bluuebunny/crossref_metadata_2025 huggingface dataset:
Frameshift mutations of YPEL3 alter sensory circuit function in Drosophila
Authors: Kim Jung Hwan , Singh Monika , Pan Geng , Lopez Adrian , Zito Nicholas , Bosse Benjamin , Ye Bing
Published: September 2019

A frameshift mutation in Yippee-like (YPEL) 3 was recently found from a rare human disorder with peripheral neurological conditions including hypotonia and areflexia. The YPEL gene family is highly conserved from yeast to human, but their functions are poorly defined. Moreover, the pathogenicity of the human YPEL3 variant is completely unknown. To tackle these issues, we generated a Drosophila model of human YPEL3 variant by CRISPR-mediated In-del mutagenesis. Gene-trap analysis suggests that Drosophila YPEL3 (dYPEL3) is predominantly expressed in subsets of neurons, including nociceptors. Analysis on chemical nociception induced by allyl-isothiocyanate (AITC), a natural chemical stimulant, revealed a reduced nociceptive response in dYPEL3 mutants. Subsequent circuit analysis showed a reduction in the activation of second-order neurons (SONs) in the pathway without affecting nociceptor activation upon AITC treatment. Although the gross axonal and dendritic development of nociceptors was not affected, the synaptic contact between nociceptors and SONs were decreased by dYPEL3 mutations. Together, these suggest that the frameshift mutation in human YPEL3 causes neurological conditions by weakening synaptic connection through presynaptic mechanisms.
Predicting the genetic ancestry of 2.6 million New York City patients using clinical data
Authors: Ramlall Vijendra , Quinnies Kayla M. , Vanguri Rami , Lorberbaum Tal , Goldstein David B. , Tatonetti Nicholas P.
Published: September 2019

Ancestry is an essential covariate in clinical genomics research. When genetic data are available, dimensionality reduction techniques, such as principal components analysis, are used to determine ancestry in complex populations. Unfortunately, these data are not always available in the clinical and research settings. For example, electronic health records (EHRs), which are a rich source of temporal human disease data that could be used to enhance genetic studies, do not directly capture ancestry. Here, we present a novel algorithm for predicting genetic ancestry using only variables that are routinely captured in EHRs, such as self-reported race and ethnicity, and condition billing codes. Using patients that have both genetic and clinical information at Columbia University/ New York-Presbyterian Irving Medical Center, we developed a pipeline that uses only clinical data to predict the genetic ancestry of all patients of which more than 80% identify as other or unknown. Our ancestry estimates can be used in observational studies of disease inheritance, to guide genetic cohort studies, or to explore health disparities in clinical care and outcomes.
Control of cartilage homeostasis and osteoarthritis progression by mTORC1/4E-BP/eIF4E axis
Authors: Katsara Olga , Attur Mukundan , Kolupaeva Victoria
Published: September 2019

As world population growing older, burden of age-related conditions soars. One of them is osteoarthritis (OA), a debilitating joint disease with no effective treatment. Articular cartilage degeneration is a central event in OA, and changes in expression of many genes in OA cartilage are well-documented. Still, the specific mechanisms are rarely known. We showed that in OA cartilage the increased abundance of many proteins, including extracellular matrix protein Fibronectin (Fn1) and an orphan nuclear receptor Nr4a1 is translationally controlled and requires inactivation of 4EBP, an inhibitor of cap-dependent translation. Importantly, intra-articular injection of the translation inhibitor 4E1RCat reduces Fn1 and Nr4a upregulation in a rodent OA model and delays cartilage degeneration. Our results support the hypothesis that maintaining proper translational control is an important homeostatic mechanism, the loss of which contributes to OA development.
Xmas ESC: A new female embryonic stem cell system that reveals the BAF complex as a key regulator of the establishment of X chromosome inactivation
Authors: Keniry Andrew , Jansz Natasha , Gearing Linden J. , Wanigasuriya Iromi , Chen Joseph , Nefzger Christian M. , Hickey Peter F. , Gouil Quentin , Liu Joy , Breslin Kelsey A. , Iminitoff Megan , Beck Tamara , Tapia del Fierro Andres , Whitehead Lachlan , Kinkel Sarah A. , Taberlay Phillippa C. , Willson Tracy , Pakusch Miha , Ritchie Matthew E. , Hilton Douglas J. , Polo Jose M. , Blewitt Marnie E.
Published: September 2019

Although female pluripotency significantly differs to male, complications within vitroculture of female embryonic stem cells (ESC) have severely limited the use and study of these cells. We report a replenishable female ESC system, Xmas, that has enabled us to optimise a protocol for preserving the XX karyotype. Our protocol also improves male ESC fitness. We utilised our Xmas ESC system to screen for regulators of the female-specific process of X chromosome inactivation, revealing chromatin remodellers Smarcc1 and Smarca4 as key regulators of establishment of X inactivation. The remodellers create a nucleosome depleted region at gene promotors on the inactive X during exit from pluripotency, without which gene silencing fails. Our female ESC system provides a tractable model for XX ESC culture that will expedite study of female pluripotency and has enabled us to discover new features of the female-specific process of X inactivation.
Genome and community-level interaction insights on wide carbon utilizing and element cycling function of Hydrothermarchaeota from hydrothermal sediment
Authors: Zhou Zhichao , Liu Yang , Xu Wei , Pan Jie , Luo Zhu-Hua , Li Meng
Published: September 2019

Hydrothermal vents release reduced compounds and small organic carbons into surrounding seawaters, providing essential substrates for microbial-derived biosynthesis and bioenergy transformations. Despite the wide distribution of Marine Benthic Group-E archaea (referred to as Hydrothermarchaeota) in hydrothermal environments, little is known on their genome blueprints and ecofunctions. Here, we studied four relatively high-completeness (> 80%) metagenome-assembled genomes (MAGs) from a black smoker chimney and surrounding sulfide sediments in the Mid-Atlantic Ridge of the South Atlantic Ocean (BSmoChi-MAR) as well as publicly available datasets. Comparative genomics suggest that Hydrothermarchaeota members have versatile carbon metabolism, including assimilating proteins, lactate and acetate, degrading aromatics anaerobically, oxidizing C1compounds (CO, formate, and formaldehyde), utilizing methyl-compounds, and incorporating CO2by tetrahydromethanopterin-based Wood–Ljungdahl (WL) pathway and Calvin–Benson–Bassham (CBB) cycle with type III Ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO). They could oxidize sulfur, arsenic, and hydrogen, and respire anaerobically via sulfate reduction and denitrification based on genomic evidence. The redundancy of carbon utilizing and element cycling functions, and the interactive processes of syntrophic and sequential utilization of substrates from community-level metabolic prediction, enable wide accessibility of carbon and energy sources to microorganisms. Hydrothermarchaeota members derived important functional components from the community through lateral gene transfer, and became clade-distinctive on genome content, which might serve as a niche-adaptive strategy to metabolize potential heavy metals, C1compounds, and reduced sulfur compounds.

Importance

This study provides comprehensive metabolic insights on Hydrothermarchaeota from comparative genomics, evolution and community-level aspects. Hydrothermarchaeota synergistically participates in a wide range of carbon utilizing and element cycling processes with other microbes in the community. We expand the current understanding of community interactions within hydrothermal sediment environments, suggesting that microbial interactions driven by functions are essential to nutrient and element cycling.
Diverse flanking sequence types ofblaNDMin IncX3 and IncB/O/K/Z plasmids inEscherichia coliisolated from poultry
Authors: Zhu Jia-Hang , Cai Run-Mao , Zhang Li-Juan , Zheng Xing-Run , Lu Yue-Wei , Zhao Qiu-Yun , Chang Man-Xia , Jiang Hong-Xia
Published: September 2019

We identified 33blaNDM-harboringEscherichia coliin 470 poultry samples from Shandong and Guangdong provinces during 2016 to 2017 and included the subtypesblaNDM-1,blaNDM-5andblaNDM-9.TheblaNDMgene possessed by all strains was plasmid-borne and ranged in size from 46 to 265 kb. The plasmids included the replicon types IncX3, IncY, IncB/O/K/Z and IncHI2 and most were transferable and stable in recipient host bacteria. Sequences flankingblaNDMin IncX3 and IncB/O/K/Z plasmids were diverse and the mobile element IS26played an important role in the evolution of the IncB/O/K/ZblaNDMplasmids.
Plasmid transmitted small multidrug resistant (SMR) efflux pumps differ in gene regulation and enhance tolerance to quaternary ammonium compounds (QAC) when grown as biofilms
Authors: Slipski Carmine J. , Jamieson Taylor R. , Lam Amy , Shing Vanessa Leung , Bell Kelli , Zhanel George G. , Bay Denice C.
Published: September 2019

Small multidrug resistance (SMR) efflux pump genes are commonly identified from integrons carried by multidrug-resistant (MDR) plasmids. SMR pumps are annotated as ‘qac’ for their ability to confer resistance to quaternary ammonium compounds (QACs) but few qac are characterized to date. Hence, we have examined SMR sequence diversity, antimicrobial susceptibility, and gene expression from >500 sequenced proteobacterial plasmids. SMR sequence diversity from plasmid database surveys identified 20 unique SMR sequences annotated as qacE/EΔ1/F/G/H/I/L, or sugE. Phylogenetic analysis shows ‘Qac’ sequences are homologous to archetypical SMR member EmrE, and share a single sequence origin. In contrast, SugE sequences are homologous to archetypical member Gdx/SugE and likely originate from different species. SMR genes, qacE, qacEΔ1, qacF, qacG, qacH, and sugE(p), were over-expressed in Escherichia coli to determine their QAC antimicrobial susceptibility as planktonic, colony, and biofilms. SMRs (except qacEΔ1/sugE) expressed in biofilms significantly increased its QAC tolerance as compared to planktonic and colony growth. Analysis of upstream SMR nucleotide regions indicate sugE(p) genes are regulated by type II guanidinium riboswitches, whereas qacE and qacEΔ1 have a conserved class I integron Pq promoter, and qacF/G/H are regulated by integron Pc promoter in variable cassettes region. Beta-galactosidase assays were used to characterize growth conditions regulating Pq and Pc promoters and revealed that Pq and Pc have different expression profiles during heat, peroxide, and QAC exposure. Altogether, this study reveals that biofilm growth methods are optimal for SMR-mediated QAC susceptibility testing and suggests SMR gene regulation on plasmids is similar to chromosomally inherited SMR members.
Screening the Medicines for Malaria Venture Pathogen Box for invasion and egress inhibitors of the blood stage of Plasmodium falciparum reveals several inhibitory compounds
Authors: Dans Madeline G. , Weiss Greta E. , Wilson Danny W. , Sleebs Brad E. , Crabb Brendan S. , de Koning-Ward Tania F. , Gilson Paul R.
Published: September 2019

To identify potential inhibitors of egress and invasion in the asexual blood stage of Plasmodium falciparum, we screened the Medicines for Malaria Venture (MMV) Pathogen Box. This compound library comprises of 400 drugs against neglected tropical diseases, including 125 with antimalarial activity. For this screen, we utilised transgenic parasites expressing a bioluminescent reporter, Nanoluciferase (Nluc), to measure inhibition of parasite egress and invasion in the presence of the Pathogen Box compounds. At a concentration of 2 µM, we found 15 compounds that inhibited parasite egress by >40% and 24 invasion-specific compounds that inhibited invasion by >90%. We further characterised 11 of these inhibitors through cell-based assays and live cell microscopy and found two compounds that inhibited merozoite maturation in schizonts, one compound that inhibited merozoite egress, one compound that directly inhibited parasite invasion and one compound that slowed down invasion and arrested ring formation. The remaining compounds were general growth inhibitors that acted during the egress and invasion phase of the cell cycle. We found the sulfonylpiperazine, MMV020291, to be the most invasion-specific inhibitor, blocking successful merozoite internalisation within human RBCs and having no substantial effect on other stages of the cell cycle. This has greater implications for the possible development of an invasion-specific inhibitor as an antimalarial in a combination based therapy, in addition to being a useful tool for studying the biology of the invading parasite.

Importance

Plasmodium falciparum causes the most severe form of malaria and with emerging resistance to frontline treatments, there is the need to identify new drug targets in the parasite. One of the most critical processes during the asexual blood stage in the parasite’s lifecycle is the egress from old red blood cells (RBCs) and subsequent invasion of new RBCs. Many unique parasite ligands, receptors and enzymes are employed during egress and invasion that are essential for parasite proliferation and survival, therefore making these processes druggable targets. Identifying novel compounds that inhibit these essential processes would further their development into possible antimalarials that would be highly effective at killing asexual RBC stage parasites when used in combination with drugs that target the intraerythrocytic growth phase. These compounds potentially may also be used as novel tools to study the complex biology of parasites to gain further insight into the mechanisms behind egress and invasion.
Lyb-2-4, a unique genomic region of hypervirulent carbapenem-resistant Acinetobacter baumannii
Authors: Zheng Chao , Zhang Jinyong , Zhang Min , Liu Zhou , Zhong Yuxin , Liu Shiyi , Cui Ruiqin , Deng Qiuyang , Xu Yanji , Shi Yun , Zeng Hao , Yang Xiyao , Lin Chuchu , Luo Yutian , Chen Huaisheng , Wu Weiyuan , Wu Jinsong , Zhang Tianle , Lu Yuemei , Liu Xueyan , Zou Quanming , Huang Wei
Published: September 2019

Acinetobacter baumannii is an important human pathogen due to its multi-drug resistance, but is usually with low-grade virulence. Although a mouse model revealed different virulence grades of clinical carbapenem-resistant A. baumannii (CRAB) strains, the genetic basis remains unknown. We collected 61 CRAB isolates from intensive care unit of Shenzhen People’s Hospital (Shenzhen, China), and analyzed them used whole genome sequencing (WGS), multilocus sequence typing (MLST) and core genome MLST (cgMLST), transmission chain reconstruction and Comparative genomic tools. A mouse pneumonia model was used to confirm the hypervirulent phenotype. Eleven complex types (CT) were identified based on core genome multilocus sequence typing scheme. CT512 showed higher transmissibility and bloodstream infection rates than other CTs. A genomic region Lyb-2-4 was shared by CT512 and CT2092 but not CT2085. The mortality rates of patient infected with CRAB harboring Lyb-2-4 was significantly higher than those infected with CRAB isolates without Lyb-2-4 (77.8% vs 24.5%, p < 0.01). In the mouse model, the survival rates of strains containing the Lyb-2-4 region (LAC-4, 5122 and 2092) were significantly lower than for strains without Lyb-2-4 (7152, 71517, 20859 and ATCC17978). One open reading frame (ORF) was a marker for the presence of Lyb-2-4, and PCR of a segment of this ORF, designated as hvcT, served as a tag for hypervirulent CRAB. Our study should be very useful in advising the clinician to implement medical intervention earlier, and also making the worldwide surveillance of these hypervirulent CRAB strains easier.

IMPORTANCE

Hypervirulent CRAB strains are expected to pose a threat to human health because infection of these strains is associated with high mortality and multidrug resistance. The rapid hypervirulent CRAB identification assay will facilitate prompt medical intervention. Our findings should provoke surveillance for hypervirulent CRAB strains harboring Lyb-2-4 in other countries. Further research should focus on the mechanism of hypervirulence, the acquisition of this genomic region and the development of control measures to prevent further dissemination.
Intraspecific trait variability and community assembly in hawkmoths (Lepidoptera:Sphingidae) across an elevational gradient in the eastern Himalayas, India
Authors: Mungee Mansi , Athreya Ramana
Published: September 2019

Recent progress in functional ecology has advanced our understanding of the role of intraspecific (ITV) and interspecific (STV) trait variation in community assembly across environmental gradients. Studies on plant communities have generally found STV as the main driver of community trait variation, whereas ITV plays an important role in determining species co-existence and community assembly. However, similar studies of faunal taxa, especially invertebrates, are very few in number.

We investigated variation of hawkmoth (Lepidoptera:Sphingidae) traits along an environmental gradient spanning 2600 m in the eastern Himalayas and its role in community assembly, using the morpho-functional traits of body mass (BM), wing loading (WL) and wing aspect ratio (AR).

We employ the recently proposedT-statisticsto test for non-random assembly of hawkmoth communities and the relative importance of the two opposing forces for trait divergence (internal filters) and convergence (external filters).

Community-wide trait-overlap decreased for all three traits with increasing environmental distance, suggesting the presence of elevation specific optimum morphology (i.e. functional response traits). Community weighted mean of BM and AR increased with elevation. Overall, the variation was dominated by species turnover but ITV accounted for 25%, 23% and <1% variability of BM, WL and AR, respectively. T-statistics, which incorporates ITV, revealed that elevational communities had a non-random trait distribution, and that community assembly was dominated by internal filtering throughout the gradient.

This study was carried out using easily measurable morpho-traits obtained from calibrated field images of a large number (3301) of individuals. That these also happened to be important environmental response traits resulted in a significant signal in the metrics that we investigated. Such studies of abundant and hyperdiverse invertebrate groups across large environmental gradients should considerably improve our understanding of community assembly processes.
Genetic correlations across genetically determined and developmentally plastic alternative reproductive tactics
Authors: Abbott Jessica K. , Rios-Cardenas Oscar , Morris Molly
Published: September 2019

Alternative reproductive tactics occur when individuals of the same sex have a suite of morphological and/or behavioural traits that allow them to pursue different reproductive strategies. A common pattern is e.g. the existence of “courter” and “sneaker” tactics within males. We have previously argued that alternative reproductive tactics should be subject to genetic conflict over the phenotypic expression of traits, similar to sexual antagonism. In this process, which we called intra-locus tactical conflict, genetically determined tactics experience conflicting selection on a shared phenotypic trait, such as body size, but a positive genetic correlation between tactics in body size prevents either tactic from reaching its optimum. Recently, other authors have attempted to extend this idea to developmentally plastic alternative reproductive tactics, with mixed results. However, it is not clear whether we should expect intra-locus tactical conflict in developmentally plastic tactics or not. We have therefore run a series of simulation models investigating under what conditions we should expect to see positive estimates of the inter-tactical genetic correlation, since a positive genetic correlation is a prerequisite for the existence of intra-locus tactical conflict. We found that for autosomal, X-linked, and Y-linked genetically-determined tactics, estimated inter-tactical genetic correlations were generally high. However, for developmentally plastic tactics, the genetic correlation depends on the properties of the switching threshold between tactics. If it is fixed, then estimated genetic correlations are positive, but if there is genetic variation in the switch-point, then any sign and magnitude of estimated genetic correlation is possible, even for highly heritable traits where the true underlying correlation is perfect. This means that caution should be used when investigating genetic constraints in plastic phenotypes.
StemBond hydrogels optimise the mechanical microenvironment for embryonic stem cells
Authors: Labouesse Céline , Agley Chibeza C. , Tan Bao Xiu , Hofer Moritz , Winkel Alex , Stirparo Giuliano G. , Stuart Hannah T. , Verstreken Christophe M. , Mansfield William , Bertone Paul , Franze Kristian , Silva Jose C. R. , Chalut Kevin J.
Published: September 2019

Studies of mechanical signalling are typically performed by comparing cells cultured on soft and stiff hydrogel-based substrates. However, it is challenging to independently and robustly control both substrate stiffness and tethering of extracellular matrix (ECM) to substrates, making ECM tethering a potentially confounding variable in mechanical signalling investigations. Moreover, poor ECM tethering can lead to weak cell attachment. To address this, we developed StemBond hydrogels, a hydrogel formulation in which ECM tethering is stable and can be varied independently of stiffness. We show that soft StemBond hydrogels provide an optimal format for culturing embryonic stem (ES) cells. We find that soft StemBond substrates improve the homogeneity of ES cell populations, boost their self-renewal, and increase the efficiency of cellular reprogramming. Our findings underline how soft microenvironments impact mechanosensitive signalling pathways regulating self-renewal and differentiation, indicating that optimising the complete mechanical microenvironment will offer greater control over stem cell fate specification.
Will an outbreak exceed available resources for control? Estimating the risk from invading pathogens using practical definitions of a severe epidemic
Authors: Thompson R.N. , Gilligan C.A. , Cunniffe N.J.
Published: September 2019

Forecasting whether or not initial reports of disease will be followed by a severe epidemic is an important component of disease management. Standard epidemic risk estimates involve assuming that infections occur according to a branching process and correspond to the probability that the outbreak persists beyond the initial stochastic phase. However, an alternative assessment is to predict whether or not initial cases will lead to a severe epidemic in which available control resources are exceeded. We show how this risk can be estimated by considering three practically relevant potential definitions of a severe epidemic; namely, an outbreak in which: i) a large number of hosts are infected simultaneously; ii) a large total number of infections occur; and iii) the pathogen remains in the population for a long period. We show that the probability of a severe epidemic under these definitions often coincides with the standard branching process estimate for the major epidemic probability. However, these practically relevant risk assessments can also be different from the major epidemic probability, as well as from each other. This holds in different epidemiological systems, highlighting that careful consideration of what constitutes a severe epidemic in an ongoing outbreak is vital for accurate risk quantification.
Rich polymorphic variants of alpha satellite 34mer higher order repeats in hg38 assembly of human chromosome Y
Authors: Vlahović Ines , Glunčić Matko , Paar Vladimir
Published: September 2019

A challenging problem in human population genetics is related to the unique role of human Y chromosome, with properties that distinguish humans from other species. Centromeres in primate genomes are constituted of tandem repeats of ∼ 171 bp alpha satellite monomers, commonly organized into higher order repats (HORs). Because of gaps in DNA sequencing, HOR regions as genomic “black holes” have been understudied in spite of crucial importance. Only recently the sequencing of more complete satellite DNAs becomes accessible. In human Y chromosome the largest alpha satellite higher order repeat unit 34/36mer was found, but its polymorphic variants were not investigated. Here, we study the human Y chromosome centromeric genomic sequence from hg38 assembly using our novel ALPHAsub algorithm for simple identification of alpha satellite arrays and robust GRM algorithm for HOR identification in repeat sequences. We determine the monomer alignment scheme for alpha satellite HOR array based on canonical 34mer HOR, discovering a wealth of novel polymorphic variants which include the HOR-type monomer duplications, monomer deletions/insertions or rearrangements and non-HOR insertions.

Author Summary

The centromere is important for segregation of chromosomes during cell division in eukaryotes. Its destabilization results in chromosomal missegregation, aneuploidy, hallmarks of cancers and birth defects. In primate genomes centromeres contain tandem repeats of ∼ 171 bp alpha satellite DNA, commonly organized into higher order repeats (HORs). In this work, we used our bioinformatics algorithms to study the human Y chromosome centromeric genomic sequence and we discover a wealth of novel polymorphic variants which include the HOR-type monomer duplications, monomer deletions/insertions or rearrangements and non-HOR insertions. These results could help to understand the role of alpha satellites and alpha HOR structures in centromeric organization and function, in particular their role in creating a functional kinetochore that is crucial for chromosome segregation during cell division.
Activation of specific mushroom body output neurons inhibits proboscis extension and feeding behavior
Authors: Chia Justine , Scott Kristin
Published: September 2019

The ability to modify behavior based on prior experience is essential to an animal’s survival. For example, animals may become attracted to a previously neutral odor or reject a previously appetitive food source upon learning. In Drosophila, the mushroom bodies (MBs) are critical for olfactory associative learning and conditioned taste aversion, but how the output of the MBs affects specific behavioral responses is unresolved. In conditioned taste aversion, Drosophila shows a specific behavioral change upon learning: proboscis extension to sugar is reduced after a sugar stimulus is paired with an aversive stimulus. While studies have identified MB output neurons (MBONs) that drive approach or avoidance behavior, whether the same MBONs impact proboscis extension behavior is unknown. Here, we tested the role of MB pathways in modulating proboscis extension and identified 10 MBON split-GAL4 lines that upon activation significantly decreased proboscis extension to sugar. Activating several of these lines also decreased sugar consumption, revealing that these MBONs have a general role in modifying feeding behavior beyond proboscis extension. Although the MBONs that decreased proboscis extension and ingestion are different from those that drive avoidance behavior in another context, the diversity of their arborizations demonstrates that a distributed network influences proboscis extension behavior. These studies provide insight into how the MB flexibly alters the response to taste compounds and modifies feeding decisions.
Convergence of unisensory-evoked signals via multiple pathways to the cerebellum
Authors: Shimuta Misa , Sugihara Izumi , Ishikawa Taro
Published: September 2019

The cerebellum receives signals directly from peripheral sensory systems and indirectly from the neocortex. To reveal how these different types of signals are processed in the cerebellar cortex,in vivowhole-cell recordings from granule cells and unit recordings from Purkinje cells were performed in mice in which primary somatosensory cortex (S1) could be optogenetically inhibited. Tactile stimulation of the upper lip produced two-phase granule cell responses (with latencies of ∼ 8 ms and 28 ms), for which only the late phase was S1 dependent. Complex spikes and the late phase of simple spikes in Purkinje cells were also S1 dependent. These results indicate that individual granule cells integrate convergent inputs from the periphery and neocortex, and send their outputs to Purkinje cells, which then combine those signals with climbing fiber signals from the neocortex.
Longitudinal Changes of Resting-State Functional Connectivity of Amygdala Following Fear Learning and Extinction
Authors: Martynova Olga , Tetereva Alina , Balaev Vladislav , Portnova Galina , Ushakov Vadim , Ivanitsky Alexey
Published: September 2019

Altered functional connectivity of the amygdala has been observed in a resting state immediately after fear learning, even one day after aversive exposure. The persistence of increased resting-state functional connectivity (rsFC) of the amygdala has been a critical finding in patients with stress and anxiety disorders. However, longitudinal changes in amygdala rsFC have rarely been explored in healthy participants. To address this issue, we studied the rsFC of the amygdala in two groups of healthy volunteers. The control group participated in three fMRI scanning sessions of their resting state at the first visit, one day, and one week later. The experimental group participated in three fMRI sessions on the first day: a resting state before fear conditioning, a fear extinction session, and a resting state immediately after fear extinction. Furthermore, this group experienced scanning after one day and week. The fear-conditioning paradigm consisted of visual stimuli with a distinct rate of partial reinforcement by electric shock. During the extinction, we presented the same stimuli in another sequence without aversive pairing. In the control group, rsFC maps were statistically similar between sessions for the left and right amygdala. However, in the experimental group, the increased rsFC mainly of the left amygdala was observed after extinction, one day, and one week. The between-group comparison also demonstrated an increase in the left amygdala rsFC in the experimental group. Our results indicate that functional connections of the left amygdala influenced by fear learning may persist for several hours and days in the human brain.
Physics-based predictive simulations to explore the differential effects of motor control and musculoskeletal deficits on gait dysfunction in cerebral palsy: a retrospective case study
Authors: Falisse Antoine , Pitto Lorenzo , Kainz Hans , Hoang Hoa , Wesseling Mariska , Van Rossom Sam , Papageorgiou Eirini , Bar-On Lynn , Hallemans Ann , Desloovere Kaat , Molenaers Guy , Van Campenhout Anja , De Groote Friedl , Jonkers Ilse
Published: September 2019

Model-based simulations of walking have the theoretical potential to support clinical decision making by predicting the functional outcome of treatments in terms of walking performance. Yet before using such simulations in clinical practice, their ability to identify the main treatment targets in specific patients needs to be demonstrated. In this study, we generated predictive simulations of walking with a medical imaging based neuro-musculoskeletal model of a child with cerebral palsy presenting crouch gait. We explored the influence of altered muscle-tendon properties, reduced neuromuscular control complexity, and spasticity on gait function in terms of joint kinematics, kinetics, muscle activity, and metabolic cost of transport. We modeled altered muscle-tendon properties by personalizing Hill-type muscle-tendon parameters based on data collected during functional movements, simpler neuromuscular control by reducing the number of independent muscle synergies, and spasticity through delayed muscle activity feedback from muscle force and force rate. Our simulations revealed that, in the presence of aberrant musculoskeletal geometries, altered muscle-tendon properties rather than reduced neuromuscular control complexity and spasticity were the primary cause of the crouch gait pattern observed for this child, which is in agreement with the clinical examination. These results suggest that muscle-tendon properties should be the primary target of interventions aiming to restore a more upright gait pattern for this child. This suggestion is in line with the gait analysis following muscle-tendon property and bone deformity corrections. The ability of our simulations to distinguish the contribution of different impairments on walking performance opens the door for identifying targeted treatment strategies with the aim of designing optimized interventions for neuro-musculoskeletal disorders.
Two faces of perceptual awareness during the attentional blink: Gradual and discrete
Authors: Karabay Aytaç , Wilhelm Sophia A. , de Jong Joost , Wang Jing , Martens Sander , Akyürek Elkan G.
Published: September 2019

In a series of experiments, the nature of perceptual awareness during the attentional blink was investigated. Previous work has considered the attentional blink as a discrete, all-or-none phenomenon, indicative of general access to conscious awareness. Using continuous report measures in combination with mixture modeling, the outcomes showed that perceptual awareness during the attentional blink can be a gradual phenomenon. Awareness was not exclusively discrete, but also exhibited a gradual characteristic whenever the spatial extent of attention induced by the first target spanned more than a single location. Under these circumstances, mental representations of blinked targets were impoverished, but did approach the actual identities of the targets. Conversely, when the focus of attention covered only a single location, there was no evidence for any partial knowledge of blinked targets. These two different faces of awareness during the attentional blink challenge current theories of both awareness and temporal attention, which cannot explain the existence of gradual awareness of targets during the attentional blink. To account for the current outcomes, an adaptive gating model is proposed that casts awareness on a continuum between gradual and discrete, rather than as being of either single kind.
The B. subtilis Rok protein compacts and organizes DNA by bridging
Authors: Qin L. , Erkelens A.M. , Markus D. , Dame R.T.
Published: September 2019

Rok from Bacillus subtilis is an abundant DNA binding protein similar in function to H-NS-like proteins found in many proteobacteria. Rok binds across the genome with a preference for A/T rich DNA. Such DNA often contains genes of foreign origin that are silenced due to Rok binding. Rok also has been implied in global organization of the B. subtilis genome. However, how Rok binds to DNA and how it represses transcription is unclear. Also, it is unknown whether Rok-mediated gene repression can be induced or relieved following changes in physico-chemical conditions, as noted for H-NS-like proteins. Here we investigate the DNA binding properties of Rok and determine the effects of physico-chemical conditions on these properties. We demonstrate that Rok is a DNA bridging protein similar to H-NS like proteins from E. coli (H-NS), Pseudomonas sp. (MvaT) and Mycobacteria (Lsr2). Strikingly, unlike these proteins, the ability of Rok to bridge DNA is not affected by changes in physico-chemical conditions. Not being a direct sensor of such changes sets Rok apart from other H-NS like proteins. It implies the existence of other (protein-mediated) mechanisms to relieve Rok-mediated gene silencing in response to changes in environmental conditions.
Polypyrimidine Tract Binding Proteins are essential for B cell development
Authors: Monzón-Casanova Elisa , Matheson Louise S. , Tabbada Kristina , Zarnack Kathi , Smith Christopher W. J. , Turner Martin
Published: September 2019

Polypyrimidine Tract Binding Protein 1 (PTBP1) is a RNA-binding protein (RBP) expressed throughout B cell development. Deletion of Ptbp1 in mouse pro-B cells results in upregulation of PTBP2 and normal B cell development. We show that PTBP2 compensates for PTBP1 in B cell ontogeny as deletion of both Ptbp1 and Ptbp2 results in a complete block at the pro-B cell stage and a lack of mature B cells. In pro-B cells PTBP1 ensures precise synchronisation of the activity of cyclin dependent kinases at distinct stages of the cell cycle, suppresses S-phase entry and promotes progression into mitosis. PTBP1 controls mRNA abundance and alternative splicing of important cell cycle regulators including CYCLIN-D2, c-MYC, p107 and CDC25B. Our results reveal a previously unrecognised mechanism mediated by a RBP that is essential for B cell ontogeny and integrates transcriptional and post-translational determinants of progression through the cell cycle.
VE-cadherin endocytosis controls vascular integrity and patterning during development
Authors: Grimsley-Myers Cynthia M. , Isaacson Robin H. , Cadwell Chantel M. , Campos Jazmin , Hernandes Marina S. , Myers Kenneth R. , Seo Tadahiko , Giang William , Griendling Kathy K. , Kowalczyk Andrew P.
Published: September 2019

Tissue morphogenesis requires dynamic intercellular contacts that are subsequently stabilized as tissues mature. The mechanisms governing these competing adhesive properties are not fully understood. Using gain- and loss-of-function approaches, we tested the role of p120-catenin (p120) and VE-cadherin (VE-cad) endocytosis in vascular development using mouse mutants that exhibit increased (VE-cadGGG/GGG) or decreased (VE-cadDEE/DEE) internalization. VE-cadGGG/GGGmutant mice exhibited reduced VE-cad-p120 binding, reduced VE-cad levels, microvascular hemorrhaging, and decreased survival. By contrast, VE-cadDEE/DEEmutants exhibited normal vascular permeability but displayed microvascular patterning defects. Interestingly, VE-cadDEE/DEEmutant mice did not require endothelial p120, demonstrating that p120 is dispensable in the context of a stabilized cadherin.In vitro, VE-cadDEE mutant cells displayed defects in polarization and cell migration that were rescued by uncoupling VE-cadDEE from actin. These results indicate that cadherin endocytosis coordinates cell polarity and migration cues through actin remodeling. Collectively, our results indicate that regulated cadherin endocytosis is essential for both dynamic cell movements and establishment of stable tissue architecture.

Summary Statement

This study uses mouse genetic andin vitroapproaches to demonstrate that cadherin endocytosis is critical for the formation of blood vessels during development by promoting actin-dependent collective cell migration, whereas the inhibition of this endocytosis by p120 binding is essential for vessel stabilization.
Self-organised symmetry breaking in zebrafish reveals feedback from morphogenesis to pattern formation
Authors: Trivedi Vikas , Fulton Timothy , Attardi Andrea , Anlas Kerim , Dingare Chaitanya , Martinez-Arias Alfonso , Steventon Benjamin
Published: September 2019

A fundamental question in developmental biology is how the early embryo breaks initial symmetry to establish the spatial coordinate system later important for the organisation of the embryonic body plan. In zebrafish, this is thought to depend on the inheritance of maternal mRNAs [1–3], cortical rotation to generate a dorsal pole of beta-catenin activity [4–8] and the release of Nodal signals from the yolk syncytial layer (YSL) [9–12]. Recent work aggregating mouse embryonic stem cells has shown that symmetry breaking can occur in the absence of extra-embryonic tissue [19,20]. To test whether this is also true in zebrafish, we separated embryonic cells from the yolk and allowed them to develop as aggregates. These aggregates break symmetry autonomously to form elongated structures with an anterior-posterior pattern. Extensive cell mixing shows that any pre-existing asymmetry is lost prior to the breaking morphological symmetry, revealing that the maternal pre-pattern is not strictly required for early embryo patterning. Following early signalling events after isolation of embryonic cells reveals that a pole of Nodal activity precedes and is required for elongation. The blocking of PCP-dependent convergence and extension movements disrupts the establishment of opposing poles of BMP and Wnt/TCF activity and the patterning of anterior-posterior neural tissue. These results lead us to suggest that convergence and extension plays a causal role in the establishment of morphogen gradients and pattern formation during zebrafish gastrulation.
Plant-microbe co-evolution: allicin resistance in aPseudomonas fluorescensstrain (PfAR-1) isolated from garlic
Authors: Borlinghaus Jan , Bolger Anthony , Schier Christina , Vogel Alexander , Gruhlke Martin C. H. , Slusarenko Alan J.
Published: September 2019

The antibiotic defense substance allicin (diallylthiosulfinate) is produced by garlic (Allium sativumL.) after tissue damage, giving garlic its characteristic odor. Allicin is a redox-toxin that oxidizes thiols in glutathione and cellular proteins. A highly allicin-resistantPseudomonas fluorescensstrain (PfAR-1) was isolated from garlic, and genomic clones were shotgun electroporated into an allicin-susceptibleP. syringaestrain (Ps4612). Recipients showing allicin-resistance had all inherited a group of genes from one of three similar genomic islands (GI), that had been identified in anin silicoanalysis of thePfAR-1 genome. A core fragment of 8-10 congruent genes with redox-related functions, present in each GI, was shown to confer allicin-specific resistance toP. syringae, and even to an unrelatedE. colistrain. Transposon mutagenesis and overexpression analyses revealed the contribution of individual candidate genes to allicin-resistance. Moreover,PfAR-1 was unusual in having 3glutathione reductase(glr) genes, two copies in two of the GIs, but outside of the core group, and one copy in thePfAR-1 genome. Glr activity was approximately 2-fold higher inPfAR-1 than in related susceptiblePf0-1, with only a singleglrgene. Moreover, anE. coliΔglrmutant showed increased susceptibility to allicin, which was complemented byPfAR-1glr1. Taken together, our data support a multi-component resistance mechanism against allicin, achieved through horizontal gene transfer during coevolution, and allowing exploitation of the garlic ecological niche. GI regions syntenic withPfAR-1 GIs are present in other plant-associated bacterial species, perhaps suggesting a wider role in adaptation to plantsper se.
Parasite transmission in aquatic ecosystems under climate change: joint effects of temperature, host behavior and elimination of parasite larvae by predators
Authors: Gopko M. , Mironova E. , Pasternak A. , Mikheev V. , Taskinen J.
Published: September 2019

A moderate raise in temperature was suggested to enhance the impact of parasites on aquatic ecosystems. Under higher temperatures, poikilothermic animals (e.g. fish), increase their activity, which can result in a more frequent encounter with parasites. However, temperature increase may also trigger processes counteracting an increased risk of parasitic infections. For instance, removal of free-living stages of parasites by filter-feeding organisms can increase with temperature and potentially mitigate disease risk in ecosystems under climate change.

In our study, we aimed to find out whether an increased infection transmission under higher temperatures can be, at least, partly compensated by the increased removal of parasitic larvae be aquatic predators. In addition, we planned to reveal the behavioral mechanism underlying the more successful transmission of the parasite at higher temperatures.

We experimentally studied how temperature, the behavior of fish host (rainbow trout) and the presence of filter-feeding mussels in the environment influence transmission success of trematode larvae (Diplostomum pseudospathaceumcercariae) to fish host.

We found that temperature raise increased, while presence of filter-feeding mussels in the environment decreased infection intensities in fish. However, the effect of mussel’s presence was constant within the tested range of water temperatures (15-23ºC), which suggests that it cannot compensate for the observed increased transmission of parasites under temperature raise. The difference in fish individual behavior (swimming activity) before the exposure to parasites was a substantial factor the affecting host’s vulnerability to infection. However, fish motor activity only weakly correlated with temperature, therefore, it is unlikely to be responsible for the increased infection success under warmer conditions. After exposure to parasites, fish strongly decreased their activity. This decrease was temperature-dependent and more pronounced in bolder (more active) fish, which leads to lower variability in activity of fish exposed to parasites compared with the safe environment. Post-exposure activity did not influence the infection intensity.

In general, we showed that the elimination of trematode larvae by filter-feeders is unlikely to deter the potential effects of global warming on host-parasite interactions in temperate freshwater ecosystems.
Causal inference for the effect of environmental chemicals on chronic kidney disease
Authors: Zhao Jing , Hinton Paige , Ma Qin
Published: September 2019

There is evidence from a limited number of statistical and animal studies that suggest that perfluoroalkyl acids (PFAs) are linked to a decline in kidney function. Thus, PFA exposure may be a modifiable risk factor for chronic kidney disease (CKD). As PFA is pervasive throughout our environment, determining its health effects is an important public health concern. We examined cross-sectional data from the 2009-2010 cycle of NHANES using generalized propensity score (GPS) analysis and univariate and multivariate ordinary least squares (OLS) regression to determine the link between urinary PFA concentration and estimated glomerular filtration rate (eGFR). GPS estimation methods used were Hirano-Imbens, additive spline, and a generalized additive model. Each of the statistical models used associated an increase in PFA concentration with a decline in eGFR, though the eGFR fit using the multivariate regression model were consistently higher than from the other four models. We conclude that PFA is a modifiable risk factor for CKD and GPS analysis produces credible results in estimating the effect of chemical exposures on continuous measure of kidney functions such as eGFR.

Graphical abstract