bluuebunny/crossref_metadata_2025 huggingface dataset:
Galectin-3, A Novel Endogenous Trem2 Ligand, Regulates Inflammatory Response and Aβ Fibrilation in Alzheimer’s Disease
Authors: Boza-Serrano Antonio , Ruiz Rocío , Sanchez-Varo Raquel , Yang Yiyi , García-Revilla Juan , Jimenez-Ferrer Itzia , Paulus Agnes , Wennström Malin , Vilalta Anna , Allendorf David , Davila Jose Carlos , Dunning Christopher , Stegmayr John , Jiménez Sebastian ,   The Netherland Brain, Roca-Ceballos Maria Angustias , Navarro-Garrido Victoria , Swanberg Maria , Hsieh Christine L. , Miguel-Real Luis , Englund Elisabet , Linse Sara , Leffler Hakon , Nilsson Ulf J. , Gutierrez Antonia , Brown Guy C. , Vitorica Javier , Venero Jose Luis , Deierborg Tomas
Published: December 2018

Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, intraneuronal tau neurofibrillary tangles and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer’s disease) mice, and found specifically expressed in microglia associated with Aβ plaques. Single nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated to an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data demonstrated the requirement of gal3 to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Electron microscopy of gal3 in AD mice demonstrated i) a preferential expression of gal3 by plaque-associated microglia, ii) its presence in the extracellular space and iii) its association to Aβ plaques. Low concentrations (1 nM) of pure gal3 promoted cross-seeding fibrilization of pure Aβ. Importantly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of insoluble Aβ aggregates that were absent when gal3 was lacking. High-resolution microscopy (STORM) demonstrated close co-localization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 CRD domain. Furthermore, gal3 stimulated the TREM2-DAP12 signaling pathway. In conclusion, we provide evidence that gal3 is a central regulator of microglial immune response in AD. It drives proinflammatory activation and Aβ aggregation, as well as acting as an endogenous ligand to TREM2, a key receptor driving microglial response under disease conditions. Gal3 inhibition may, hence, be a potential pharmacological approach to counteract AD.
Biomass segregation between biofilm and flocs improves the control of nitrite-oxidizing bacteria in mainstream partial nitritation and anammox processes
Authors: Laureni Michele , Weissbrodt David G. , Villez Kris , Robin Orlane , de Jonge Nadieh , Rosenthal Alex , Wells George , Nielsen Jeppe Lund , Morgenroth Eberhard , Joss Adriano
Published: December 2018

The control of nitrite-oxidizing bacteria (NOB) challenges the implementation of partial nitritation and anammox (PN/A) processes under mainstream conditions. The aim of the present study was to understand how operating conditions impact microbial competition and the control of NOB in hybrid PN/A systems, where biofilm and flocs coexist. A hybrid PN/A moving-bed biofilm reactor (MBBR; also referred to as integrated fixed film activated sludge or IFAS) was operated at 15 °C on aerobically pre-treated municipal wastewater (23 mgNH4-N·L−1). Ammonium-oxidizing bacteria (AOB) and NOB were enriched primarily in the flocs, and anammox bacteria (AMX) in the biofilm. After decreasing the dissolved oxygen concentration (DO) from 1.2 to 0.17 mgO2·L−1 - with all other operating conditions unchanged - washout of NOB from the flocs was observed. The activity of the minor NOB fraction remaining in the biofilm was suppressed at low DO. As a result, low effluent NO3− concentrations (0.5 mgN·L−1) were consistently achieved at aerobic nitrogen removal rates (80 mgN·L−1·d−1) comparable to those of conventional treatment plants. A simple dynamic mathematical model, assuming perfect biomass segregation with AOB and NOB in the flocs and AMX in the biofilm, was able to qualitatively reproduce the selective washout of NOB from the flocs in response to the decrease in DO-setpoint. Similarly, numerical simulations indicated that flocs removal is an effective operational strategy to achieve the selective washout of NOB. The direct competition for NO2− between NOB and AMX - the latter retained in the biofilm and acting as a “NO2-sink” - was identified by the model as key mechanism leading to a difference in the actual growth rates of AOB and NOB (i.e., μNOB < μAOB in flocs) and allowing for the selective NOB washout. Experimental results and model predictions demonstrate the increased operational flexibility, in terms of variables that can be easily controlled by operators, offered by hybrid systems as compared to solely biofilm systems for the control of NOB in mainstream PN/A applications.

Highlights

Hybrid PN/A systems provide increased operational flexibility for NOB control

AOB and NOB enrich primarily in the flocs, and AMX in the biofilm (“NO2-sink”)

AMX use NO2− allowing to differentiate AOB and NOB growth rates

A decrease in DO or an increase in floc removal leads to selective NOB washout from flocs

The activity of the minor NOB fraction in the biofilm is suppressed at limiting DO
Mesenchymal stromal cells release CXCL1/2/8 and induce chemoresistance and macrophage polarization
Authors: Couderc Bettina , Le Naour Augustin , Prat Mélissa , Mevel Renaud , Thibault Benoit , Lemaitre Lea , Leray Helene , Golzio Muriel , Lefevre Lise , Mery Eliane , Martinez Alejandra , Ferron Gwenael , Delord Jean-Pierre , Coste Agnès
Published: December 2018

Factors released by surrounding cells such as cancer-associated mesenchymal stromal cells (CA-MSCs) are involved in tumor progression and chemoresistance. We determine the mechanisms by which a naïve MSC could become a CA-MSC and characterize CA-MSCs. Ovarian tumor cells (OTC) trigger the transformation of MSCs to CA-MSCs expressing different pro-tumoral, genes and secreting high amounts of CXCR1/2 ligands (CXCL1, CXCL2 and IL-8) implicated in the chemoresistance of cancer cells. CXCR1/2 ligands can also inhibit the immune response against OTC. Indeed, through their released factors, CA-MSCs can trigger the differentiation of monocytes to pro-tumoral M2 phenotype macrophages known to promote the tumor progression. When CXCR1/2 receptors are inhibited, these CA-MSC-activated macrophages lose their M2 functions and acquire an anti-tumoral phenotype. Both ex vivo and in vivo a CXCR1/2 inhibitor can sensitize OTC to carboplatin even in the presence of a pro-tumoral microenvironment. This inhibitor can circumvent the pro-tumoral effects of CA-MSCs. As high concentrations of CXCR1/2 ligands in blood from patients can be associated with chemoresistance, CXCR1/2 inhibition could be a potential therapeutic strategy to revert chemoresistance.
Enrichment of short mutant cell-free DNA fragments enhanced detection of pancreatic cancer
Authors: Liu Xiaoyu , Liu Lingxiao , Ji Yuan , Li Changyu , Wei Tao , Yang Xuerong , Zhang Yuefang , Cai Xuyu , Yang Ting , Gao Yangbin , Xu Weihong , Rao Shengxiang , Jin Dayong , Lou Wenhui , Qiu Zilong , Wang Xiaolin
Published: December 2018

Analysis of cell-free DNA (cfDNA) is promising for broad applications in clinical settings, but with significant bias towards late-stage cancers. Although recent studies have discussed the diverse and degraded nature of cfDNA molecules, little is known about its impact on the practice of cfDNA analysis. Here we reported a new targeted sequencing by combining single-strand library preparation and target capture (SLHC-seq). By applying the new technology in plasma cfDNA from pancreatic cancer patients, we achieved higher efficiency in analysis of mutations than previously reported using other detection assays. SLHC-seq rescued short or damaged cfDNA fragments along to increase the sensitivity and accuracy of circulating-tumor DNA detection. Most importantly, we found that the small mutant fragments are prevalent in early-stage patients, which provides strong evidence for fragment size-based early detection of pancreatic cancer. Collectively, the new pipeline enhanced our understanding of cfDNA biology and provide new insights for liquid biopsy.
The skull of StW 573, a 3.67 Ma Australopithecus skeleton from Sterkfontein Caves, South Africa
Authors: Clarke Ronald J , Kuman Kathleen
Published: December 2018

Here we present the first full anatomical description of the 3.67 million-year-old Australopithecus skull StW 573 that was recovered with its skeleton from the Sterkfontein Member 2 breccia in the Silberberg Grotto. Analysis demonstrates that it is most similar in multiple key morphological characters to a group of fossils from Sterkfontein Member 4 and Makapansgat that are here distinguished morphologically as A. prometheus. This taxon contrasts with another group of fossils from those sites assigned to A. africanus. The anatomical reasons for why these groupings should not be lumped together (as is frequently done for the South African fossils) are discussed in detail. In support of this classification, we also present for the first time a palate (StW 576 from Sterkfontein Member 4) newly reconstructed by RJC, which has a uniquely complete adult dentition of an A. africanus. The StW 573 skull also has certain similarities with other earlier Australopithecus fossils in East Africa, A. afarensis and A. anamensis, which are discussed. One of its most interesting features is a pattern of very heavy anterior dental wear unlike that found in A. africanus but resembling that found in A. anamensis at 4.17 Ma. While StW 573 is the only hominid fossil in Sterkfontein Member 2, we conclude that competitive exclusion probably accounts for the synchronous and sympatric presence of two species of Australopithecus in the younger deposits at Makapansgat and Sterkfontein Member 4. Because the StW 573 skull is associated with a near-complete skeleton that is also described for the first time in this special issue, we are now able to use this individual to improve our understanding of more fragmentary finds in the South African fossil record of Australopithecus.
Evolution of the HIV-1 RRE during natural infection reveals nucleotide changes that correlate with altered structure and increased activity over time
Authors: Sherpa Chringma , Jackson Patrick E. H. , Gray Laurie R. , Anastos Kathryn , Le Grice Stuart F. J. , Hammarskjold Marie-Louise , Rekosh David
Published: December 2018

The HIV-1 Rev Response Element (RRE) is acis-acting RNA element characterized by multiple stem-loops. Binding and multimerization of the HIV Rev protein on the RRE promotes nucleocytoplasmic export of incompletely spliced mRNAs, an essential step in HIV replication. Most of our understanding of the Rev-RRE regulatory axis comes from studies of lab-adapted HIV clones. However, in human infection, HIV evolves rapidly and mechanistic studies of naturally occurring Rev and RRE sequences are essential to understanding this system. We previously described the functional activity of two RREs found in circulating viruses in a patient followed during the course of HIV infection. The “early” RRE was less functionally active than the “late” RRE despite differing in sequence by only four nucleotides. In this study, we describe the sequence, function, and structural evolution of circulating RREs in this patient using plasma samples collected over six years of untreated infection. RRE sequence diversity varied over the course of infection with evidence of selection pressure that led to sequence convergence as disease progressed. An increase in RRE functional activity was observed over time, and a key mutation was identified that correlates with a major conformational change in the RRE and increased functional activity. Additional mutations were found that may have contributed to increased activity as a result of greater Shannon entropy in RRE stem-loop II, which is key to primary Rev binding.

Importance

HIV-1 replication requires interaction of the viral Rev protein with acis-acting regulatory RNA, the Rev Response Element (RRE), whose sequence changes over time during infection within a single host. In this study, we show that the RRE is subject to selection pressure and that RREs from later time points in infection tend to have higher functional activity. Differences in RRE functional activity are attributable to specific changes in RNA structure. Our results suggest that RRE evolution during infection may be important for HIV pathogenesis and that efforts to develop therapies acting on this viral pathway should take this into account.
optoPAD: a closed-loop optogenetics system to study the circuit basis of feeding behaviors
Authors: Moreira José-Maria , Itskov Pavel M. , Goldschmidt Dennis , Steck Kathrin , Walker Samuel J. , Ribeiro Carlos
Published: December 2018

The regulation of feeding plays a key role in determining the fitness of animals through its impact on nutrition. Elucidating the circuit basis of feeding and related behaviors is an important goal in neuroscience. We recently used a system for closed-loop optogenetic manipulation of neurons contingent on the fly’s feeding behavior to dissect the impact of a specific subset of taste neurons on yeast feeding (Steck et al., 2018). Here we describe the development and validation of this system, which we term the optoPAD. We use the optoPAD to induce appetitive and aversive effects on feeding by activating or inhibiting gustatory neurons in closed loop – effectively creating virtual taste realities. The use of optogenetics allowed us to vary the dynamics and probability of stimulation in single flies and assess the impact on feeding behavior quantitatively and with high throughput. These data demonstrate that the optoPAD is a powerful tool to dissect the circuit basis of feeding behavior, allowing the efficient implementation of sophisticated behavioral paradigms to study the mechanistic basis of animals’ adaptation to dynamic environments.
Discovery of cancer driver genes based on nucleotide context
Authors: Dietlein Felix , Weghorn Donate , Taylor-Weiner Amaro , Richters André , Reardon Brendan , Liu David , Lander Eric S. , Van Allen Eliezer M. , Sunyaev Shamil R.
Published: December 2018

Many cancer genomes contain large numbers of somatic mutations, but few of these mutations drive tumor development. Current approaches to identify cancer driver genes are largely based on mutational recurrence, i.e. they search for genes with an increased number of nonsynonymous mutations relative to the local background mutation rate. Multiple studies have noted that the sensitivity of recurrence-based methods is limited in tumors with high background mutation rates, because passenger mutations dilute their statistical power. Here, we observe that passenger mutations tend to occur in characteristic nucleotide sequence contexts, while driver mutations follow a different distribution pattern determined by the location of functionally relevant genomic positions along the protein-coding sequence. To discover new cancer genes, we searched for genes with an excess of mutations in unusual nucleotide contexts that deviate from the characteristic context around passenger mutations. By applying this statistical framework to whole-exome sequencing data from 12,004 tumors, we discovered a long tail of novel candidate cancer genes with mutation frequencies as low as 1% and functional supporting evidence. Our results show that considering both the number and the nucleotide context around mutations helps identify novel cancer driver genes, particularly in tumors with high background mutation rates.
Dissociated cortical phase- and amplitude-coupling patterns in the human brain
Authors: Siems Marcus , Siegel Markus
Published: December 2018

Coupling of neuronal oscillations may reflect and facilitate the communication between neuronal populations. Two primary neuronal coupling modes have been described: phase-coupling and amplitude-coupling. Theoretically, both coupling modes are independent, but so far, their neuronal relationship remains unclear. Here, we combined MEG, source-reconstruction and simulations to systematically compare cortical phase-coupling and amplitude-coupling patterns in the human brain. Importantly, we took into account a critical bias of amplitude-coupling measures due to phase-coupling. We found differences between both coupling modes across a broad frequency range and most of the cortex. Furthermore, by combining empirical measurements and simulations we ruled out that these results were caused by methodological biases, but instead reflected genuine neuronal amplitude coupling. Overall, our results suggest that cortical phase- and amplitude-coupling patterns are non-redundant, which may reflect at least partly distinct neuronal mechanisms. Furthermore, our findings highlight and clarify the compound nature of amplitude coupling measures.

Highlights

Systematic comparison of cortical phase- and amplitude-coupling patterns

Demonstration of genuine amplitude coupling independent of phase coupling bias

Amplitude- and phase coupling patterns differ across many cortical regions and frequencies
Species-specific strategies increase unpredictability of escape flight in eared moths
Authors: Hügel Theresa , Goerlitz Holger R.
Published: December 2018

Many prey animals form mixed-species groups. Mixed-species groups provide various benefits ranging increased food intake to increased chance of predator detection. The escape-tactic diversity hypothesis predicts another benefit. It postulates that the overall unpredictability of evasive movement is increased if multiple species with different evasive tactics mix, resulting in enhanced predator protection for the whole group. Echolocating bats and eared moths are a textbook example of predator-prey interactions. Moths exhibit evasive flight with diverse tactics; however, the variability of their evasive flight within and between species has never been systematically quantified. We therefore recorded flight strength of eight moth species in response to the same level of simulated bat predation. We show species-specific and size-independent differences in both overall flight strength and in change of flight strength over time, confirming the escape-tactic diversity hypothesis for eared moths. Additionally, we show strong inter-individual differences in evasive flight within some species. This diversity in escape tactic between eared moths increases the overall unpredictability of their evasive flight in mixed-species groups, likely providing better protection against predatory bats for the single individual.
The chaperone-client network subordinates cell-cycle entry to growth and stress
Authors: Moreno David F , Parisi Eva , Yahya Galal , Vaggi Federico , Csikasz-Nagy Attila , Aldea Martí
Published: December 2018

The precise coordination of growth and proliferation has a universal prevalence in cell homeostasis. As a prominent property, cell size is modulated by the coordination between these processes in bacterial, yeast and mammalian cells, but the underlying molecular mechanisms are largely unknown. Here we show that multifunctional chaperone systems play a concerted and limiting role in cell-cycle entry, specifically driving nuclear accumulation of the G1 Cdk-cyclin complex. Based on these findings, we establish and test a molecular competition model that recapitulates cell-cycle-entry dependence on growth rate. As key predictions at a single-cell level, we show that availability of the Ydj1 chaperone and nuclear accumulation of the G1 cyclin Cln3 are inversely dependent on growth rate and readily respond to changes in protein synthesis and stress conditions that alter protein folding requirements. Thus, chaperone workload would subordinate Start to the biosynthetic machinery and dynamically adjust proliferation to the growth potential of the cell.
Structural venomics: evolution of a complex chemical arsenal by massive duplication and neofunctionalization of a single ancestral fold
Authors: Pineda Sandy S. , Chin Yanni K-Y. , Undheim Eivind A.B. , Senff Sebastian , Mobli Mehdi , Dauly Claire , Escoubas Pierre , Nicholson Graham M. , Kaas Quentin , Mattick John S. , King Glenn F.
Published: December 2018

Spiders are the most successful venomous animals on the planet, with more than 47,000 extant species. Most spider venoms are dominated by disulfide-rich peptides (DRPs) with a diverse range of pharmacological activities. Although some venoms contain thousands of unique peptides, little is known about the mechanisms used to generate such complex chemical arsenals. We used a combined transcriptomic, proteomic and structural biology approach to demonstrate that the lethal Australian funnel-web spider produces 33 superfamilies of venom peptides and proteins, more than described for any other arachnid. We show that 15 of the 26 DRP superfamilies form an ultra-stable inhibitor cystine knot motif, and that these DRPs are the major contributor to the diversity of the venom peptidome. NMR data reveal that most of these DRPs are structurally related and range in complexity from simple to highly elaborated knottin domains that likely evolved from a single ancestral fold.
Lgr5+ stem/progenitor cells reside at the apex of the embryonic hepatoblast pool
Authors: Prior Nicole , Hindley Christopher J , Rost Fabian , Melendez Esteban Elena , Lau Winnie W. Y. , Gottgens Berthold , Rulands Steffen , Simons Benjamin D , Huch Meritxell
Published: December 2018

During mouse embryogenesis, progenitors within the liver known as hepatoblasts give rise to adult hepatocyte and cholangiocyte cells. Hepatoblasts, which are specified at E8.5-E9.0, have been regarded as a homogeneous population of progenitors, which initiate differentiation into hepatocytes and cholangiocytes from E13.5 onwards. Recently, sub-populations of transcriptionally different hepatoblasts have been identified as already present at E11.5 by single cell RNAseq (scRNAseq) analysis. However, whether these transcriptional differences result from functionally heterogeneous hepatoblast populations is unknown. Here we show that the hepatoblast pool is not only transcriptionally but also functionally heterogeneous and that a sub-population of E9.5-E10.0 hepatoblasts exhibits a previously unidentified early commitment to cholangiocyte fate. Importantly, we also identify a sub-population of bona-fide E9.5 hepatoblasts which express the adult stem cell marker Lgr5 and contribute to liver development by generating both hepatocyte and cholangiocyte progeny that persist for the life-span of the mouse. Using a combination of lineage tracing and scRNAseq, we show that Lgr5 marks E9.5-E10.0 bi-potent liver progenitors residing at the apex of a hierarchy of the hepatoblast population. Notably, isolated Lgr5+ hepatoblasts can be clonally expanded in vitro into embryonic liver organoids, which can commit to hepatocyte or cholangiocyte fates dependent upon the culture conditions. Our study represents the first functional demonstration of heterogeneity within E9.5 hepatoblasts and identifies Lgr5 as a marker for a sub-population of truly bi-potent liver progenitors.
The STROBE: a system for closed-looped optogenetic control of freely feeding flies
Authors: Musso Pierre-Yves , Junca Pierre , Jelen Meghan , Feldman-Kiss Damian , Zhang Han , Chan Rachel C.W. , Gordon Michael D.
Published: December 2018

Manipulating feeding circuits in freely moving animals is challenging, in part because the timing of sensory inputs is affected by the animal’s behavior. To address this challenge in Drosophila, we developed the Sip-Triggered Optogenetic Behavior Enclosure (“STROBE”). The STROBE is a closed-looped system for real-time optogenetic activation of feeding flies, designed to evoke neural excitation coincident with food contact. We demonstrate that optogenetic stimulation of sweet sensory neurons in the STROBE drives attraction to tasteless food, while activation of bitter sensory neurons promotes avoidance. Moreover, feeding behavior in the STROBE is modified by the fly’s internal state, as well as the presence of chemical taste ligands. We also find that mushroom body dopaminergic neurons and their respective post-synaptic partners drive opposing feeding behaviors following activation. Together, these results establish the STROBE as a new tool for dissecting fly feeding circuits and suggest a role for mushroom body circuits in processing naïve taste responses.
Mitogenomes illuminate the origin and migration patterns of the indigenous people of the Canary Islands
Authors: Fregel Rosa , Ordóñez Alejandra C. , Santana-Cabrera Jonathan , Cabrera Vicente M. , Velasco-Vazquez Javier , Alberto Verónica , Moreno-Benítez Marco A. , Delgado-Darias Teresa , Rodríguez-Rodríguez Amelia del Carmen , Hernández Juan Carlos , Pais Jorge , González-Montelongo Rafaela , Lorenzo-Salazar José M. , Flores Carlos , de Mercadal M. Carmen Cruz , Álvarez-Rodríguez Nuria , Shapiro Beth , Arnay Matilde , Bustamante Carlos D.
Published: December 2018

The Canary Islands’ indigenous people have been the subject of substantial archaeological, anthropological, linguistic and genetic research pointing to a most probable North African Berber source. However, neither agreement about the exact point of origin nor a model for the indigenous colonization of the islands has been established. To shed light on these questions, we analyzed 48 ancient mitogenomes from 25 archaeological sites from the seven main islands. Most lineages observed in the ancient samples have a Mediterranean distribution, and belong to lineages associated with the Neolithic expansion in the Near East and Europe (T2c, J2a, X3a…). This phylogeographic analysis of Canarian indigenous mitogenomes, the first of its kind, shows that some lineages are restricted to Central North Africa (H1cf, J2a2d and T2c1d3), while others have a wider distribution, including both West and Central North Africa, and, in some cases, Europe and the Near East (U6a1a1, U6a7a1, U6b, X3a, U6c1). In addition, we identify four new Canarian-specific lineages (H1e1a9, H4a1e, J2a2d1a and L3b1a12) whose coalescence dates correlate with the estimated time for the colonization of the islands (1stmillennia CE). Additionally, we observe an asymmetrical distribution of mtDNA haplogroups in the ancient population, with certain haplogroups appearing more frequently in the islands closer to the continent. This reinforces results based on modern mtDNA and Y-chromosome data, and archaeological evidence suggesting the existence of two distinct migrations. Comparisons between insular populations show that some populations had high genetic diversity, while others were probably affected by genetic drift and/or bottlenecks. In spite of observing interinsular differences in the survival of indigenous lineages, modern populations, with the sole exception of La Gomera, are homogenous across the islands, supporting the theory of extensive human mobility after the European conquest.
Health seeking behaviour and cost of fever treatment to households in a malaria endemic setting of northern Ghana: A cross sectional study
Authors: Dalaba Maxwell , Akweongo Patricia , Adongo Philip Baba , Dalinjong Philip Ayizem , Chatio Samuel , Oduro Abraham
Published: December 2018

Background

This study examined the health seeking behaviours and cost of treatment of malaria to households in the Kassena-Nankana district of Ghana.

Methods

A cross-sectional household survey was conducted between July and September 2015. Individuals who had an episode of fever or malaria in the past two weeks identified during routine Health and Demographic Surveillance System data collection were selected for the study. Socio-demographic characteristics, treatment seeking behaviours and cost of treatment of malaria were obtained from the patient perspective.

Results

Out of the 1,845 households visited, 21.3% (393/1,845) reported to have had an episode of fever or malaria in the past two weeks. Of the 393 people with malaria, 66.9% (263/393) reported taking an antimalarial. About 53.6% (141/263) of the antimalarials were obtained from formal healthy facilities. About 36.1% (95/263) reported to have taken Dihydroartemisinin-piperaquine, 35.4% (93/263) took Artesunate–Amodiaquine and 21.7% (57/263) took Artemether-Lumefantrine. Only 49.6%% (195/393) of the study participants had their blood sample taken for illness (microscopic or Rapid Diagnostic Test). Only 23.6% (62/263) took antimalarial within 24 hours of the onset of illness. The overall average costs (direct and indirect cost) incurred by households per malaria treatment was GH¢27.82/US$7.32 (range: GH¢0.2/ US$0.05 - GH¢200/ US$52.63). The average cost incurred in the treatment of malaria by those who were enrolled into the National Health Insurance Scheme (NHIS) was GH¢24.75/US$6.51 and those not enrolled was GH¢43.95/US$11.57.

Conclusions

Prompt treatment such as treatment within 24 hours of onset of malaria was low. The average costs to households per malaria treatment was GH¢27.82/US$7.32 and the preferred antimalarial was Dihydroartemisinin-piperaquine. There was a positive effect of NHIS enrolment on cost of treatment as the insured incurred less cost (US$5 less) in treatment than the uninsured.
Cross-Lagged Panel Model in Medical Research: A Cautionary Note
Authors: Usami Satoshi , Todo Naoya , Murayama Kou
Published: December 2018

Longitudinal designs provide a strong inferential basis for uncovering reciprocal effects or causality between variables. For this analytic purpose, a cross-lagged panel model (CLPM) has been widely used in medical research, but the use of the CLPM has recently been criticized in methodological literature because parameter estimates in the CLPM conflate between-person and within-person processes. The aim of this study is to present some alternative models of the CLPM that can be used to examine reciprocal effects, and to illustrate potential consequences of ignoring the issue. A literature search, case studies, and simulation studies are used for this. We examined more than 300 medical papers published since 2009 that applied cross-lagged longitudinal models, finding that in all studies only a single model (typically, the CLPM) was performed and potential alternative models were not considered to test reciprocal effects. In 49% of the studies, only two time points were used, which makes it impossible to test such alternative models. Case studies and simulation studies showed that the CLPM often has worse model fit and markedly different estimates of cross-lagged parameters than alternative models, suggesting that research that relies on the CLPM only may draw erroneous conclusions regarding the presence, predominance, and sign of reciprocal effects as well as about causality.
Epigenetic mutational landscape in breast cancer: role of the histone methyltransferase gene KMT2D in triple negative tumors
Authors: Morcillo García Sara , Noblejas López María del Mar , Nieto Jiménez Cristina , Pérez Peña Javier , Nuncia Cantarero Miriam , Györffy Balázs , Amir Eitan , Pandiella Atanasio , Galán Moya Eva María , Ocaña Alberto
Published: December 2018

Purpose: Epigenetic regulating proteins like histone methyltransferases produce variations in several functions, some of them associated with the generation of oncogenic processes. Mutations of genes involved in these functions have been recently associated with cancer, and strategies to modulate their activity are currently in clinical development.
Methods: By using data extracted from the METABRIC study, we searched for mutated genes linked with detrimental outcome in invasive breast carcinoma (n = 772). Then, we used downstream signatures for each mutated gene to associate that signature with clinical prognosis using the online tool “Genotype-2-Outcome” (http://www.g-2-o.com). Next, we performed functional annotation analyses to classify genes by functions, and focused on those associated with the epigenetic machinery.
Results: We identified KMT2D, SETD1A and SETD2, included in the lysine methyltransferase activity function, as linked with poor prognosis in invasive breast cancer. KMT2D, which codes for a histone methyltransferase that acts as a transcriptional regulator, was mutated in 6% of triple negative breast tumors and found to be linked to poor survival. Genes regulated by KMT2D included RAC3, KRT23, or KRT14, among others, which are involved in cell communication and signal transduction. Finally, low expression of KMT2D at the transcriptomic level, which mirror what happens when KMT2D is mutated and functionally inactive, confirmed its prognostic value.
Conclusion: In the present work, we describe epigenetic modulating genes which are found to be mutated in breast cancer. We identify the histone methyltransferase KMT2D, which is mutated in 6% of triple negative tumors and linked with poor survival.
Evolution of host resistance and damage-limiting mechanisms to an emerging bacterial pathogen
Authors: Bonneaud Camille , Tardy Luc , Giraudeau Mathieu , Hill Geoffrey , McGraw Kevin , Wilson Alastair
Published: December 2018

Understanding how hosts minimise the cost of emerging infections has fundamental implications for epidemiological dynamics and the evolution of pathogen virulence. Despite this, few experimental studies conducted in natural populations have explicitly tested whether hosts evolve resistance, which prevents infections or reduces pathogen load through immune activation, or tolerance, which limits somatic damages without decreasing pathogen load. In addition, none have done so controlling for the virulence of the pathogen isolate used, despite critical effects on host responses to infection. Here, we conducted an experimental inoculation study to test whether eastern North American house finches (Haemorrhous mexicanus) have evolved resistance or tolerance to their emerging bacterial pathogen, Mycoplasma gallisepticum, using 55 distinct isolates of varying virulence. First, we show that peak pathogen loads, which occurred around 8 days post-inoculation, did not differ between experimentally inoculated finches from disease-exposed (eastern) versus unexposed (western) population. However, pathogen loads subsequently decreased faster and to a greater extent in finches from exposed populations, indicating that they were able to clear the infection through adaptive immune processes. Second, we found no between-population difference in the regression of clinical symptom severity on pathogen load; if tolerance had evolved then the slope of this regression is predicted to be shallower (less negative) in the exposed population. However, finches from exposed populations displayed lower symptom severity for a given pathogen load, suggesting that damage-limitation mechanisms have accompanied the evolution of immune clearance. These observations show that resistance and damage-limitation mechanisms - including, but not limited to the standard conceptualisation of tolerance - should not be seen as mutually exclusive. Nevertheless, we propose that host resistance is especially likely to evolve in response to pathogens such as M. gallisepticum that require virulence for successful infection and transmission.
Dengue and Chikungunya among Febrile Outpatients in Kinshasa, Democratic Republic of Congo: a cross-sectional study
Authors: Proesmans Sam , Katshongo Freddy , Milambu John , Fungula Blaise , Muhindo Mavoko Hypolite , Ahuka-Mundeke Steve , Inocencio da Luz Raquel , Van Esbroeck Marjan , Ariën Kevin K. , Cnops Lieslotte , De Smet Birgit , Lutumba Pascal , Van geertruyden Jean-Pierre , Vanlerberghe Veerle
Published: December 2018

Background
Pathogens causing acute fever, with the exception of malaria, remain largely unidentified in sub-Saharan Africa, given the local unavailability of diagnostic tests and the broad differential diagnosis.

Methodology/Principal Findings
We conducted a cross-sectional study including outpatient acute febrile syndromes in both children and adults, between November 2015 and June 2016 in Kinshasa, Democratic Republic of Congo. Serological and molecular diagnostic tests for arboviral infections were performed on blood, including PCR and NS1-RDT for acute, and ELISA and IFAT for past infections.

Conclusions/Significance
Among 342 patients, aged 2 to 68 years, 45.3% tested positive on malaria Rapid Diagnostic Test. However, 87.7% received antimalarial and 64.3% antibacterial treatment. Further investigation among 235 fever cases revealed 19 (8.1%) acute dengue and 2 (0.9%) acute chikungunya infections, with an important proportion of participants already exposed to flaviviridae (possibly dengue) and alphaviridae (possibly chikungunya) in the past, namely 30.2 % and 26.4% respectively. We found no evidence of exposure to Zika nor yellow fever virus.
Recycling of single-stranded DNA-binding protein by the bacterial replisome
Authors: Spenkelink Lisanne M. , Lewis Jacob S. , Jergic Slobodan , Xu Zhi-Qiang , Robinson Andrew , Dixon Nicholas E. , van Oijen Antoine M.
Published: December 2018

Single-stranded DNA-binding proteins (SSBs) support DNA replication by protecting single-stranded DNA from nucleolytic attack, preventing intra-strand pairing events, and playing many other regulatory roles within the replisome. Recent developments in single-molecule approaches have led to a revised picture of the replisome that is much more complex in how it retains or recycles protein components. Here we visualise how anin vitroreconstitutedE. colireplisome recruits SSB by relying on two different molecular mechanisms. Not only does it recruit new SSB molecules from solution to coat newly formed single-stranded DNA on the lagging strand, but it also internally recycles SSB from one Okazaki fragment to the next. We show that this internal transfer mechanism is balanced against recruitment from solution in a manner that is concentration dependent. By visualising SSB dynamics in live cells, we show that both internal transfer and external exchange mechanisms are physiologically relevant.
The kinetochore protein Spc105, a novel interaction partner of LaeA, regulates development and secondary metabolism in Aspergillus flavus
Authors: Zhi QingQing , He Lei , Li JieYing , Li Jing , Wang ZhenLong , He GuangYao , He Zhumei
Published: December 2018

Nuclear protein LaeA is known as the global regulator of secondary metabolism in Aspergillus. LaeA connects with VeA and VelB to form a heterotrimeric complex, which coordinates fungal development and secondary metabolism. Here, we describe a new interaction partner of LaeA, the kinetochore protein Spc105, from the aflatoxin-producing fungus Aspergillus flavus. We showed that in addition to involvement in nuclear division, Spc105 is required for normal conidiophore development and sclerotia production of A. ﬂavus. Moreover, Spc105 positively regulates the production of secondary metabolites such as aflatoxin and kojic acid, and negatively regulates the production of cyclopiazonic acid. Transcriptome analysis of the ?spc105 strain revealed that 23 backbone genes were differentially expressed, corresponding to 19 of the predicted 56 secondary metabolite gene clusters, suggesting a broad regulatory role of Spc105 in secondary metabolism. Notably, the reduced expression of laeA in our transcriptome data led to the discovery of the correlation between Spc105 and LaeA, and double mutant analysis indicated a functional interdependence between Spc105 and LaeA. Further, yeast two-hybrid (Y2H) and GST pull-down assays revealed that Spc105 interacts directly with the S-adenosylmethionine (SAM)-binding domain of LaeA, and that the leucine zipper motif in Spc105 is required for this interaction. The Spc105-LaeA interaction identified in our study indicates a cooperative interplay of distinct regulators in A. flavus, providing new insights into fungal secondary metabolism regulation networks.
K-paracelsian (KAlSi3O8·H2O) and identification of a simple building scheme of dense double-crankshaft zeolite topologies
Authors: Boruntea Cristian-R. , Vennestrøm Peter N. R. , Lundegaard Lars F.
Published: December 2018

During screening of the phase space using KOH and 1-methyl-4-aza-1-azoniabicyclo[2.2.2]octane hydroxide (1-methyl-DABCO) under hydrothermal zeolite synthesis conditions, K-paracelsian was synthesized. Scanning electron microscopy, energy dispersive X-ray spectroscopy and ex situ powder X-ray diffraction analysis revealed a material that is compositionally closely related to the mineral microcline and structurally closely related to the mineral paracelsian, both of which are feldspars. In contrast to the feldspars, K-paracelsian contains intrazeolitic water corresponding to one molecule per cage. In the case of K-paracelsian it might be useful to consider it a link between feldspars and zeolites. It was also shown that K-paracelsian can be described as the simplest endmember of a family of dense double-crankshaft zeolite topologies. By applying the identified building principle, a number of known zeolite topologies can be constructed. Furthermore, it facilitates the construction of a range of hypothetical small-pore structures that are crystallo-chemically healthy, but which have not yet been realized experimentally.
Exploring the role of accounting in the People’s Commune of China between 1958 and 1966
Authors: Xu Lina , Zhang Eagle , Cortese Corinne
Published: December 2018

Purpose

The purpose of this paper is to consider the role of accounting in the construction and maintenance of political hegemony during Mao’s People’s Commune movement in China between 1958 and 1966. Drawing on concepts of ideological power and intellectual diffusion in political and civil society from Gramsci’s theory of hegemony, it analyses the process by which accounting intellectuals established a set of socialist accounting practices to meet the political challenges of the People’s Commune.

Design/methodology/approach

Gramsci’s theory is adopted to examine how the accounting systems of People’s Commune acted as a mechanism that reflected Mao’s political ideas.

Findings

This paper demonstrates that the accounting system that emerged during these socio-political movements served the ideological purpose of reinforcing Mao’s political ideology and his hegemonic leadership. Accounting functioned within the spheres of both political and civil society to facilitate a national collective will, and to construct behaviours that satisfied the political requirements of the People’s Commune.

Originality/value

This paper will contribute to the accounting history in China from 1958 to 1966.
Corrosion resistance of carbon steel under an aerobic acidic condition in the presence of borate as corrosion inhibitor
Authors: Cui Jun , Yuan Wenjiao , Pei Yuansheng
Published: December 2018

Purpose

A high-boron concentration solution is commonly used as a buffer system in the study of metal corrosion. However, it is impossible to apply such a high-boron concentration solution in the practical use because of the high-cost and environment problem.

Design/methodology/approach

In this study, the authors examined the effect of a low dosage of boric acid and borax mixture as inhibitor to suppress carbon steel corrosion in 1 M HCl solution by weight loss experiment and various electrochemistry methods (potentiodynamic polarization curves, electrochemical impedance spectra and electrochemical noise).

Findings

Results showed that the borate mixture exhibited an anodic-type inhibitor characteristic, when the total boron concentration was in the range of 100∼150 mg L−1. The passivation performance derived from the formation of a passive film with and FeBO3-FeOOH structure, whose integrity and thickness gradually increased with the increasing boron concentration.

Originality/value

Low boron solution could protect carbon steel from the attraction of corrosive ions by forming a passive film with Fe-O-B structure. The findings broaden the application range of borate solution in the industry.
The influence of SAR government performance on people’s trust toward Central government
Authors: Chris Cheung Hin Wah , So Man Yum Larry , Choi Chi U. Francis , Chow Chin Fung Philip
Published: December 2018

Purpose

The purpose of this paper is to explore the influence of Special Administrative Region (SAR) performance on the “trust” of Hong Kong and Macau people, who “live” under similar context of “one country, two systems,” toward Beijing Central Government. The different perceptions, relating to the abovementioned issue, of the young peoples’ are also investigated. Implication for civic education in these two societies will be brought to light.

Design/methodology/approach

This study adopts secondary data analysis on the captioned topic. To further illustrate the said issue, this study reviews and analyzes data from protest campaigns in both societies.

Findings

This paper finds that the performance of Hong Kong and Macau SAR Governments has different impacts on the peoples’ “trust” toward Central Government. It may attribute to the different perceptions about the role of Central Government and levels of democratization in these societies. Civic education emphasizing the “core spirit” of “One country, two systems,” roles of SAR and Central Governments could enable young people better comprehend their relationship with Mainland China and their role as SAR–Chinese citizens.

Originality/value

This paper is an exploratory study for providing implications for further research on this topic.
Teaching Chinese in Canada: epics of three Chinese scholars
Authors: Lan Kenneth
Published: December 2018

Purpose

The purpose of this paper is to reveal the development of Chinese studies in selective Canadian universities through examining the remarkable careers of three middle-aged ethnic Chinese intellectuals.

Design/methodology/approach

This paper analyses the origin and growth of East Asian Studies programs in Canada by first describing the backgrounds of the three scholars. Why did Canadian universities accept them despite their Chinese origin?

Findings

Canadian universities are indeed the incubators of racial tolerance. Racism existed in the 1950s but was only confined to the collegial level. Universities generally welcomed a diversified representation of their payroll. While none of three academics founded East Asian Studies programs in their institutions, they had forcibly become their mascots and had lured more students into lifelong studies of the Far East. Despite the early fanfare of their recruitments, all three had become disillusioned with their employers as years passed. They felt their contributions were taken for granted and had shifted their career focuses elsewhere. The Asia-Pacific is still marginally focussed in the Canadian academe.

Originality/value

The three men and many others in the field have sowed the seed for the study of China and the East Asian region in Canada. It is up to future “East Asianists” to carry on this tradition that they had built in the twentieth century.