bluuebunny/crossref_metadata_2025 huggingface dataset:
A statistical approach for tracking clonal dynamics in cancer using longitudinal next-generation sequencing data
Authors: Vavoulis Dimitrios V. , Cutts Anthony , Taylor Jenny C. , Schuh Anna
Published: January 2020

Tumours are composed of genotypically and phenotypically distinct cancer cell populations (clones), which are subject to a process of Darwinian evolution in response to changes in their local micro-environment, such as drug treatment. In a cancer patient, this process of continuous adaptation can be studied through next-generation sequencing of multiple tumour samples combined with appropriate bioinformatics and statistical methodologies. One family of statistical methods for clonal deconvolution seeks to identify groups of mutations and estimate the prevalence of each group in the tumour, while taking into account its purity and copy number profile. These methods have been used in the analysis of cross-sectional data, as well as for longitudinal data by discarding information on the timing of sample collection. Two key questions are how (in the case of longitudinal data) can we incorporate such information in our analyses and if there is any benefit in doing so. Regarding the first question, we incorporated information on the temporal spacing of longitudinally collected samples into standard non-parametric approaches for clonal deconvolution by modelling the time dependence of the prevalence of each clone as aGaussian process. This permitted reconstruction of the temporal profile of the abundance of each clone continuously from several sparsely collected samples and without any strong prior assumptions on the functional form of this profile. Regarding the second question, we tested various model configurations on a range of whole genome, whole exome and targeted sequencing data from patients with chronic lymphocytic leukaemia, on liquid biopsy data from a patient with melanoma and on synthetic data. We demonstrate that incorporating temporal information in our analysis improves model performance, as long as data of sufficient volume and complexity are available for estimating free model parameters. We expect that our approach will be useful in cases where collecting a relatively long sequence of tumour samples is feasible, as in the case of liquid cancers (e.g. leukaemia) and liquid biopsies. The statistical methodology presented in this paper is freely available atgithub.com/dvav/clonosGP.
Deciphering cattle temperament measures derived from a four-platform standing scale using genetic factor analytic modeling
Authors: Yu Haipeng , Morota Gota , Celestino Elfren F. , Dahlen Carl R. , Wagner Sarah A. , Riley David G. , Hanna Lauren L. Hulsman
Published: January 2020

The animal’s reaction to human handling (i.e., temperament) is critical for work safety, productivity, and welfare. Subjective phenotyping methods have been traditionally used in beef cattle production. Even so, subjective scales rely on the evaluator’s knowledge and interpretation of temperament, which may require substantial experience. Selection based on such subjective scores may not precisely change temperament preferences in cattle. The objectives of this study were to investigate the underlying genetic interrelationships among temperament measurements using genetic factor analytic modeling and validate a movement-based objective method (four-platform standing scale, FPSS) as a measure of temperament. Relationships among subjective methods of docility score (DS), temperament score (TS), 12 qualitative behavior assessment (QBA) attributes and objective FPSS including the standard deviation of total weight on FPSS over time (SSD) and coefficient of variation of SSD (CVSSD) were investigated using 1,528 calves at weaning age. An exploratory factor analysis (EFA) identified two latent variables account for TS and 12 QBA attributes, termeddifficultandeasyfrom their characteristics. Inclusion of DS in EFA was not a good fit because it was evaluated under restraint and other measures were not. A Bayesian confirmatory factor analysis inferred thedifficultandeasyscores discovered in EFA. This was followed by fitting a pedigree-based Bayesian multi-trait model to characterize the genetic interrelationships amongdifficult,easy, DS, SSD, and CVSSD. Estimates of heritability ranged from 0.18 to 0.4 with the posterior standard deviation averaging 0.06. The factors ofdifficultandeasyexhibited a large negative genetic correlation of −0.92. Moderate genetic correlation was found between DS anddifficult(0.36),easy(−0.31), SSD (0.42), and CVSSD (0.34) as well as FPSS withdifficult(CVSSD: 0.35; SSD: 0.42) andeasy(CVSSD: −0.35; SSD: −0.4). Correlation coefficients indicate selection could be performed with either and have similar outcomes. We contend that genetic factor analytic modeling provided a new approach to unravel the complexity of animal behaviors and FPSS-like measures could increase the efficiency of genetic selection by providing automatic, objective, and consistent phenotyping measures that could be an alternative of DS, which has been widely used in beef production.
The zinc cluster transcription factor Rha1 is a positive filamentation regulator inCandida albicans
Authors: Omran Raha Parvizi , Law Chris , Dumeaux Vanessa , Morschhäuser Joachim , Whiteway Malcolm
Published: January 2020

Zinc cluster transcription factors are essential fungal specific regulators of gene expression. In the dimorphic pathogenCandida albicans,they control processes ranging from metabolism and stress adaptation to mating, virulence, and antifungal resistance. Here, we have identified the geneCaORF19.1604as encoding a zinc cluster transcription factor that acts as a regulator of filament development. Hyperactivation ofCaORF19.1604, which we have namedRHA1forRegulator ofHyphalActivity, leads to a wrinkled colony morphology under non-hyphal growth conditions, to pseudohyphal growth and filament formation, to invasiveness and enhanced biofilm formation.  Cells with activated Rha1 are sensitive to cell wall modifying agents such as Congo red and the echinocandin drug caspofungin but show normal sensitivity to fluconazole. RNA-sequencing-based transcriptional profiling of the activated Rha1 strain reveals the up-regulation of genes for core filamentation and cell-wall-adhesion-related proteins such as Als1, Als3, Ece1, and Hwp1. Upregulation is also seen for the genes for the hyphal-inducing transcription factors Brg1 and Ume6 and genes encoding several enzymes involved in arginine metabolism, while downregulation is seen for the hyphal repressor Nrg1. The deletion ofBRG1blocks the filamentation caused by activated Rha1, while null mutants ofUME6result in a partial block. Deletion ofRHA1can partially reduce healthy hyphal development triggered by environmental conditions such as Spider medium or serum at 37°C.

In contrast to the limited effect of either single mutant, the doublerha1 ume6deletion strain is totally defective in both serum and Spider medium stimulated hyphal development. While the loss of Brg1 function blocks serum-stimulated hyphal development, this block can be significantly bypassed by Rha1 hyperactivity, and the combination of Rha1 hyperactivity and serum addition can generate significant polarization in evenbrg1 ume6double mutants. Our results thus suggest that in response to external signals, Rha1 functions to facilitate the switch from an Nrg1 controlled yeast state to a Brg1/Ume6 regulated hyphal state.

Author Summary

Candida albicansis the predominant human fungal pathogen, generating a mortality rate of 40% in systemically infected patients. The ability ofCandida albicansto change its morphology is a determinant of its tissue penetration and invasion in response to variant host-related stimuli. The regulatory mechanism for filamentation includes a complex network of transcription factors that play roles in regulating hyphae associated genes. We identify here a new regulator of filamentation from the zinc cluster transcription factor family. We present evidence suggesting that this transcription factor assists the Nrg1/Brg1 switch regulating hyphal development.
Overcoming the inhibitory microenvironment surrounding oligodendrocyte progenitor cells following demyelination
Authors: Saraswat Darpan , Shayya Hani J. , Polanco Jessie J. , Tripathi Ajai , Welliver R. Ross , Pol Suyog U. , Seidman Richard A. , Broome Jacqueline E. , O’Bara Melanie A. , van Kuppervelt Toin H. , Phillips Joanna J. , Dutta Ranjan , Sim Fraser J.
Published: January 2020

Chronic demyelination in the human CNS is characterized by an inhibitory microenvironment that impairs recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) leading to failed remyelination and axonal atrophy. By network-based transcriptomics, we identified sulfatase 2 (Sulf2) mRNA in activated human primary OPCs. Sulf2, an extracellular endosulfatase, modulates the signaling microenvironment by editing the pattern of sulfation on heparan sulfate proteoglycans. We found that Sulf2 was increased in demyelinating lesions in multiple sclerosis and was actively secreted by human OPCs. In experimental demyelination, elevated OPC Sulf1/2 expression directly impaired progenitor recruitment and subsequent generation of oligodendrocytes thereby limiting remyelination. Sulf1/2 potentiates the inhibitory microenvironment by promoting BMP and WNT signaling in OPCs. Importantly, pharmacological sulfatase inhibition using PI-88 accelerated oligodendrocyte recruitment and remyelination by blocking OPC-expressed sulfatases. Our findings define an important inhibitory role of Sulf1/2 and highlight the potential for modulation of the heparanome in the treatment of chronic demyelinating disease.
Reduced function of the glutathione S-transferase S1 suppresses behavioral hyperexcitability inDrosophilaexpressing a mutant voltage-gated sodium channel
Authors: Chen Hung-Lin , Kasuya Junko , Lansdon Patrick , Kaas Garrett , Tang Hanxi , Sodders Maggie , Kitamoto Toshihiro
Published: January 2020

Voltage-gated sodium (Nav) channels play a central role in the generation and propagation of action potentials in excitable cells such as neurons and muscles. To determine how the phenotypes of Nav-channel mutants are affected by other genes, we performed a forward genetic screen for dominant modifiers of the seizure-prone, gain-of-functionDrosophila melanogasterNav-channel mutant,paraShu. Our analyses using chromosome deficiencies, gene-specific RNA interference, and single-gene mutants revealed that a null allele ofglutathione S-transferase S1(GstS1) dominantly suppressesparaShuphenotypes. ReducedGstS1function also suppressed phenotypes of other seizure-prone Nav-channel mutants,paraGEFS+andparabss. Notably,paraShumutants expressed 50% lessGstS1than wild-type flies, further supporting the notion thatparaShuandGstS1interact functionally. Introduction of a loss-of-functionGstS1mutation into aparaShubackground led to up- and down-regulation of various genes, with those encoding cytochrome P450 (CYP) enzymes most significantly over-represented in this group. BecauseGstS1is a fly ortholog of mammalian hematopoietic prostaglandin D synthase, and in mammals CYPs are involved in the oxygenation of polyunsaturated fatty acids including prostaglandins, our results raise the intriguing possibility that bioactive lipids play a role inGstS1-mediated suppression ofparaShuphenotypes.
Single-cell metabolic dynamics of early activated CD8 T cells during the primary immune response to infection
Authors: Levine Lauren S. , Hiam Kamir J. , Marquez Diana M. , Tenvooren Iliana , Contreras Diana C. , Rathmell Jeffrey C. , Spitzer Matthew H.
Published: January 2020

Memory T cells conventionally rely on oxidative phosphorylation and short-lived effector T cells on glycolysis. Here, we investigate how T cells arrive at these states during an immune response. In order to understand the metabolic state of rare, early activated T cells, we adapted mass cytometry to quantify metabolic regulators at single-cell resolution in parallel with cell signaling, proliferation, and effector function. We interrogated CD8 T cell activation in vitro as well as the trajectory of CD8 T cells responding toListeria monocytogenesinfection, a well-characterizedin vivomodel for studies of T cell differentiation. This approach revealed a unique metabolic state in early activated T cells characterized by maximal expression of glycolytic and oxidative metabolic proteins. Peak utilization of both pathways was confirmed by extracellular flux analysis. Cells in this transient state were most abundant five days post-infection before rapidly downregulating metabolic protein expression. This approach should be useful for mechanistic investigations of metabolic regulation of immune responses.
Effectiveness of protected areas in conserving tropical forest birds
Authors: Cazalis Victor , Princé Karine , Mihoub Jean-Baptiste , Kelly Joseph , Butchart Stuart H.M. , Rodrigues Ana S.L.
Published: January 2020

Protected areas are the cornerstones of global biodiversity conservation efforts1,2, but to fulfil this role they must be effective at conserving the ecosystems and species that occur within their boundaries. This is particularly imperative in tropical forest hotspots, regions that concentrate a major fraction of the world’s biodiversity while also being under intense human pressure3–5. But these areas strongly lack adequate monitoring datasets enabling to contrast biodiversity in protected areas with comparable unprotected sites6,7. Here we take advantage of the world’s largest citizen science biodiversity dataset – eBird8– to quantify the extent to which protected areas in eight tropical forest biodiversity hotspots are effective at retaining bird diversity, and to understand the underlying mechanisms. We found generally positive effects of protection on the diversity of bird species that are forest-dependent, endemic to the hotspots, or threatened or Near Threatened, but not on overall bird species richness. Furthermore, we show that in most of the hotspots examined this is driven by protected areas preventing both forest loss and degradation. Our results support calls for increasing the extent and strengthening the management efforts within protected areas to reduce global biodiversity loss9–11.
RdDM pathway is required forTobamovirus-induced symptomatology production
Authors: Leone Melisa , Zavallo Diego , Venturuzzi Andrea , Asurmendi Sebastián
Published: January 2020

Small RNAs (sRNA) are important molecules for gene regulation in plants and play an essential role in plant-pathogen interactions. Researchers have evaluated the relationship between viral infections as well as the endogenous accumulation of sRNAs and the transcriptional changes associated with the production of symptoms, little is known about a possible direct role of epigenetics, mediated by 24-nt sRNAs, in the induction of these symptoms.

With the use of different RNA directed DNA methylation pathway mutants and triple demethylase mutants, here we demonstrate that the disruption of RdDM pathway during viral infection produced alterations in the plant transcriptomic changes (because of the infection) and in symptomatology.

This study represents the initial step in exposing that DNA methylation directed by endogenous sRNAs has an important role, uncoupled to defense, in the production of symptoms associated with plant-virus interactions.

Significance statement

The crop yield losses induced by phytoviruses are mainly associated with the symptoms of the disease. DNA modifications as methylation, can modulate the information coded by the sequence, process named epigenetics. Viral infection can change the expression patterns of different genes linked to defenses and symptoms. This work represents the initial step to expose the role of epigenetic process, in the production of symptoms associated with plants-virus interactions.
The RNA-binding protein, Rasputin/G3BP, enhances the stability and translation of its target mRNAs
Authors: Laver John D. , Ly Jimmy , Winn Allison K. , Karaiskakis Angelo , Lin Sichun , Nie Kun , Benic Giulia , Jaberi-Lashkari Nima , Cao Wen Xi , Khademi Alireza , Westwood J. Timothy , Sidhu Sachdev S. , Morris Quaid , Angers Stephane , Smibert Craig A. , Lipshitz Howard D.
Published: January 2020

G3BP RNA-binding proteins are important components of stress granules (SGs). Here we analyze the role ofDrosophilaG3BP, Rasputin (RIN), in unstressed cells, where RIN is not SG associated. Immunoprecipitation followed by microarray analysis identified over 550 mRNAs that copurify with RIN. The mRNAs found in SGs are long and translationally silent. In contrast, we find that RIN-bound mRNAs, which encode core components of the transcription, splicing and translation machinery, are short, stable and highly translated. We show that RIN is associated with polysomes and provide evidence for a direct role for RIN and its human homologs in stabilizing and upregulating the translation of their target mRNAs. We propose that when cells are stressed the resulting incorporation of RIN/G3BPs into SGs sequesters them away from their short target mRNAs. This would downregulate the expression of these transcripts, even though they are not incorporated into stress granules.
Small molecule inhibitors and a kinase-dead expressing mouse model demonstrate that the kinase activity of Chk1 is essential for mouse embryos and cancer cells
Authors: Muralidharan Somsundar V , Nilsson Lisa M , Lindberg Mattias F , Nilsson Jonas A
Published: January 2020

Chk1 kinase is downstream of the ATR kinase in the sensing of improper replication. Previous cell culture studies have demonstrated that Chk1 is essential for replication and Chk1 inhibitors are efficacious against tumors with high-level replication stress such as Myc-induced lymphoma cells. Treatment with Chk1 inhibitors also combines well with certain chemotherapeutic drugs and effects associates with induction of DNA damage and reduction of Chk1 protein levels. Most studies of Chk1 function has relied on the use of inhibitors. Whether or not a mouse or cancer cells could survive if a kinase-dead form of Chk1 is expressed has not been investigated before. Here we generate a mouse model that expresses a kinase-dead (D130A) allele in the mouse germline. We find that this mouse is overtly normal and does not have problems with erythropoiesis with ageing as previously been shown for a mouse expressing one null allele. However, similar to a null allele, homozygous kinase-dead mice cannot be generated and timed pregnancies of heterozygous mice suggest lethality of homozygous blastocysts at around the time of implantation. By breeding the kinase-dead Chk1 mouse with a conditional allele we are able to demonstrate that expression of only one kinase-dead allele, but no wildtype allele, ofChek1is lethal for Myc-induced cancer cells. Finally, treatment of melanoma cells with tumor-infiltrating T cells or CAR-T cells is effective even if Chk1 is inhibited, suggesting that Chk1 inhibitors can be safely administered in patients where immunotherapy is an essential component of the arsenal against cancer.
Translation is required for miRNA-dependent decay of endogenous transcripts
Authors: Biasini Adriano , de Pretis Stefano , Tan Jennifer Y. , Abdulkarim Baroj , Wischnewski Harry , Dreos Rene , Pelizzola Mattia , Ciaudo Constance , Marques Ana Claudia
Published: January 2020

Posttranscriptional repression by microRNA (miRNA) occurs through transcript destabilization or translation inhibition. Whereas RNA degradation explains most miRNA-dependent repression, transcript decay occurs co-translationally, raising questions regarding the requirement of target translation to miRNA-dependent transcript destabilization. To assess the contribution of translation to miRNA-mediated RNA destabilization, we decoupled these two molecular processes by dissecting the impact of miRNA loss of function on cytosolic long noncoding RNAs (lncRNAs). We show, that despite interacting with miRNA loaded RNA-induced silencing complex (miRISC), the steady state abundance and degradation rates of these endogenously expressed non-translated transcripts are minimally impacted by miRNA loss. To validate the requirement of translation for miRNA-dependent decay, we fused a miRISC bound lncRNA, whose levels are unaffected by miRNAs, to the 3’end of a protein-coding gene reporter and show that this results in its miRNA-dependent transcript destabilization. Furthermore, analysis of the few lncRNAs whose levels are regulated by miRNAs revealed these tend to associate with translating ribosomes and are likely misannotated micropeptides, further substantiating the necessity of target translation for miRNA-dependent transcript decay. Our analyses reveal the strict requirement of translation for miRNA-dependent transcript destabilization and demonstrate that the levels of coding and noncoding transcripts are differently affected by miRNAs.
Cultural variation impacts paternal and maternal genetic lineages of the Hmong-Mien and Sino-Tibetan groups from Thailand
Authors: Kutanan Wibhu , Shoocongdej Rasmi , Srikummool Metawee , Hübner Alexander , Suttipai Thanatip , Srithawong Suparat , Kampuansai Jatupol , Stoneking Mark
Published: January 2020

The Hmong-Mien (HM) and Sino-Tibetan (ST) speaking groups are known as hill tribes in Thailand; they were the subject of the first studies to show an impact of patrilocality vs. matrilocality on patterns of mitochondrial (mt) DNA vs. male-specific portion of the Y chromosome (MSY) variation. However, HM and ST groups have not been studied in as much detail; here we report and analyze 234 partial MSY sequences (∼2.3 mB) and 416 complete mtDNA sequences from 14 populations that, when combined with our previous published data, provides the largest dataset yet for the hill tribes. We find a striking difference between Hmong and IuMien (Mien-speaking) groups: the Hmong are genetically different from both the IuMien and all other Thai groups, whereas the IuMien are genetically more similar to other linguistic groups than to the Hmong. In general, we find less of an impact of patrilocality vs. matrilocality on patterns of mtDNA vs. MSY variation than previous studies. However, there is a dramatic difference in the frequency of MSY and mtDNA lineages of Northeast Asian (NEA) origin vs. Southeast Asian (SEA) origin in HM vs. ST groups: HM groups have high frequencies of NEA MSY lineages but lower frequencies of NEA mtDNA lineages, while ST groups show the opposite. A potential explanation is that the ancestors of Thai HM groups were patrilocal, while the ancestors of Thai ST groups were matrilocal. Overall, these results attest to the impact of cultural practices on patterns of mtDNA vs. MSY variation.
Risk Factors for Chikungunya Outbreak in Kebridhar City, Somali Ethiopia, 2019. Unmatched Case-Control Study
Authors: Alayu Mikias , Teshome Tesfalem , Amare Hiwot , Kinde Solomon , Belay Desalegn , Assefa Zewdu
Published: January 2020

Background

Chikungunya Virusis a Ribose Nucleic Acid (RNA) virus transmitted by a mosquito bite.Aedes AegyptiandAedes Albopictusare responsible vectors forChikungunya Virustransmission. CHIKV outbreaks are characterized by rapid spread and infection rates as high as 75%. A combination of health system efforts and healthy behavior practices by the community is essential for effective control.

Methods

Unmatched case control study was done to identify risk factors of this outbreak. One case to two controls ratios was calculated. All cases during the study period (74 cases) and 148 controls were included in the study. Bivariate and multivariable analysis were implemented. Serum samples were tested by Real Time Polymerase Chain Reaction at Ethiopian Public Health Institute laboratory.

Results

A total of 74 chikungunya fever cases were reported starting from 19thMay 2019 to 8thJune 2019. Not using bed net at day time sleeping (P- value < 0.001, AOR 20.8, 95CI 6.4 – 66.7), presence of open water holding container (P- value 0.023, AOR 4, 95CI 1.2 – 13.5), presence of larvae in water holding container (P- value 0.015, AOR 4.8, 95CI 1.4 – 16.8), ill person with similar sign and symptoms in the family or neighbors (P- value <0.001, AOR 27.9, 95CI 6.5 – 120.4) and wearing not full body cover clothes (P- value 0.002, AOR 8.1, 95CI 2.2 – 30.1) were significant risk factors.

Conclusion

Using bed nets at day time sleeping, cover the water holding containers, wearing full body cover cloths are protective factors.
Use of unmanned aerial vehicles (UAVs) for mark-resight nesting population estimation of adult female green sea turtles at Raine Island
Authors: Dunstan Andrew , Robertson Katherine , Fitzpatrick Richard , Pickford Jeff , Meager Justin
Published: January 2020

Nester abundance is a key measure of the performance of the world’s largest green turtle rookery at Raine Island, Australia. Abundance surveys have been undertaken in waters adjacent to Raine Island reef using mark-resight counts by surface observer (SO), underwater video (UWV) and unmanned aerial vehicle (UAV) (since 1984, 2013 and 2016 respectively). UAV and UWV may provide more cost-effective and less biased alternatives, but estimates must be comparable with the historical estimates. Here we compare the three methods.

The relative likelihood of resighting a marked turtle was significantly higher by SO than the other methods, which led to lower mark-resight population estimates than by UAV or UWV. Most (96%) variation in resighting probabilities was associated with survey period, with comparatively little variation between consecutive days of sampling or time of day. This resulted in preliminary correction factors of 1.53 and 1.73 from SO-UWV and SO-UAV, respectively. However, the SO and UWV estimates were the most similar when turtle densities were the lowest, suggesting that correction factors need to take into account turtle density and that more data are required.

We hypothesise that the UAV and UWV methods improved detection rates of marked turtles because they allowed subsequent review and frame-by-frame analysis, thus reducing observer search error. UAVs were the most efficient in terms of survey time, personnel commitment and weather tolerance compared to the SO and UWV methods.

This study indicates that using UAVs for in-water mark-resight turtle abundance estimation is an efficient and accurate method that can provide an accurate adjustment for historical abundance estimates. Underwater video may continue to be useful as a backup alternative to UAV surveys.
Meta-analysis of 139 extantTaraocean metagenomes to unveil the relationship between taxonomy and functionality in prokaryotes inhabiting aquatic ecosystems
Authors: Starke Robert
Published: January 2020

The total microbiome functionality of bacteria was recently predicted to be 35.5 ±0.2 million of KEGG functions. Logically, due to the limitation in space and resource availability of the local community, local functionality will only comprise a small subset of the total functionality but the relationship between taxonomy and functionality is still uncertain. Here, I used a meta-analysis of 139 extant Tara ocean seawater samples from 68 locations across to globe with information on prokaryotic taxonomy on species level from 16S metabarcoding and functionality of prokaryotes on eggNOG gene family level from metagenomes to unveil the relationship between taxonomy and functionality, and to predict the global distribution of functionality. Functional richness showed a statistically significant increase with increasing species richness (P <0.0001, R2=0.64) and increasing species diversity (P <0.0001, R2=0.26) while functional diversity was similar across the different waters, ranging from 2.96 to 3.22. Globally, the highest functional richness was found in the Northern Pacific Ocean and in the North Atlantic Ocean, and decreased at extreme latitudes. Taken together, I unveil the relationship between taxonomy and functionality, and predict the global distribution of functional richness in prokaryotes inhabiting aquatic ecosystems, implying more pronounced effects in terrestrial ecosystems due to larger differences in environmental parameters especially for functional diversity.
Absence of Sac2/INPP5F enhances the phenotype of a Parkinson’s disease mutation of synaptojanin 1
Authors: Cao Mian , Park Daehun , Wu Yumei , De Camilli Pietro
Published: January 2020

Many genes whose mutations cause, or increase the risk of, Parkinson’s disease (PD) have been identified. An inactivating mutation (R258Q) in the Sac inositol phosphatase domain of synaptojanin 1 (SJ1/PARK20), a phosphoinositide phosphatase implicated in synaptic vesicle recycling, results in PD. The gene encoding Sac2/INPP5F, another Sac domain containing protein, was identified as a PD risk locus by GWAS. Knock-In mice carrying the SJ1 patient mutation (SJ1RQKI) exhibit PD features, while Sac2 knockout mice (Sac2KO) do not have obvious neurological defects. We report a “synthetic” effect of the SJ1 mutation and the KO of Sac2 in mice. Most mice with both mutations died perinatally. The occasional survivors had stunted growth, died within 3 weeks, and showed abnormalities of striatal dopaminergic nerve terminals at an earlier stage than SJ1RQKI mice. The abnormal accumulation of endocytic factors observed at synapses of cultured SJ1RQKI neurons was more severe in double mutant. Our results suggest that SJ1 and Sac2 have partially overlapping functions and are consistent with a potential role of Sac2 as a PD risk gene.
The Linker Domain of SNAP25 Acts as a Flexible Molecular Spacer to Ensure Efficient S-Acylation
Authors: Salaun Christine , Greaves Jennifer , Tomkinson Nicholas C.O. , Chamberlain Luke H.
Published: January 2020

S-Acylation of the SNARE protein SNAP25 is mediated by a subset of Golgi zDHHC enzymes, in particular zDHHC17. The ankyrin repeat (ANK) domain of this enzyme interacts with a short linear motif known as the zDHHC ANK binding motif (zDABM) in SNAP25 (112-VVASQP-117), which is downstream of the S-acylated cysteine-rich domain (85-CGLCVCPC-92). In this study, we have investigated the importance of the flexible linker (amino acids 93-111; referred to as the “mini-linker” region) that separates the zDABM and S-acylated cysteines. Shortening the mini-linker had no effect of zDHHC17 interaction but blocked S-acylation. Insertion of additional flexible glycine-serine repeats had no effect on S-acylation, whereas extended and rigid alanine-proline repeats perturbed this process. Indeed, a SNAP25 mutant in which the mini-linker region was substituted with a flexible glycine-serine linker of the same length underwent efficient S-acylation. Furthermore, this mutant displayed the same intracellular localisation as wild-type SNAP25, showing that the sequence of the mini-linker is not important in this context. By using the results of previous peptide array experiments, we generated a SNAP25 mutant predicted to have a higher affinity zDABM, and this mutant showed enhanced interaction with zDHHC17 in cells. Interestingly, this mutant was S-acylated with reduced efficiency, implying that a lower affinity interaction of the SNAP25 zDABM with zDHHC17 is optimal for S-acylation efficiency. Overall, the results of this study show that amino acids 93-111 in SNAP25 act as a flexible molecular spacer to ensure efficient coupling of enzyme-substrate interaction and S-acylation.
Political connections, joint audit and tax avoidance: evidence from Islamic banking industry
Authors: Ajili Hana , Khlif Hichem
Published: January 2020

Purpose

The purpose of this paper is to examine the association between political connections and tax avoidance in Islamic banking industry and to test whether joint audit affects this relationship.

Design/methodology/approach

Tax avoidance is measured using effective tax rate while political connections represent an indicator variable that equals 1 if a bank has at least one politically connected director on the board of directors and zero otherwise.

Findings

This study documents that political connections are negatively associated with effective tax rate, while joint audit is positively related to the same variable. We also find that the negative association between political connections and effective tax rate becomes insignificant for joint-audited banks, while it remains negative and significant for banks audited by one auditors.

Originality/value

The findings of this study have policy implications for banking industry because joint audit reduces the adverse effect of political connections on tax avoidance.
Local responses to a national initiative on organised crime and local government procurement fraud
Authors: Doig Alan , Sproat Peter A.
Published: January 2020

Purpose

The purpose of this paper is to research how local councils in England responded to a national initiative intended to address the risk of the involvement of organised crime in local government procurement fraud. In so doing, it considers definitional issues before undertaking original research to explore how councils responded and, through in-depth interviews with three councils, what initial explanations may explain the responses. It concludes that the national initiative was insufficiently thought-through, and that councils’ responses were significantly influenced by the relevance of the threat of organised crime, financial constraints and competing priorities.

Design/methodology/approach

The case study involves a literature review, an analysis of official documentation, a questionnaire to local councils in the north of England and semi-structured interviews with anti-fraud practitioners in three councils in the northeast of England. The approach is to provide an analysis of the implementation of a national initiative to promote a local government response to procurement fraud by organised crime.

Findings

On the basis of original research, the paper proposes that the national initiative was insufficiently thought-through, and that councils’ responses were influenced by the relevance of the threat of organised crime, financial constraints and competing priorities.

Research limitations/implications

The research looks at a national initiative and how local councils responded within the context of financial and other constraints. The research is limited in terms of the range of responses it sought, and that it only studied the experience of three local councils in detail. On the other hand, its findings support further research into the implementation of national initiatives in terms of practice on the ground.

Practical implications

The findings identify issues surrounding the design and implementation of national anti-fraud policies from the perspective of local government and will be of value to practitioners and academics interested in fraud, policing, organised crime, local government and policy making.

Originality/value

The paper is the first study in the UK on the local implementation of national strategies on procurement fraud and organised crime and raises positive and less-positive aspects of how far national strategies and intentions are addressed on the ground, with a focus on what factors may influence local implementation.
Coexistence among morphologically similar hummingbird species is promoted via density compensation in a Mexican temperate forest
Authors: Lara Carlos , Curiel‐Durán Hugo Antonio , Castillo‐Guevara Citlalli
Published: January 2020

When limits on the exploitation of shared resources are exceeded among morphologically similar species, competitive exclusion and/or character displacement is expected. However, competition may not be sufficiently intense to engender these phenomena, but it may alter the densities of their local populations, a deterministic phenomenon known as density compensation. Hummingbirds are the most phenotypically specialized nectar‐feeding birds, and trait variation within their communities may facilitate finer resource partitioning, which is ideal to test hypotheses related to coexistence. Here, we used simulation models to investigate whether hummingbird ensembles with high morphological similarity to one or several competitors display a reduction in population density as a result of competition in two contrasting habitats (pine forest and second‐growth vegetation). In both habitats, four scenarios based on morphological proximity to neighbors were analyzed non‐parametrically using multivariate metrics. No evidence of density compensation was found in the pine forest in any scenario. Conversely, evidence of density compensation in the second‐growth habitat was found, with the relationship strongest when scenarios represented competition between more proximal neighbors. Our data suggest that the redistribution of hummingbird species between contrasting habitats leads to certain subgroups of morphologically similar species having to pay a population cost to coexist in a given habitat due to density compensation. Thus, competition may not be the leading determinant of hummingbird ensemble structures, which instead appears to be attributable to a combination of mechanisms that operate at local and regional scales, such as source‐sink dynamics.
“It is a different world in here”: collective identification and shared experiential knowledge between psychiatric inpatients
Authors: Kessing Malene L.
Published: January 2020

This paper explores the social relations between inpatients in psychiatric wards. Combining Barker's (2002) concept of ‘collective illness identity’ with Nelson's (1993) concept of ‘epistemological communities’, I draw attention to the inpatients’ collective identification and experiential knowledge. Through the analysis, three aspects of the inpatients’ relationships are unfolded. First, how the inpatients, through bodily expressions and narrative accounts, construct a collective illness identity based on shared experiences of symptoms and suffering. Second, the ways in which the inpatients use their shared experiential knowledge to support one another and challenge the mental health professionals. Third, how the inpatients’ reflections on the long‐term potential of their relationships reveal a number of concerns related to their continuation. Centrally, the paper points to the potential and challenges that arise from the inpatients’ relations to one another and their embeddedness in a specific time and space. Empirically, the paper draws on five months of participant observation conducted in two psychiatric wards in Denmark and interviews with 14 psychiatric patients.
Potential carcinogenic heterocyclic aromatic amines (HAAs) in foodstuffs: Formation, extraction, analytical methods, and mitigation strategies
Authors: Dong Hao , Xian Yanping , Li Haixia , Bai Weidong , Zeng Xiaofang
Published: January 2020

During the heat treatment of proteinaceous food, heterocyclic aromatic amines (HAAs), a kind of strong mutagens/carcinogens are formed. HAAs can be classified into two major groups based on the heating temperature, which are thermic HAAs generally formed in 150 to 300 °C and pyrolytic HAAs produced above 300 °C. This review focuses on the formation mechanisms of HAAs and identifies different mechanisms of the formation of HAAs in foodstuffs. Moreover, an overview of the available extraction, purification methods, and instrumental analytical methods in the last two decades is shown to determine the HAAs in various foodstuffs. Finally, based on the factors that affect the formation of HAAs in heat‐processed foodstuffs, such as the cooking method, food type, the recipe, and the content of substances with enhancing or inhibiting effects on the formation of HAAs, this review also highlights the most promising strategies for mitigating HAAs, which include adjusting cooking methods or process conditions, adding natural product extracts, antioxidants or other compounds, or reasonable selection of types of foodstuff. The review intends to provide a broad but comprehensive understanding of the formation, extraction, purification, analytical methods, and possible mitigation strategies for isolated and identified HAAs.
Intimate partner violence screening and response in New South Wales emergency departments: A multi‐site feasibility study
Authors: Spangaro Jo , Vajda Jacqualine , Klineberg Emily , Lin Sen , Griffiths Chris , Saberi Elham , Field Emma , Miller Alex , McNamara Lorna
Published: January 2020

Objective

To test feasibility of a systematic approach to routine screening and response for intimate partner violence among women presenting to three New South Wales EDs.

Methods

This prospective feasibility study was conducted over 6 months in two rural and one major tertiary metropolitan ED in New South Wales. Women aged 16–45 years triaged category 3–5 (treat within 30 min/1 h/2 h), who could be approached privately, were screened for intimate partner violence using the validated HITS (Hurts, Insults, Threatens and Screams or Swears) tool. The follow‐up protocol for patients who disclosed abuse, specified a social work/psychology (psychosocial) response within 1 h. Outcomes of interest were screening rates of eligible presentations, disclosures of abuse, psycho‐social referral and responses. Interviews conducted with ED medical directors and nurse unit managers at each site explored barriers and facilitators.

Results

A total of 1047 women (11.4% of eligible presentations) completed screening at their first or subsequent presentation. Of 868 women screened on first presentation, 18% (n= 154) disclosed intimate partner violence, with no significant differences by age group, country of birth, triage category or time/day of arrival. Key barriers to screening were high patient volume, absence of electronic prompts and lack of privacy. Of those who screened positive 49% (n= 75) received an immediate, on‐site psycho‐social response.

Conclusion

The present study demonstrates that it is both possible and relevant, given the 18% disclosure rate, to screen women in relation intimate partner violence in EDs and provide a psycho‐social response within 1 h. More needs to be done to address barriers to screening to provide opportunities for early intervention.
Clarification of apple juices with vegetable proteins monitored by multiple light scattering
Authors: Ramezani Mohsen , Ferrentino Giovanna , Morozova Ksenia , Kamrul S. M. Hasan , Scampicchio Matteo
Published: January 2020

This work proposes a novel approach based on the real‐time monitoring of the fining process of apple juices by static multiple light scattering. The change in transmission was used to determine the fining effectiveness of three vegetable proteins, respectively, red lentil, green lentil, and green pea proteins. Further treatment with gelatin‐bentonite was used as a control. The modified Gompertz function was applied to fit the transmission signals. According to (1) the rate of flocculation and (2) the rate of sedimentation, the best fining efficiency was achieved by red lentil, which was similar to that of gelatin‐bentonite and higher than green lentil and green pea proteins. This ranking was obtained at any dose from 60 to 900 mg per liter of juice. The results suggest the use of red lentil as a potential fining agent for apple juices and highlight the advantages of using static multiple light scattering technique as a quality control tool for studying the kinetics of the fining process.

Practical Application

The study proposed the use of vegetable proteins as fining agents for apple juices. Their efficiency was ably monitored in real time by static multiple light scattering.
Quantifying the human milk oligosaccharides 2’‐fucosyllactose and 3‐fucosyllactose in different food applications by high‐performance liquid chromatography with refractive index detection
Authors: Christensen Anne Støvlbæk , Skov Sabina Holm , Lendal Sara Eun , Hornshøj Bettina Høj
Published: January 2020

In recent years, production of biosynthesized human milk oligosaccharides (HMOs) has become scalable to industrial standards. As a result, infant formula fortified with 2’‐fucosyllactose (2’‐FL), the most abundant HMO in human breast milk, is now commercially available. 2’‐FL and 3‐fucosyllactose (3‐FL), another abundant HMO, are thought to be beneficial for infant health and development. Products containing HMOs are projected to expand in the future, showing the need for robust, easily applicable analytical methods for the quantitative assessment of HMOs in different food applications. We present here a validated high‐performance liquid chromatography method for the quantification of 2’‐FL and 3‐FL in whole milk, infant formula, and cereal bars. The sample preparation was simple dispersion and extraction of the sample. The samples were analyzed by hydrophilic interaction liquid chromatography with refractive index detection and a runtime of 19 min. The method had a high degree of linearity (R2 > 0.9995) in the range 0.2 to 12 mg/mL. The recovery for 2’‐FL was 88% to 105% and for 3‐FL 94% to 112%. The limit of detection (LOD) for whole milk was 0.1 mg/mL for 2’‐FL and 0.2 mg/mL for 3‐FL. In infant formula and cereal bars, the LOD was 0.6 mg/g for both 2’‐FL and 3‐FL. To show the practical application of this method, it was successfully utilized in stability studies of 2’‐FL and 3‐FL in whole milk, UHT milk, and yoghurt. The method provides a means of simultaneous and robust quantification of 2’‐FL and 3‐FL in various food matrices with high accuracy and high reproducibility.

Practical Application

2’‐Fucosyllactose (2’‐FL) and 3‐fucosyllactose (3‐FL) are two of the most abundant human milk oligosaccharides (HMOs) present in human breast milk. We present a fast HPLC method for the robust quantification of these two compounds in infant formula, whole milk, UHT milk, cereal bars, and yoghurt. This method can easily be set up by food producers and researchers to analyze the dosage of 2’‐FL and 3‐FL in their product or perform shelf life studies in different food applications.
Rate‐All‐That‐Apply (RATA) comparison of taste profiles for different sweeteners in black tea, chocolate milk, and natural yogurt
Authors: Tan Vicki Wei Kee , Wee May Sui Mei , Tomic Oliver , Forde Ciarán G.
Published: January 2020

Growing health concerns have increased interest in reducing the consumption of added sugars, which can be achieved by substituting or replacing sugar with sweeteners to maintain sensory intensity and quality. The growing availability of sweeteners has increased the complexity of the perceptual landscape as sweeteners differ in the qualitative, intensity, and temporal properties. A sweetener that can match the perceptual properties of sucrose in different food matrices is likely to have broad applications. In complex foods, sweetness is influenced by the taste interactions with the existing tastants and possible matrix effects that influence release and perception of sweetness. The current study compared the taste properties of three food matrices (black tea, chocolate milk, and natural yogurt) sweetened by sucrose to those sweetened using eight different sweeteners (acesulfame‐K, aspartame, erythritol, luo han guo (Mogroside), palatinose (iso‐maltulose), stevia (Reb‐A), sucralose, and sucrose–allulose mixture) using Rate‐All‐That‐Apply. The sensory properties of each sweetener differed across matrices, with sucrose–allulose mixture, aspartame, erythritol, palatinose, and sucralose having the most similar taste to sucrose across all foods. By contrast, acesulfame‐K, stevia, and luo han guo had taste profiles that most varied from sucrose, characterized by side tastes such as bitterness, chemical taste, and a low sweetness. Sweeteners differed most from sucrose when presented in natural yogurt compared to tea and chocolate milk. A food's taste properties can suppress sweetness intensity and promote undesirable side tastes. Taken together, these findings highlight the importance of testing sweeteners in complex foods and help identify sweeteners and sweetener combinations that can replicate the sweetness of sucrose and support sugar reduction.

Practical Application

Food manufacturers and researchers can refer to the results of the sensory profiles to identify suitable sweeteners substitutes for sucrose in foods with similar taste profiles to those tested. The current article highlights important changes to sweetener sensory properties when presented in different complex foods, and provides an indication of the potential for calorie reduction by substituting sucrose with a range of low or no calorie sweeteners.