bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stochastic challenges to interrupting helminth transmission
Authors: Hardwick Robert J. , Werkman Marleen , Truscott James E. , Anderson Roy M. 
Published: December 2019

AbstractPredicting the effect of different programmes designed to control both the morbidity induced by helminth infections and parasite transmission is greatly facilitated by the use of mathematical models of transmission and control impact. In such models, it is essential to account for the many sources of uncertainty — natural, or otherwise — to ensure robustness in prediction and to accurately depict variation around an expected outcome. In this paper, we investigate how well the standard deterministic models match the predictions made using individual-based stochastic simulations. We also explore how well concepts which derive from deterministic models, such as ‘breakpoints’ in transmission, apply in the stochastic world. Employing an individual-based stochastic model framework we also investigate how transmission and control are affected by the migration of infected people into a defined community. To give our study focus we consider the control of soil-transmitted helminths (STH) by mass drug administration (MDA), though our methodology is readily applicable to the other helminth species such as the schistosome parasites and the filarial worms. We show it is possible to theoretically define a ‘stochastic breakpoint’ where much noise surrounds the expected deterministic breakpoint. We also discuss the concept of the ‘interruption of transmission’ independent of the ‘breakpoint’ concept where analyses of model behaviour illustrate the current limitations of deterministic models to account for the ‘fade-out’ or transmission extinction behaviour in simulations. Our analysis of migration confirms a relationship between the critical infected human migration rate scale (i.e., order of magnitude) per unit of time and the death rate of infective stages that are released into the free-living environment. This relationship is shown to determine the likelihood that control activities aim at chemotherapeutic treatment of the human host will eliminate transmission. The development of a new stochastic simulation code for STH in the form of a publicly-available open-source python package which includes features to incorporate many population stratifications, different control interventions including mass drug administration (with defined frequency, coverage levels and compliance patterns) and inter-village human migration is also described.
Foraging behavior across paths that vary in risk cues and frequency of occurrence
Authors: Lessig Emily K. , Nonacs Peter 
Published: December 2019

AbstractCooperatively foraging species often adjust their search strategies in complex environments to efficiently find and exploit food sources. These strategies become more complicated when food and risk can be simultaneously present and when they differ in predictability. For example, there may be multiple paths to reach a foraging site that vary in risk. This study examines how colonies of Argentine ants (Linepithema humile) respond to such a situation where identical-length paths differ in how they present risk. The risk cues are either a live competitor (velvety tree ants,Liometopum occidentale(LO)) or formic acid (FA), a defensive chemical commonly associated with formicine ant species. Across four paths to food, the presence of cues also varied from always to never present. Although the non-risky path was used more often, in no case did colonies completely avoid the paths with risk. Overall, moreL. humileworkers explored paths associated with LO than with FA. This had a significant impact on foraging ability where LO colonies were faster at finding food than FA colonies. Further, L.humileworkers’ response to FA was similar over time while declined for LO, suggesting a ‘dear enemy’ habituation and reduction in aggression over time. Thus, it appears thatL. humileforagers categorize risk cues and will vary their responses in potentially effective ways.
Near-complete Lokiarchaeota genomes from complex environmental samples using long and short read metagenomic analyses
Authors: Caceres Eva F. , Lewis William H. , Homa Felix , Martin Tom , Schramm Andreas , Kjeldsen Kasper U. , Ettema Thijs J. G. 
Published: December 2019

AbstractAsgard archaea is a recently proposed superphylum currently comprised of five recognised phyla: Lokiarchaeota, Thorarchaeota, Odinarchaeota, Heimdallarchaeota and Helarchaeota. Members of this group have been identified based on culture-independent approaches with several metagenome-assembled genomes (MAGs) reconstructed to date. However, most of these genomes consist of several relatively small contigs, and, until recently, no complete Asgard archaea genome is yet available. Large scale phylogenetic analyses suggest that Asgard archaea represent the closest archaeal relatives of eukaryotes. In addition, members of this superphylum encode proteins that were originally thought to be specific to eukaryotes, including components of the trafficking machinery, cytoskeleton and endosomal sorting complexes required for transport (ESCRT). Yet, these findings have been questioned on the basis that the genome sequences that underpin them were assembled from metagenomic data, and could have been subjected to contamination and other assembly artefacts. Even though several lines of evidence indicate that the previously reported findings were not affected by these issues, having access to high-quality and preferentially fully closed Asgard archaea genomes is needed to definitively close this debate. Current long-read sequencing technologies such as Oxford Nanopore allow the generation of long reads in a high-throughput manner making them suitable for their use in metagenomics. Although the use of long reads is still limited in this field, recent analyses have shown that it is feasible to obtain complete or near-complete genomes of abundant members of mock communities and metagenomes of various level of complexity. Here, we show that long read metagenomics can be successfully applied to obtain near-complete genomes of low-abundant members of complex communities from sediment samples. We were able to reconstruct six MAGs from different Lokiarchaeota lineages that show high completeness and low fragmentation, with one of them being a near-complete genome only consisting of three contigs. Our analyses confirm that the eukaryote-like features previously associated with Lokiarchaeota are not the result of contamination or assembly artefacts, and can indeed be found in the newly reconstructed genomes.
Characterization ofSETD1Ahaploinsufficiency in humans andDrosophiladefines a novel neurodevelopmental syndrome
Authors: Kummeling Joost , Stremmelaar Diante E , Raun Nicholas , Reijnders Margot RF , Willemsen Marjolein H , Ruiterkamp-Versteeg Martina , Schepens Marga , Man Calvin CO , Gilissen Christian , Cho Megan T , McWalter Kirsty , Sinnema Margje , Wheless James W , Simon Marleen EH , Genetti Casie A , Casey Alicia M , Terhal Paulien A , van der Smagt Jasper J , van Gassen Koen L , Joset Pascal , Bahr Angela , Steindl Katharina , Rauch Anita , Keller Elmar , Raas-Rothschild Annick , Koolen David A , Agrawal Pankaj B , Hoffman Trevor L , Powell-Hamilton Nina N , Thiffault Isabelle , Engleman Kendra , Zhou Dihong , Bodamer Olaf , Hoefele Julia , Riedhammer Korbinian M , Schwaibold Eva MC , Tasic Velibor , Schubert Dirk , Top Deniz , Pfundt Rolph , Higgs Martin R , Kramer Jamie M , Kleefstra Tjitske 
Published: December 2019

AbstractDefects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants ofSETD1Ainvolved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency ofSETD1Aby investigating 15 predominantly pediatric individuals who all havede novo SETD1Avariants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion ofSETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as Loss-of-Function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals withSETD1Avariants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that theDrosophila MelanogasterSETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominantde novoLoF variants inSETD1Aand further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.
Characterization of a novel type III CRISPR-Cas effector provides new insights into the allosteric activation and suppression of the Cas10 DNase
Authors: Lin Jinzhong , Feng Mingxia , Zhang Heping , She Qunxin 
Published: December 2019

AbstractAntiviral defense by type III CRISPR-Cas systems relies on two distinct activities of their effectors: the RNA-activated DNA cleavage and synthesis of cyclic oligoadenylate. Both activities are featured as indiscriminate nucleic acid cleavage and subjected to the spatiotemporal regulation. To yield further insights into the involved mechanisms, we reconstituted LdCsm, a lactobacilli III-A system inEscherichia coli. Upon activation by target RNA, this immune system mediates robust DNA degradation but lacks the synthesis of cyclic oligoadenylates. Mutagenesis of the Csm3 and Cas10 conserved residues revealed that Csm3 and multiple structural domains in Cas10 function in the allosteric regulation to yield an active enzyme. Target RNAs carrying various truncations in the 3′ anti-tag were designed and tested for their influence on DNA binding and DNA cleavage of LdCsm. Three distinct ternary LdCsm complexes were identified. In particular, binding of target RNAs carrying a single nucleotide in the 3′ anti-tag to LdCsm yielded an active LdCsm DNase regardless whether the nucleotide shows a mismatch, as in the cognate target RNA (CTR), or a match in the noncognate target RNAs (NTR), to the 5’ tag of crRNA. In addition, further increasing the number of 3′ anti-tag in CTR facilitated the substrate binding and enhanced the substrate degradation whereas doing the same as in NTR gradually decreased the substrate binding and eventually shut off the DNA cleavage by the enzyme. Together, these results provide the mechanistic insights into the allosteric activation and repression of LdCsm enzymes.
Transcriptome profiling ofVariovorax paradoxusEPS under different growth conditions reveals regulatory and structural novelty in biofilm formation
Authors: Fredendall Richard J. , Stone Jenny L. , Pehl Michael J. , Orwin Paul M. 
Published: December 2019

ABSTRACTWe used transcriptome analysis by paired-end strand specific RNA-seq to evaluate the specific changes in gene expression associated with the transition to static biofilm growth in the rhizosphere plant growth promoting bacteriumVariovorax paradoxusEPS. Triplicate biological samples of exponential growth, stationary phase, and static biofilm samples were examined. DESeq2 and Rockhopper were used to identify robust and widespread shifts in gene expression the transcriptomic signals specific to each growth phase. Weidentified 1711 protein coding genes (28%) using DESeq2 that had altered expression greater than 2-fold specifically in biofilms compared to exponential growth. Fewer genes were specifically differentially expressed in stationary phase culture (757, 12%). A small set of genes (103/6020) were differentially expressed in opposing fashions in biofilm and stationary phase, indicating potentially substantial shifts in phenotype. Gene Ontology analysis showed that the only class of genes specifically upregulated in biofilms were associated with nutrient transport, highlighting the importance of nutrient uptake in the biofilm. The biofilm specific genes did not overlap substantially with the loci identified by mutagenesis studies, although some were present in both sets. The most highly upregulated biofilm specific gene is predicted to be a part of the RNA degradosome, which indicates that RNA stability is used to regulate the biofilm phenotype. Two small putative proteins, Varpa_0407 and Varpa_3832, are highly expressed specifically in biofilms and are predicted to be secreted DNA binding proteins, that may stabilize extracellular DNA as a component of the biofilm matrix. An flp/tad type IV pilus locus (Varpa_5148-60) is strongly downregulated in specifically in biofilms, in contrast with results from other systems for these pili. Mutagenesis confirms that this locus is important in surface motility rather than biofilm formation. These experimental results suggest thatV. paradoxusEPS biofilms have substantial regulatory and structural novelty.
Dopaminergic Neurodegeneration Induced by Parkinson’s Disease-Linked G2019S LRRK2 is Dependent on Kinase and GTPase Activity
Authors: Nguyen An Phu Tran , Tsika Elpida , Kelly Kaela , Levine Nathan , Chen Xi , West Andrew B. , Boularand Sylviane , Barneoud Pascal , Moore Darren J. 
Published: December 2019

AbstractMutations in theleucine-rich repeat kinase 2(LRRK2) gene cause late-onset, autosomal dominant familial Parkinson’s disease (PD) and represent the most common known cause of PD. LRRK2 can function as both a protein kinase and GTPase and PD-linked mutations are known to influence both of these enzymatic activities. While PD-linked LRRK2 mutations can commonly induce neuronal damage and toxicity in cellular models, the mechanisms underlying these pathogenic effects remain uncertain. Rodent models based upon familial LRRK2 mutations often lack the hallmark features of PD and robust neurodegenerative phenotypes in general. Here, we develop a robust pre-clinical model of PD in adult rats induced by the brain delivery of recombinant adenoviral vectors with neuronal-specific expression of full-length human LRRK2 harboring the most common G2019S mutation. In this model, G2019S LRRK2 induces the robust degeneration of substantia nigra dopaminergic neurons, a pathological hallmark of PD. Introduction of a stable kinase-inactive mutation or in-diet dosing with the selective kinase inhibitor, PF-360, attenuates neurodegeneration induced by G2019S LRRK2. Neuroprotection provided by pharmacological kinase inhibition is mediated by an unusual mechanism involving the selective and robust destabilization of human LRRK2 protein in the rat brain relative to endogenous LRRK2. Our study further demonstrates that dopaminergic neurodegeneration induced by G2019S LRRK2 critically requires normal GTPase activity. The introduction of hypothesis-testing mutations that increase GTP hydrolysis or impair GTP binding activity provide neuroprotection against G2019S LRRK2 via distinct mechanisms. Taken together, our data demonstrate that G2019S LRRK2 induces neurodegenerationin vivovia a mechanism that is dependent on kinase and GTPase activity. Our study provides a robust rodent model ofLRRK2-linked PD and nominates kinase inhibition and modulation of GTPase activity as promising disease-modifying therapeutic targets.
Climbing fiber synapses rapidly inhibit neighboring Purkinje cells via ephaptic coupling
Authors: Han Kyung-Seok , Chen Christopher H. , Khan Mehak M. , Guo Chong , Regehr Wade G. 
Published: December 2019

AbstractClimbing fibers (CFs) from the inferior olive (IO) provide strong excitatory inputs onto the dendrites of cerebellar Purkinje cells (PC), and trigger distinctive responses known as complex spikes (CSs). We find that in awake, behaving mice, a CS in one PC suppresses conventional simple spikes (SSs) in neighboring PCs for several milliseconds. This involves a novel form of ephaptic coupling, in which an excitatory synapse nonsynaptically inhibits neighboring cells by generating large negative extracellular signals near their dendrites. The distance dependence of CS-SS ephaptic signaling, combined with the known divergence of CF synapses made by IO neurons, allows a single IO neuron to influence the output of the cerebellum by synchronously suppressing the firing of potentially over one hundred PCs. Optogenetic studiesin vivoand dynamic clamp studies in slice indicate that such brief PC suppression can effectively promote firing in neurons in the deep cerebellar nuclei and motor thalamus.
Astrocytes improve neuronal health after cisplatin treatment through mitochondrial transfer
Authors: English Krystal , Shepherd Andrew , Nzor Ndidi-Ese , Trinh Ronnie , Kavelaars Annemieke , Heijnen Cobi J. 
Published: December 2019

AbstractNeurodegenerative disorders, including chemotherapy-induced cognitive impairment, are associated with neuronal mitochondrial dysfunction. Cisplatin, a commonly used chemotherapeutic, induces neuronal mitochondrial dysfunctionin vivoandin vitro. Astrocytes are key players in supporting neuronal development, synaptogenesis, axonal growth, metabolism and, potentially, mitochondrial health. We tested the hypothesis that astrocytes transfer healthy mitochondria to neurons after cisplatin treatment to restore neuronal health. We used anin vitrosystem in which astrocytes containing mito-mCherry-labeled mitochondria were co-cultured with primary cortical neurons damaged by cisplatin. Culture of primary cortical neurons with cisplatin reduced neuronal survival and depolarized neuronal mitochondrial membrane potential. Cisplatin induced abnormalities in neuronal calcium dynamics characterized by increased resting calcium levels, reduced calcium responses to stimulation with KCl, and slower calcium clearance. The same dose of cisplatin that caused neuronal damage did not affect astrocyte survival or astrocytic mitochondrial respiration. Co-culture of cisplatin-treated neurons with astrocytes increased neuronal survival, restored neuronal mitochondrial membrane potential, and normalized neuronal calcium dynamics especially in those neurons that had received mitochondria from astrocytes. These beneficial effects of astrocytes were associated with transfer of mitochondria from astrocytes to cisplatin-treated neurons. The Rho-GTPase Miro-1 is known to contribute to mitochondrial motility and transfer. We show that siRNA-mediated knockdown of Miro-1 in astrocytes reduced mitochondrial transfer from astrocytes to neurons and prevented the normalization of neuronal calcium dynamics.In conclusion, we identified transfer of mitochondria from astrocytes to neurons damaged by cisplatin as an important repair mechanism to protect cortical neurons against the toxic effects of this chemotherapeutic.Significance statementChemotherapy-induced neurotoxicity is a serious health problem and little is known about the underlying mechanisms. Especially neurons are very sensitive to cisplatin treatment. We show that astrocytes can protect neurons damaged by cisplatin by improving neuronal survival, mitochondrial health, and calcium dynamicsin vitro. This beneficial effect of astrocytes is dependent on the transfer of mitochondria from astrocytes to the damaged neurons. Our findings provide evidence for an important endogenous protective neuro-glial mechanism that could contribute to prevention of neuronal death as a result of cisplatin treatment and thereby aid in sustaining brain health of patients during chemotherapy.
Honeybee colony performance affected by crop diversity and farmland structure: a modelling framework
Authors: Horn Juliane , Becher Matthias A. , Johst Karin , Kennedy Peter J. , Osborne Juliet L. , Radchuk Viktoriia , Grimm Volker 
Published: December 2019

AbstractForage availability has been suggested as one driver of the observed decline in honeybees. However, little is known about the effects of its spatiotemporal variation on colony success. We present a modelling framework for assessing honeybee colony viability in cropping systems. Based on two real farmland structures, we developed a landscape generator to design cropping systems varying in crop species identity, diversity, and relative abundance. The landscape scenarios generated were evaluated using the existing honeybee colony model BEEHAVE, which links foraging to in-hive dynamics. We thereby explored how different cropping systems determine spatiotemporal forage availability and, in turn, honeybee colony viability (e.g., time to extinction,TTE) and resilience (indicated by, e.g. brood mortality). To assess overall colony viability, we developed metrics,PHandPP,which quantified how much nectar and pollen provided by a cropping system per year was converted into a colony’s adult worker population. Both crop species identity and diversity determined the temporal continuity in nectar and pollen supply and thus colony viability. Overall farmland structure and relative crop abundance were less important, but details mattered. For monocultures and for four-crop species systems composed of cereals, oilseed rape, maize and sunflower,PHandPPwere below the viability threshold. Such cropping systems showed frequent, badly timed, and prolonged forage gaps leading to detrimental cascading effects on life stages and in-hive work force, which critically reduced colony resilience. Four-crop systems composed of rye-grass-dandelion pasture, trefoil-grass pasture, sunflower and phacelia ensured continuous nectar and pollen supply resulting inTTE> 5 years, andPH(269.5 kg) andPP(108 kg) being above viability thresholds for five years. Overall, trefoil-grass pasture, oilseed rape, buckwheat and phacelia improved the temporal continuity in forage supply and colony’s viability. Our results are hypothetical as they are obtained from simplified landscape settings, but they nevertheless match empirical observations, in particular the viability threshold. Our framework can be used to assess the effects of cropping systems on honeybee viability and to develop land-use strategies that help maintain pollination services by avoiding prolonged and badly timed forage gaps.
Dual Orexin and MCH neuron-ablated mice display severe sleep attacks and cataplexy
Authors: Hung Chi Jung , Ono Daisuke , Kilduff Thomas S. , Yamanaka Akihiro 
Published: December 2019

SummaryOrexin/hypocretin-producing and melanin-concentrating hormone-producing (MCH) neurons are co-extensive in the tuberal hypothalamus and project throughout the brain to regulate sleep/wakefulness. Ablation of orexin neurons in mice decreases wakefulness and results in a narcolepsy-like phenotype, whereas ablation of MCH neurons increases wakefulness. Since it is unclear how orexin and MCH neurons interact to regulate sleep/wakefulness, we generated conditional transgenic mice in which both orexin and MCH neurons could be ablated. Double-ablated mice exhibited increased wakefulness and decreased both rapid eye movement (REM) and non-REM (NREM) sleep. The total time in cataplexy and the mean cataplexy bout duration increased significantly in double-ablated mice compared with orexin neuron-ablated mice, suggesting that MCH neurons normally suppress cataplexy and that compromised MCH neurons may exacerbate symptoms in some narcoleptic patients. Double-ablated mice also showed frequent sleep attacks with elevated spectral power in the delta and theta range during wakefulness, a state with EEG characteristics indistinguishable from the transition from NREM into REM sleep. Together, these results indicate a functional interaction between orexin and MCH neuronsin vivothat suggests the synergistic involvement of these neuronal populations in the sleep/wakefulness cycle.