafts.
Serostatus testing and dengue vaccine cost–benefit thresholds
Authors: Pearson Carl A. B. , Abbas Kaja M. , Clifford Samuel , Flasche Stefan , Hladish Thomas J.
Published: August 2019

The World Health Organization (WHO) currently recommends pre-screening for past infection prior to administration of the only licensed dengue vaccine, CYD-TDV. Using a threshold modelling analysis, we identify settings where this guidance prohibits positive net-benefits, and are thus unfavourable. Generally, however, our model shows test-then-vaccinate strategies can improve CYD-TDV economic viability: effective testing reduces unnecessary vaccination costs while increasing health benefits. With sufficiently low testing cost, those trends outweigh additional screening costs, expanding the range of settings with positive net-benefits. This work highlights two aspects for further analysis of test-then-vaccinate strategies. We found that starting routine testing at younger ages could increase benefits; if real tests are shown to sufficiently address safety concerns, the manufacturer, regulators and WHO should revisit guidance restricting use to 9-years-and-older recipients. We also found that repeat testing could improve return-on-investment (ROI), despite increasing intervention costs. Thus, more detailed analyses should address questions on repeat testing and testing periodicity, in addition to real test sensitivity and specificity. Our results follow from a mathematical model relating ROI to epidemiology, intervention strategy, and costs for testing, vaccination and dengue infections. We applied this model to a range of strategies, costs and epidemiological settings pertinent to CYD-TDV. However, general trends may not apply locally, so we provide our model and analyses as an R package available via CRAN, denvax. To apply to their setting, decision-makers need only local estimates of age-specific seroprevalence and costs for secondary infections.
Mathematical models incorporating a multi-stage cell cycle replicate normally-hidden inherent synchronization in cell proliferation
Authors: Vittadello Sean T. , McCue Scott W. , Gunasingh Gency , Haass Nikolas K. , Simpson Matthew J.
Published: August 2019

We present a suite of experimental data showing that cell proliferation assays, prepared using standard methods thought to produce asynchronous cell populations, persistently exhibit inherent synchronization. Our experiments use fluorescent cell cycle indicators to reveal the normally hidden cell synchronization, by highlighting oscillatory subpopulations within the total cell population. These oscillatory subpopulations would never be observed without these cell cycle indicators. On the other hand, our experimental data show that the total cell population appears to grow exponentially, as in an asynchronous population. We reconcile these seemingly inconsistent observations by employing a multi-stage mathematical model of cell proliferation that can replicate the oscillatory subpopulations. Our study has important implications for understanding and improving experimental reproducibility. In particular, inherent synchronization may affect the experimental reproducibility of studies aiming to investigate cell cycle-dependent mechanisms, including changes in migration and drug response.
Kink-type solutions of the SIdV equation and their properties
Authors: Zhang Guofei , He Jingsong , Wang Lihong , Mihalache Dumitru
Published: August 2019

We study the nonlinear integrable equation,
u

t

+ 2((
u

x

u

xx

)/
u
) =
ϵu

xxx

, which is invariant under scaling of dependent variable and was called the SIdV equation (see Sen
et al.
2012
Commun. Nonlinear Sci. Numer. Simul
.
17
, 4115–4124 (
doi:10.1016/j.cnsns.2012.03.001
)). The order-
n
kink solution
u

[
n
]

of the SIdV equation, which is associated with the
n
-soliton solution of the Korteweg–de Vries equation, is constructed by using the
n
-fold Darboux transformation (DT) from zero ‘seed’ solution. The kink-type solutions generated by the onefold, twofold and threefold DT are obtained analytically. The key features of these kink-type solutions are studied, namely their trajectories, phase shifts after collision and decomposition into separate single kink solitons.
A functional trade-off between trophic adaptation and parental care predicts sexual dimorphism in cichlid fish
Authors: Ronco Fabrizia , Roesti Marius , Salzburger Walter
Published: August 2019

Although sexual dimorphism is widespread in nature, its evolutionary causes often remain elusive. Here we report a case where a sex-specific conflicting functional demand related to parental care, but not to sexual selection, explains sexual dimorphism in a primarily trophic structure, the gill rakers of cichlid fishes. More specifically, we examined gill raker length in a representative set of cichlid fish species from Lake Tanganyika featuring three different parental care strategies: (i) uni-parental mouthbrooding, whereby only one parental sex incubates the eggs in the buccal cavity; (ii) bi-parental mouthbrooding, whereby both parents participate in mouthbrooding; and (iii) nest guarding without any mouthbrooding involved. As predicted from these different parental care strategies, we find sexual dimorphism in gill raker length to be present only in uni-parental mouthbrooders, but not in bi-parental mouthbrooders nor in nest guarders. Moreover, variation in the extent of sexual dimorphism among uni-parental mouthbrooders appears to be related to trophic ecology. Overall, we present a previously unrecognized scenario for the evolution of sexual dimorphism that is not related to sexual selection or initial niche divergence between sexes. Instead, sexual dimorphism in gill raker length in uni-parental mouthbrooding cichlid fish appears to be the consequence of a sex-specific functional trade-off between a trophic function present in both sexes and a reproductive function present only in the brooding sex.
Type X strains of
Toxoplasma gondii
are virulent for southern sea otters (
Enhydra lutris nereis)
and present in felids from nearby watersheds
Authors: Shapiro Karen , VanWormer Elizabeth , Packham Andrea , Dodd Erin , Conrad Patricia A. , Miller Melissa
Published: August 2019

Why some
Toxoplasma gondii
-infected southern sea otters (
Enhydra lutris nereis
) develop fatal toxoplasmosis while others have incidental or mild chronic infections has long puzzled the scientific community. We assessed robust datasets on
T. gondii
molecular characterization in relation to detailed necropsy and histopathology results to evaluate whether parasite genotype influences pathological outcomes in sea otters that stranded along the central California coast. Genotypes isolated from sea otters were also compared with
T. gondii
strains circulating in felids from nearby coastal regions to assess land-to-sea parasite transmission. The predominant
T. gondii
genotypes isolated from 135 necropsied sea otters were atypical Type X and Type X variants (79%), with the remainder (21%) belonging to Type II or Type II/X recombinants. All sea otters that died due to
T. gondii
as a primary cause of death were infected with Type X or X-variant
T. gondii
strains. The same atypical
T. gondii
strains were detected in sea otters with fatal toxoplasmosis and terrestrial felids from watersheds bordering the sea otter range. Our results confirm a land–sea connection for virulent
T. gondii
genotypes and highlight how faecal contamination can deliver lethal pathogens to coastal waters, leading to detrimental impacts on marine wildlife.
Coevolution influences the evolution of filial cannibalism, offspring abandonment and parental care
Authors: Klug Hope , Bonsall Michael B.
Published: August 2019

Understanding evolutionary patterns of parental investment and care has been a long-standing focus in studies of evolutionary and behavioural ecology. Indeed, patterns of investment and care are highly diverse, and fully understanding such diversity has been challenging. Recently, several studies have highlighted the need to consider coevolutionary dynamics in studies of parental care, as parental care is likely to co-occur and co-originate with a range of other traits. Two traits that commonly co-occur with parental care are offspring abandonment (the termination of parental investment prior to full independence in offspring) and filial cannibalism (the consumption of one's offspring). Here, we use a mathematical framework to explore how co-occurrence and coevolution among care, abandonment and cannibalism can influence the life-history conditions under which care is expected to evolve. Our results suggest that in some cases, the evolution of parental care can be inhibited by offspring abandonment and filial cannibalism. In other cases, abandonment and filial cannibalism that benefits parents can promote the evolution of parental care. It is particularly interesting that behaviours that seem so contrary to care—that is, eating or abandoning one's young—can in some cases broaden the conditions under which care can evolve. In general, our findings highlight that considering co-occurrence and coevolutionary dynamics between two or more traits is essential to understanding the evolution of trait diversity.
WhichTF is dominant in your open chromatin data?
Authors: Tanigawa Yosuke , Dyer Ethan S. , Bejerano Gill
Published: August 2019

We present WhichTF, a novel computational method to identify dominant transcription factors (TFs) from chromatin accessibility measurements. To rank TFs, WhichTF integrates high-confidence genome-wide computational prediction of TF binding sites based on evolutionary sequence conservation, putative gene-regulatory models, and ontology-based gene annotations. Applying WhichTF, we find that the identified dominant TFs have been implicated as functionally important in well-studied cell types, such as NF-κB family members in lymphocytes and GATA factors in cardiac tissue. To distinguish the transcriptional regulatory landscape in closely related samples, we devise a differential analysis framework and demonstrate its utility in lymphocyte, mesoderm developmental, and disease cells. We also find TFs known for stress response in multiple samples, suggesting routine experimental caveats that warrant careful consideration. WhichTF yields biological insight into known and novel molecular mechanisms of TF-mediated transcriptional regulation in diverse contexts, including human and mouse cell types, cell fate trajectories, and disease-associated tissues.
Neuronal activity triggers uptake of hematopoietic extracellular vesicles in vivo
Authors: Kur Ivan-Maximiliano , Prouvot Pierre-Hugues , Fu Ting , Fan Wei , Müller-Braun Felicia , Das Avash , Das Saumya , Deller Thomas , Roeper Jochen , Stroh Albrecht , Momma Stefan
Published: August 2019

Communication with the hematopoietic system is a vital component of regulating brain function in health and disease. Traditionally, the major routes considered for this neuroimmune communication are either by individual molecules such as cytokines carried by blood, by neural transmission, or in more severe pathologies, by entry of peripheral immune cells into the brain. In addition, functional mRNA from peripheral blood can be directly transferred to neurons via extracellular vesicles (EVs) but the parameters that determine their uptake are unknown. We show that transfer of EVs from blood is triggered by neuronal activity in vivo. Importantly, this transfer occurs not only in pathological stimulation but also by neuronal activation caused by the physiological stimulus of novel object recognition. This discovery suggests a continuous role of EVs under pathological conditions as well as during routine cognitive tasks in the healthy brain.
Early eukaryotic origins and metazoan elaboration of MAPR family proteins
Authors: Hehenberger Elisabeth , Eitel Michael , Fortunato Sofia A.V. , Miller David J. , Keeling Patrick J. , Cahill Michael A.
Published: August 2019

Background

The membrane-associated progesterone receptor (MAPR) family consists of heme-binding proteins containing a cytochrome b5(cytb5) domain characterized by the presence of a MAPR-specific interhelical insert region (MIHIR) between helices 3 and 4 of the canonical cytb5-domain fold. Animals possess three MAPR families (PGRMC-like, Neuferricin and Neudesin).

Results

Here we show that all animal MAPR families were already present in the common ancestor of the Opisthokonta (comprising animals and fungi as well as related protistan taxa). All three MAPR genes acquired extensions C-terminal to the cytb5domain, either before or with the evolution of animals. The archetypical MAPR protein, progesterone receptor membrane component 1 (PGRMC1), contains phosphorylated tyrosines Y139 and Y180. The combination of Y139/Y180 appeared in the common ancestor of Cnidaria and bilaterally symmetrical animals, along with an early embryological organizer and synapsed neurons, and is strongly conserved in all bilateral animals. A predicted protein interaction motif in the PGRMC1 MIHIR is potentially regulated by Y139 phosphorylation. A multilayered model of animal MAPR function acquisition includes some pre-metazoan functions (e.g., heme binding and cytochrome P450 interactions) and some acquired animal-specific functions that involve regulation of strongly conserved protein interaction motifs acquired by early-branching animals.

Conclusions

This study provides a conceptual framework for future studies, against which PGRMC1’s multiple functions can perhaps be stratified and functionally dissected. In accompanying papers we show that mutational perturbation of PGRMC1 phosphorylation status of the Y180 motif is associated with dramatic changes cell pasticity assayed by protein abundances, cell morphology, mitochondrial function, genomic stability, and epigenetic status, with pathways analysis associating Y180 mutation with processes related to organizer function. These combined works reveal previously unrecognized involvement of PGRMC1 in foundational animal processes of great relevance to disease.
Selective enhancement of object representations through multisensory integration
Authors: Tovar David A. , Murray Micah M. , Wallace Mark T.
Published: August 2019

Objects are the fundamental building blocks of how we create a representation of the external world. One major distinction amongst objects is between those that are animate versus inanimate. Many objects are specified by more than a single sense, yet the nature by which multisensory objects are represented by the brain remains poorly understood. Using representational similarity analysis of human EEG signals, we show enhanced encoding of audiovisual objects when compared to their corresponding visual and auditory objects. Surprisingly, we discovered the often-found processing advantages for animate objects was not evident in a multisensory context due to greater neural enhancement of inanimate objects—the more weakly encoded objects under unisensory conditions. Further analysis showed that the selective enhancement of inanimate audiovisual objects corresponded with an increase in shared representations across brain areas, suggesting that neural enhancement was mediated by multisensory integration. Moreover, a distance-to-bound analysis provided critical links between neural findings and behavior. Improvements in neural decoding at the individual exemplar level for audiovisual inanimate objects predicted reaction time differences between multisensory and unisensory presentations during a go/no-go animate categorization task. Interestingly, links between neural activity and behavioral measures were most prominent 100 to 200ms and 350 to 500ms after stimulus presentation, corresponding to time periods associated with sensory evidence accumulation and decision-making, respectively. Collectively, these findings provide key insights into a fundamental process the brain uses to maximize information it captures across sensory systems to perform object recognition.

Significance Statement

Our world is filled with an ever-changing milieu of sensory information that we are able to seamlessly transform into meaningful perceptual experience. We accomplish this feat by combining different features from our senses to construct objects. However, despite the fact that our senses do not work in isolation but rather in concert with each other, little is known about how the brain combines the senses together to form object representations. Here, we used EEG and machine learning to study how the brain processes auditory, visual, and audiovisual objects. Surprisingly, we found that non-living objects, the objects which were more difficult to process with one sense alone, benefited the most from engaging multiple senses.
The C99 Fragment Of App Regulates Cholesterol Trafficking
Authors: Pera M. , Larrea D. , Montesinos J. , Guardia-Laguarta C. , Agrawal R.R. , Velasco K.R. , Xu Y. , Koo SY , Snead A , Sproul A. , Area-Gomez E.
Published: August 2019

The link between cholesterol homeostasis and the cleavage of the amyloid precursor protein (APP), and their relationship to the pathogenesis of Alzheimer’s disease (AD) is still unknown. Cellular cholesterol levels are regulated by a crosstalk between the plasma membrane (PM), where most of the cholesterol resides, and the endoplasmic reticulum (ER), where the protein machinery that regulates cholesterol resides. This crosstalk between PM and ER is believed to be regulated by lipid-sensing peptide(s) that can modulate the internalization of extracellular cholesterol and/or itsde novosynthesis in the ER. Our data here indicates that the 99-aa C-terminal fragment of APP (C99), a cholesterol-binding peptide, regulates cholesterol trafficking between the PM and the ER. In AD models, increases in C99 provoke the upregulation of cholesterol internalization and its delivery to the ER, which in turn result into the loss of lipid homeostasis and the appearance of AD signatures, such as higher production of longer forms of amyloid β. Our data suggest a novel role of C99 as mediator of cholesterol disturbances in AD, and as a potential early hallmark of the disease.
Radiation-Induced DNA Damage and Repair Effects on 3D Genome Organization
Authors: Sanders Jacob T. , Freeman Trevor F. , Xu Yang , Golloshi Rosela , Stallard Mary A. , Martin Rebeca San , Balajee Adayabalam S. , McCord Rachel Patton
Published: August 2019

The three-dimensional structure of chromosomes plays an important role in gene expression regulation and also influences the repair of radiation-induced DNA damage. Genomic aberrations that disrupt chromosome spatial domains can lead to diseases including cancer, but how the 3D genome structure responds to DNA damage is poorly understood. Here, we investigate the impact of DNA damage response and repair on 3D genome folding using Hi-C experiments on wild type cells and ataxia telangiectasia mutated (ATM) patient cells. Fibroblasts, lymphoblasts, and ATM-deficient fibroblasts were irradiated with 5 Gy X-rays and Hi-C was performed after 30 minutes, 24 hours, or 5 days after irradiation. 3D genome changes after irradiation were cell type-specific, with lymphoblastoid cells generally showing more contact changes than irradiated fibroblasts. However, all tested repair-proficient cell types exhibited an increased segregation of topologically associating domains (TADs). This TAD boundary strengthening after irradiation was not observed in ATM deficient fibroblasts and may indicate the presence of a mechanism to protect 3D genome structure integrity during DNA damage repair.
Massive parallel variant characterization identifiesNUDT15alleles associated with thiopurine toxicity
Authors: Suiter Chase C. , Moriyama Takaya , Matreyek Kenneth A. , Yang Wentao , Scaletti Emma Rose , Nishii Rina , Yang Wenjian , Hoshitsuki Keito , Singh Minu , Trehan Amita , Parish Chris , Smith Colton , Bhojwani Deepa , Yuen Liz YP , Li Chi-kong , Li Chak-ho , Yang Yung-li , Walker Gareth J , Goodhand James R , Kennedy Nicholas A , Klussmann Federico Antillon , Bhatia Smita , Relling Mary V. , Kato Motohiro , Hori Hiroki , Bhatia Prateek , Ahmad Tariq , Yoeh Allen E. J. , Stenmark Pål , Fowler Douglas M. , Yang Jun J.
Published: August 2019

As a prototype of genomics-guided precision medicine, individualized thiopurine dosing based on pharmacogenetics is a highly effective way to mitigate hematopoietic toxicity of this class of drugs. Recently,NUDT15deficiency was identified as a novel genetic cause of thiopurine toxicity, andNUDT15-informed preemptive dose reduction is quickly adopted in clinical settings. To exhaustively identify pharmacogenetic variants in this gene, we developed massively parallel NUDT15 function assays to determine variants’ effect on protein abundance and thiopurine cytotoxicity. Of the 3,097 possible missense variants, we characterized the abundance of 2,922 variants and found 54 hotspot residues at which variants resulted in complete loss of protein stability. Analyzing 2,935 variants in the thiopurine cytotoxicity-based assay, we identified 17 additional residues where variants altered NUDT15 activity without affecting protein stability. We identified structural elements key to NUDT15 stability and/or catalytical activity with single amino-acid resolution. Functional effects forNUDT15variants accurately predicted toxicity risk alleles in 2,398 patients treated with thiopurines, with 100% sensitivity and specificity, in contrast with poor performance of bioinformatic prediction algorithms. In conclusion, our massively parallel variant function assays identified 1,103 deleteriousNUDT15variants, providing a comprehensive reference of variant function and vastly improving the ability to implement pharmacogenetics-guided thiopurine treatment individualization.
Cryptococcus neoformansevades pulmonary immunity by modulating xylose precursor transport
Authors: Li Lucy X. , Hole Camaron R. , Rangel-Moreno Javier , Khader Shabaana A. , Doering Tamara L.
Published: August 2019

Cryptococcus neoformansis a fungal pathogen that kills almost 200,000 people each year and is distinguished by abundant and unique surface glycan structures that are rich in xylose. A mutant strain ofC. neoformansthat cannot transport xylose precursors into the secretory compartment is severely attenuated in virulence in mice, yet surprisingly is not cleared. We found that this strain failed to induce the non-protective T helper cell type 2 (Th2) responses characteristic of wild-type infection, instead promoting sustained Interleukin (IL)-12p40 induction and increased IL-17A (IL-17) production. It also stimulated dendritic cells to release high levels of pro-inflammatory cytokines, a behavior we linked to xylose expression. We further discovered that inducible bronchus associated lymphoid tissue (iBALT) forms in response to infection with either wild-type cryptococci or the mutant strain with reduced surface xylose; although iBALT formation is slowed in the latter case, the tissue is better organized. Finally, our temporal studies suggest that lymphoid structures in the lung restrict the spread of mutant fungi for at least 18 weeks after infection, in contrast to ineffective control of the pathogen after infection with wild-type cells. These studies demonstrate the role of xylose in modulation of host response to a fungal pathogen and show that cryptococcal infection triggers iBALT formation.
The Plasmodium falciparum protein VCAP1 controls Maurer’s cleft morphology, knob architecture and PfEMP1 trafficking
Authors: McHugh Emma , Carmo Olivia , Blanch Adam , Looker Oliver , Liu Boyin , Tiash Snigdha , Andrew Dean , Batinovic Steven , Low J.Y Andy , McMillan Paul , Tilley Leann , Dixon Matthew W.A
Published: August 2019

The malaria parasite, Plasmodium falciparum, traffics the virulence protein, P. falciparum erythrocyte membrane protein 1 (PfEMP1) to the surface of infected red blood cells (RBCs) via membranous organelles, known as the Maurer’s clefts. We developed a method for efficient enrichment of Maurer’s clefts and profiled the protein composition of this trafficking organelle. We identified 13 previously uncharacterised or poorly characterised Maurer’s cleft proteins. We generated transfectants expressing GFP-fusions of 7 proteins and confirmed their Maurer’s cleft location. Using co-immunoprecipitation and mass spectrometry we have generated a protein interaction map of proteins at the Maurer’s clefts. We identified two key clusters that may function in the loading and unloading of PfEMP1 into and out of the Maurer’s clefts. We focus on a putative PfEMP1 loading complex that includes the newly characterised virulence complex assembly protein 1 (VCAP1). Disruption of VCAP1 causes Maurer’s cleft fragmentation, aberrant knobs, ablation of PfEMP1 surface expression and loss of the PfEMP1 directed adhesion. ΔVCAP1 parasite lines have a growth advantage compared to wildtype parasites; and the infected RBCs are more deformable and more osmotically fragile.

Importance

The trafficking of the virulence antigen PfEMP1 and its presentation at the knob structures at the surface of parasite infected RBCs is central to severe adhesion related pathologies such as cerebral and placental malaria. This work adds to our understanding of how PfEMP1 is trafficked to the RBC membrane by defining the protein-protein interaction networks that function at the Maurer’s clefts controlling PfEMP1 loading and unloading. This work adds significantly to our understanding of virulence protein trafficking and will provide crucial knowledge that will be required to determine the mechanisms underpinning parasite driven host cell remodelling, parasite survival within the host and virulence mechanisms.
A single-cell transcriptomics CRISPR-activation screen identifies new epigenetic regulators of zygotic genome activation
Authors: Alda-Catalinas Celia , Bredikhin Danila , Hernando-Herraez Irene , Kubinyecz Oana , Santos Fátima , Eckersley-Maslin Mélanie A. , Stegle Oliver , Reik Wolf
Published: August 2019

Zygotic genome activation (ZGA) is a crucial developmental milestone that remains poorly understood. This first essential transcriptional event in embryonic development coincides with extensive epigenetic reprogramming processes and is orchestrated, in part, by the interplay of transcriptional and epigenetic regulators. Here, we developed a novel high-throughput screening method that combines pooled CRISPR-activation (CRISPRa) with single-cell transcriptomics to systematically probe candidate regulators of ZGA. We screened 230 epigenetic and transcriptional regulators by upregulating their expression with CRISPRa in mouse embryonic stem cells (ESCs). Through single-cell RNA-sequencing (scRNA-seq) of CRISPRa-perturbed cells, we generated approximately 200,000 single-cell transcriptomes, each transduced with a unique short-guide RNA (sgRNA) targeting a specific candidate gene promoter. Using integrative dimensionality reduction of the perturbation scRNA-seq profiles, we characterized molecular signatures of ZGA and uncovered 44 factors that promote a ZGA-like response in ESCs, both in the coding and non-coding transcriptome. Upon upregulation of these factors, including the DNA binding protein Dppa2, the chromatin remodeller Smarca5 and the transcription factor Patz1, ESCs adopt an early embryonic-like state. Supporting their roles as ZGA regulators, Dppa2 and Smarca5 knock-out ESCs lose expression of ZGA genes, however, overexpression of Dppa2 in Smarca5 knock-out ESCs, but not vice versa, rescues ZGA-like expression, suggesting that Smarca5 regulates ZGA upstream and via Dppa2. Together, our single-cell transcriptomic profiling of CRISPRa-perturbed cells provides comprehensive system-level insights into the molecular mechanisms that orchestrate ZGA.

Highlights

First large-scale screen combining pooled CRISPRa with scRNA-seq.

Multi-omics factor analysis identifies a ZGA-like signature for 44 of the candidate regulators.

Dppa2, Smarca5 and Patz1 were validated as strong inducers of ZGA gene expression.

Smarca5 regulates zygotic genome activation in a Dppa2-dependent manner.
Transient primary cilia mediate robust Hedgehog pathway-dependent cell cycle control
Authors: Ho Emily K. , Tsai Anaïs E. , Stearns Tim
Published: August 2019

The regulation of proliferation is one of the primary functions of Hedgehog (Hh) signaling in development. Transduction of Hh signaling requires the primary cilium, a microtubule-based organelle that is necessary for several steps in the pathway (Corbit et al., 2005; Huangfu and Anderson, 2005; Huangfu et al., 2003; Liu et al., 2005; Rohatgi et al., 2007). Many cells only build a primary cilium upon cell cycle arrest in G0. In those proliferating cells that do make a cilium, it is a transient organelle, being assembled in G1 and disassembled sometime after, although exactly when is not well-characterized (Ford et al., 2018; Pugacheva et al., 2007; Wang and Dynlacht, 2018). Thus the requirement for primary cilia presents a conundrum: how are proliferative signals conveyed through an organelle that is present for only part of the cell cycle? Here we investigate this question in a mouse medulloblastoma cell line, SMB55, that requires cilium-mediated Hh pathway activity for proliferation (Zhao et al., 2015). We show that SMB55 cells are often ciliated beyond G1 into S phase, and the presence of the cilium determines the periods of Hh pathway activity. Using live imaging over multiple cell cycles, we define two windows of opportunity for Hh pathway activity, either of which is sufficient to effect cell cycle entry. The first is in the ciliated phase of the previous cell cycle, and the second is in G1 of the cell cycle in which the decision is made. We propose that the ability of cells to integrate Hh pathway activity from more than one cell cycle imparts robustness on Hh pathway control of proliferation and may have implications for other Hh-mediated events in development.
Evolution of the PRD1-adenovirus lineage: a viral tree of life incongruent with the cellular universal tree of life
Authors: Woo Anthony C. , Gaia Morgan , Guglielmini Julien , Da Cunha Violette , Forterre Patrick
Published: August 2019

Double-stranded DNA viruses of the PRD1-adenovirus lineage are characterized by homologous major capsid proteins containing one or two β-barrel domains known as the jelly roll folds. Most of them also share homologous packaging ATPases of the FtsK/HerA superfamily P-loop ATPases. Remarkably, members of this lineage infect hosts from the three domains of life, suggesting that viruses from this lineage could be very ancient and share a common ancestor. Here we analyzed the evolutionary history of these cosmopolitan viruses by inferring phylogenies based on single or concatenated genes. These viruses can be divided into two supergroups infecting either eukaryotes or prokaryotes. The latter can be further divided into two groups of bacterioviruses and one group of archaeoviruses. This viral tree is thus incongruent with the cellular tree of life in which Archaea are closer to Eukarya and more divergent from Bacteria. We discuss various evolutionary scenarios that could explain this paradox.
Mannose receptor is a restriction factor of HIV in macrophages and is counteracted by the accessory protein Vpr
Authors: Lubow Jay , Collins David R. , Mashiba Mike , Peterson Brian , Virgilio Maria , Collins Kathleen L
Published: August 2019

HIV-1 Vpr is necessary to support HIV infection and spread in macrophages. Evolutionary conservation of Vpr suggests an important yet poorly understood role for macrophages in HIV pathogenesis. Vpr counteracts a previously unknown macrophage-specific restriction factor that targets and reduces the expression of HIV Env. Here, we report that the macrophage mannose receptor (MR), is the restriction factor targeting Env in primary human monocyte-derived macrophages. Vpr acts synergistically with HIV Nef to target distinct stages of the MR biosynthetic pathway and dramatically reduce MR expression. Silencing MR or deleting mannose residues on Env rescues Env expression in HIV-1-infected macrophages lacking Vpr. However, we also show that disrupting interactions between Env and MR reduces initial infection of macrophages by cell-free virus. Together these results reveal a Vpr-Nef-Env axis that hijacks a macrophage mannose-MR response system to facilitate infection while evading MR’s normal role, which is to trap and destroy mannose-expressing pathogens.
Global adaptation confounds the search for local adaptation
Authors: Booker Tom R. , Yeaman Sam , Whitlock Michael C.
Published: August 2019

Spatially varying selection promotes variance in allele frequencies, increasing genetic differentiation between the demes of a metapopulation. For that reason, outliers in the genome wide distribution of summary statistics measuring genetic differentiation, such asFST, are often interpreted as evidence for alleles which contribute to local adaptation. However, in spatially structured populations, the spread of beneficial mutations with spatially uniform effects can also induce transient genetic differentiation and numerous theoretical studies have suggested that species-wide, or global, adaptation makes a substantial contribution to molecular evolution. In this study, we ask whether such global adaptation affects the genome-wide distribution ofFSTand generates statistical outliers which could be mistaken for local adaptation. Using forward-in-time population genetic simulations assuming parameters for the rate and strength of beneficial mutations similar to those that have been estimated for natural populations, we show the spread of globally beneficial in parapatric populations can readily generateFSToutliers, which may be misinterpreted as evidence for local adaptation. The spread of beneficial mutations causes selective sweeps at flanking sites, so the effects of global versus local adaptation may be distinguished by examining patterns of nucleotide diversity along withFST. Our study suggests that global adaptation should be considered in the interpretation of genome-scan results and the design of future studies aimed at understanding the genetic basis of local adaptation.
Genome of an iconic Australian bird: Chromosome-scale assembly and linkage map of the superb fairy-wren (Malurus cyaneus)
Authors: Peñalba Joshua V. , Deng Yuan , Fang Qi , Joseph Leo , Moritz Craig , Cockburn Andrew
Published: August 2019

The superb fairy-wren, Malurus cyaneus, is one of the most iconic Australian passerine species. This species belongs to an endemic Australasian clade, Meliphagides, which diversified early in the evolution of the oscine passerines. Today, the oscine passerines comprise almost half of all avian species diversity. Despite the rapid increase of available bird genome assemblies, this part of the avian tree has not yet been represented by a high-quality reference. To rectify that, we present the first chromosome-scale genome assembly of a Meliphagides representative: the superb fairy-wren. We combined Illumina shotgun and mate-pair sequences, PacBio long-reads, and a genetic linkage map from an intensively sampled pedigree of a wild population to generate this genome assembly. Of the final assembled 1.07Gb genome, 894Mb (84.8%) was anchored onto 25 chromosomes resulting in a final scaffold N50 of 68.11 Mb. This high-quality bird genome assembly is also one of only a handful which is also accompanied by a genetic map and recombination landscape. In comparison to other pedigree-based bird genetic maps, we find that the zebrafinch (Taeniopygia) genetic map more closely resembles the fairy-wren map rather than the map from the more closely-related Ficedula flycatcher. Lastly, we also provide a predictive gene and repeat annotation of the genome assembly. This new high quality, annotated genome assembly will be an invaluable resource not only to the superb fairy-wren species and relatives but also broadly across the avian tree by providing a new reference point for comparative genomic analyses.
Determinants Distribution of Financing and the Implications to Profitability: Empirical Study on Cooperative Sharia Baitul Maal wa Tamwil (BMT) in Indonesia
Authors: Lisa Oyong
Published: August 2019

Financing is one of the main activities and a major source of revenue for Islamic Cooperatives. This study aimed to analyze the effect of capital structure, third party funds and non-performing financing to the finance portfolio as well as to analyze the effect of capital structure, deposits, non-performing financing and the distribution of funding to profitability. The analysis technique used is multiple regression analysis, using F test and t test. The results of the analysis showed that the capital structure, third party funds and non-performing financing significantly effect on the distribution of funding. Capital structure, third party funds, and the distribution of funding has a significant effect on profitability, Sharia Cooperative BMT in Indonesia. While non-performing financing does not affect the profitability of Islamic Cooperative Baitul Maal Tamwil in Indonesia.
CSR Disclosure, Customer Loyalty, and Firm Values (Study at Mining Company Listed in Indonesia Stock Exchange)
Authors: Isnalita  , Narsa I Made
Published: August 2019

This study aimed to examine the association of Corporate Social Responsibility (CSR) disclosure and the firm valueson customer loyalty as a mediating variable. The samples of this study weresourced from the mining companies listed on the Indonesia Stock Exchange of 2008-2014. The secondary data used was obtained from the annual reports accessed through idx.co.id, and the sales reports based on the mining's sub-sectors accessed through bi.go.id. The variables of CSR disclosure were measured by usingscoresof weighting the item categories of CSR disclosure, namely: special items, core items, and additional items. Meanwhile, customer loyalty was measured by using market share, and the firm values were measured by Tobin's Q. The results proved that customer loyalty was the intervening influence of CSR disclosure and the firm values. This was the first study thatapplied different weighting to the category of disclosure items to calculate the scores of CSR disclosure through a statistical testing. Further research, then,can use the survey or focus group discussion (FGD) to determine the weighting method.
A Study on Managers' Creation of Budgetary Slack in Emerging Economies: The Case of Vietnam
Authors: Ngo Quang-Huy , Doan Thi-Nam-Ninh , Huynh Thanh-Nha
Published: August 2019

Although the budgeting literature well documents managers' creation of budgetary slack in developed economies, lack of attention has been paid to this behaviour in emerging economies. It is doubtful that some unique characteristics, only existing in emerging economies, cause this behaviour to be different than the budgeting literature predicts. Since there is no study examining managers' creation of budgetary slack in emerging economies, such as Vietnam, to get insight into whether or not these characteristics cause the differences, the aim of this study is to replicate prior budgeting studies by using Vietnamese samples. Particularly, we investigated the impact of budgetary participation, budget emphasis, information asymmetry, and the interactions between these variables on managers' creation of budgetary slack. Data obtained from the questionnaire sent to 99 Vietnamese managers shows that the last two variables and the interaction between them induce managers' creation of budgetary slack. However, the results also indicate that the first variable and the interaction between this variable and the other two variables respectively have no impact on managers' creation of budgetary slack. These results provide some insight into the creation of budgetary slack of Vietnamese managers for future studies to extend the line of research.
Key critical success factors of BPM implementation: a theoretical and practical view
Authors: Castro Bruna Kaziano do Amaral , Dresch Aline , Veit Douglas Rafael
Published: August 2019

Purpose

The purpose of this paper is to identify the key critical factors that affect the success of Business Process Management (BPM) implementations, considering the literature and experts practical experience.

Design/methodology/approach

A systematic literature review (SLR) was conducted, and 25 articles from 12 different countries were selected and analyzed. In addition, through a survey, 113 BPM experts were consulted in order to assist in the evaluation of critical success factors (CSFs) initially identified in the bibliography.

Findings

All CSFs identified in the literature were accepted as real critical factors according to the tacit knowledge of the experts. Thus, the factors identified in the literature and approved to a large extent by the experts can serve as a basis for organizations and professionals who want to implement BPM to know of their existence, to relate to them, to control them and thus to potentiate the success of the implementation.

Originality/value

The construction of the theoretical framework based on SLR on BPM is a contribution to the bibliographic database. Another contribution is the identification and synthesis of the CSFs most cited by different authors from 12 different countries and its analysis by professionals on BPM.
The push effect of risks on supply chain performance: service-oriented firms
Authors: Truong Quang Huy , Hara Yoshinori
Published: August 2019

Purpose

The purpose of this paper is to examine the push effect of risk on supply chain (SC) performance, a new concept in the SC risk body of literature, at service-oriented firms.

Design/methodology/approach

Two models were compared: first, contains relationships between risks that show the mechanism of the push effect, i.e. the theoretical model. The other, only exists in direct effects of risks on SC performance, i.e. the competitive model.

Findings

Test results proved that the mechanism of the push effect can increase the degree of impact of each and all risks on outputs. By the push effect, risks can explain up to 65 percent variance of SC performance compared with 52 percent of the model without push effect. Moreover, the research found two kinds of the push effect: positive – increasing the impact of “pushed” factors on outputs and vice versa for negative.

Research limitations/implications

The mechanism of the push influence will be broken if mutual interaction among risks was minimized. Practitioners and managers can apply the resultant model as a “road map” in their context to achieve this purpose.

Originality/value

Vargo and Lusch (2008) argued that service-oriented firms will be a new trend since the modern-day industry tends to more focus on customer demand. SC management gradually shifted toward demand chain management that organizations will not make and sell units of output but producing customized services to customers (Walters, 2008). This transformation has led to the emergence of new risks, the impact of risk on the SC also varies and the mismatch of the current risk mitigation strategies (Luschet al., 2007). Dealing with these changes is the purpose of this research.