bluuebunny/crossref_metadata_2025 huggingface dataset:
NAD+repletion rescues female fertility during reproductive ageing
Authors: Bertoldo Michael J. , Listijono Dave R. , Ho Wing-Hong Jonathan , Riepsamen Angelique H. , Jin Xing L. , Selesniemi Kaisa , Goss Dale M. , Mahbub Saabah , Campbell Jared M. , Habibalahi Abbas , Loh Wei-Guo Nicholas , Youngson Neil A. , Maniam Jayanthi , Wong Ashley S.A. , Richani Dulama , Li Catherine , Zhao Yiqing , Marinova Maria , Kim Lynn-Jee , Lau Laurin , Wu Rachael M , Mikolaizak A. Stefanie , Araki Toshiyuki , Le Couteur David G. , Turner Nigel , Morris Margaret J. , Walters Kirsty A. , Goldys Ewa , O’Neill Christopher , Gilchrist Robert B. , Sinclair David A. , Homer Hayden A. , Wu Lindsay E.
Published: August 2019

Female infertility is a common and devastating condition with life-long health, emotional and social consequences. There is currently no pharmacological therapy for preserving oocyte quality during aging, which is the strongest risk factor for infertility. This leads to an age dependent decline in natural conception and IVF success rates (1). Here, we show that this is due in part to declining levels of the metabolic cofactor nicotinamide adenine dinucleotide (NAD+), and that restoring NAD+levels with its metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality and quantity in aged animals, leading to improved fertility. These benefits extend to the developing embryo, where NMN supplementation in embryo culture media following IVF enhances blastocyst formation in older mice. The NAD+dependent deacylase SIRT2 is sufficient, but not essential, to recapitulate the benefits ofin vivoNMN treatment, and transgenic overexpression of SIRT2 maintains oocyte spindle assembly, accurate chromosome segregation, decreased oxidative stress and overall fertility with ageing. Pharmacological elevation of NAD+may be an effective, non-invasive strategy for restoring and maintaining female fertility during ageing, and for improving the success of IVF.
Culex saltanensis and Culex interfor (Diptera: Culicidae) are susceptible and competent to transmit St. Louis encephalitis virus (Flavivirus: Flaviviridae) in central Argentina.
Authors: Beranek Mauricio , Quaglia Agustin , Peralta Giovana , Flores Fernando , Stein Marina , Diaz Adrian , Almiron Walter , Contigiani Marta
Published: August 2019

Infectious diseases caused by mosquito-borne viruses constitute health and economic problems worldwide. St. Louis encephalitis virus (SLEV) is endemic and autochthonous in the American continent. Culex pipiens quinquefasciatus is the primary urban vector of SLEV; however, Culex interfor and Culex saltanensis have also been found naturally infected with the virus, suggesting their potential role as vectors. OBJECTIVE: The aim of this study was to determine the vector competence of Cx. interfor and Cx. saltanensis for SLEV from central Argentina in comparison to Cx. p. quinquefasciatus. METHODS: Adult female mosquitoes of the three Culex species were orally infected by feeding on viremic chicks that had been inoculated with SLEV. Then, abdomens, legs and saliva blood-fed mosquitoes were analyzed by viral plaque assay and the presence of cytopathic effect on the cell culture monolayer. RESULTS: Mosquitoes were permissive to orally acquired infections, to virus dissemination, and transmission of SLEV in the saliva. Cx. saltanensis and Cx. interfor are potential vectors of SLEV. CONCLUSIONS: Our results demonstrate that in Argentina both Cx. saltanensis and Cx. interfor are susceptible to SLEV and competent for its transmission. Moreover they are abundant during SLEV epidemic period in urban area, positive for this virus in nature, and found to feed on natural hosts.
PredictingN-strain coexistence from co-colonization interactions: epidemiology meets ecology and the replicator equation
Authors: Madec Sten , Gjini Erida
Published: August 2019

Multi-type spreading processes are ubiquitous in ecology, epidemiology and social systems, but remain hard to model mathematically and to understand on a fundamental level. Here, we describe and study a multi-typesusceptible-infected-susceptible(SIS) model that allows for up to two co-infections of a host. Fitness differences betweenNinfectious agents are mediated through altered susceptibilities to secondary infections that depend on colonizer- co-colonizer interactions. By assuming small differences between such pairwise traits (and other infection parameters equal), we derive a model reduction framework using separation of timescales. This ‘quasi-neutrality’ in strain space yields a fast timescale where all types behave as neutral, and a slow timescale where non-neutral dynamics take place. On the slow timescale,Nequations govern strain frequencies and accurately approximate the dynamics of the full system withO(N2) variables. We show that this model reduction coincides with a special case of the replicator equation, which, in our system, emerges in terms of the pairwise invasion fitnesses among strains. This framework allows to build the multi-type community dynamics bottom-up from only pairwise outcomes between constituent members. We find that mean fitness of the multi-strain system, changing with individual frequencies, acts equally upon each type, and is a key indicator of system resistance to invasion. Besides efficient computation and complexity reduction, these results open new perspectives into high-dimensional community ecology, detection of species interactions, and evolution of biodiversity, with applications to other multi-type biological contests. By uncovering the link between an epidemiological system and the replicator equation, we also show our co-infection model relates to Fisher’s fundamental theorem and to conservative Lotka-Volterra systems.
A role for DIS3L2 over human nonsense-mediated mRNA decay targets
Authors: da Costa Paulo J. , Menezes Juliane , Saramago Margarida , García-Moreno Juan F. , Santos Hugo A. , Gama-Carvalho Margarida , Arraiano Cecília M. , Viegas Sandra C. , Romão Luísa
Published: August 2019

The nonsense-mediated decay (NMD) pathway selectively degrades mRNAs carrying a premature translation-termination codon but also regulates the abundance of a large number of physiological mRNAs that encode full-length proteins. In human cells, NMD-targeted mRNAs are degraded by endonucleolytic cleavage and exonucleolytic degradation from both 5’ and 3’ ends. This is done by a process not yet completely understood that recruits decapping and 5’-to-3’ exonuclease activities, as well as deadenylating and 3’-to-5’ exonuclease exosome activities. In yeast, DIS3/Rrp44 protein is the catalytic subunit of the exosome, but in humans, there are three known paralogues of this enzyme: DIS3, DIS3L1, and DIS3L2. DIS3L1 and DIS3L2 exoribonucleases localize in the same compartment where NMD occurs, but little is known about their role in this process. In order to unveil the role of DIS3L2 in NMD, here we show that some NMD-targets accumulate in DIS3L2-depleted cells. mRNA half-life analysis further supports that these NMD-targets are in fact DIS3L2 substrates. Besides, we observed that DIS3L2 acts over full-length transcripts, through a process that also involves UPF1. Moreover, DIS3L2-mediated decay is dependent on the activity of the terminal uridylyl transferases Zcchc6/11 (TUT7/4). Together, our findings establish a role for DIS3L2 and uridylation in NMD.
Anterior cingulate cortex differently modulates fronto-parietal functional connectivity between resting-state and working memory tasks
Authors: Di Xin , Zhang Heming , Biswal Bharat B
Published: August 2019

The brain fronto-parietal regions and the functional communications between them are critical in supporting working memory and other executive functions. The functional connectivity between fronto-parietal regions are modulated by working memory loads, and are shown to be modulated by a third brain region in resting-state. However, it is largely unknown that whether the third-region modulations remain the same during working memory tasks or were largely modulated by task demands. In the current study, we collected functional MRI (fMRI) data when the subjects were performing n-back tasks and in resting-state. We first used a block-designed localizer to define the fronto-parietal regions that showed higher activations in the 2-back than the 1-back condition. Next, we performed physiophysiological interaction (PPI) analysis using left and right middle frontal gyrus (MFG) and superior parietal lobule (SPL) regions, respectively, in three continuous-designed runs of resting-state, 1-back, and 2-back conditions. No regions showed consistent modulatory interactions with the seed pairs in the three conditions. Instead, the anterior cingulate cortex (ACC) showed different modulatory interactions with the right MFG and SPL among the three conditions. While increased activity of the ACC was associated with decreased functional coupling between the right MFG and SPL in resting-state, it was associated with increased functional coupling in the 2-back condition. The observed task modulations support the functional significance of the modulations of the ACC on fronto-parietal connectivity.
Attenuated Dopamine Receptor Signaling in Nucleus Accumbens Core in a Rat Model of Chemically-Induced Neuropathy
Authors: Selley D.E. , Lazenka M.F. , Sim-Selley L.J. , Potter D. N. , Chartoff Elena H. , Carlezon W.A. , Negus S.S.
Published: August 2019

Neuropathy is major source of chronic pain that can be caused by mechanically or chemically induced nerve injury. Previous work in a rat model of neuropathic pain demonstrated that bilateral formalin injection into the hind paws produced mechanical hypersensitivity (allodynia) and depressed responding for intracranial self-stimulation (ICSS). To determine whether neuropathy alters dopamine receptor responsiveness in mesolimbic brain regions, we examined dopamine D1-like and D2-like receptor (D1/2R) signaling and expression in male rats 14 days after bilateral intraplantar formalin injections into both rear paws. D2R-mediated G-protein activation and expression of the D2R long, but not short, isoform were reduced in nucleus accumbens (NAc) core, but not in NAc shell, caudate-putamen (CPu) or ventral tegmental area (VTA) of formalin-compared to saline-treated rats. In addition, D1R-stimulated adenylyl cyclase (AC) activity was also reduced in NAc core, but not in NAc shell or prefrontal cortex, of formalin-treated rats, whereas D1R expression was unaffected. Expression of other proteins involved in dopamine neurotransmission, including dopamine uptake transporter (DAT) and tyrosine hydroxylase (TH), were unaffected by formalin treatment. In behavioral tests, the effects of D2R agonists on ICSS were attenuated in formalin-treated rats, whereas the effects of D1R agonists were unchanged. These results indicate that intraplantar formalin as a model of chemically induced neuropathy produces attenuation of highly specific DA receptor signaling processes in NAc core of male rats.
Identifying branch-specific positive selection throughout the regulatory genome using an appropriate neutral proxy
Authors: Berrio Alejandro , Haygood Ralph , Wray Gregory A
Published: August 2019

Adaptive changes incis-regulatory elements are an essential component of evolution by natural selection. Identifying adaptive and functional noncoding DNA elements throughout the genome is therefore crucial for understanding the relationship between phenotype and genotype. Here, we introduce a method we calledadaptyPhy, which adds significant improvements to our earlier method that tests for branch-specific directional selection in noncoding sequences. The motivation for these improvements is to provide a more sensitive and better targeted characterization of directional selection and neutral evolution across the genome. We use ENCODE annotations to identify appropriate proxy neutral sequences and demonstrate that the conservativeness of the test can be modulated during the filtration of reference alignments. We apply the method to noncoding Human Accelerated Elements as well as open chromatin elements previously identified in 125 human tissues and cell lines to demonstrate its utility. We also simulate sequence alignments under different classes of evolution in order to validate the ability ofadaptiPhyto distinguish positive selection from relaxation of constraint and neutral evolution. Finally, we evaluate the impact of query region length, proxy neutral sequence length, and branch count on test sensitivity.
Facetto: Combining Unsupervised and Supervised Learning for Hierarchical Phenotype Analysis in Multi-Channel Image Data
Authors: Krueger Robert , Beyer Johanna , Jang Won-Dong , Kim Nam Wook , Sokolov Artem , Sorger Peter K. , Pfister Hanspeter
Published: August 2019

Facetto is a scalable visual analytics application that is used to discover single-cell phenotypes in high-dimensional multi-channel microscopy images of human tumors and tissues. Such images represent the cutting edge of digital histology and promise to revolutionize how diseases such as cancer are studied, diagnosed, and treated. Highly multiplexed tissue images are complex, comprising 109or more pixels, 60-plus channels, and millions of individual cells. This makes manual analysis challenging and error-prone. Existing automated approaches are also inadequate, in large part, because they are unable to effectively exploit the deep knowledge of human tissue biology available to anatomic pathologists. To overcome these challenges, Facetto enables a semi-automated analysis of cell types and states. It integrates unsupervised and supervised learning into the image and feature exploration process and offers tools for analytical provenance. Experts can cluster the data to discover new types of cancer and immune cells and use clustering results to train a convolutional neural network that classifies new cells accordingly. Likewise, the output of classifiers can be clustered to discover aggregate patterns and phenotype subsets. We also introduce a new hierarchical approach to keep track of analysis steps and data subsets created by users; this assists in the identification of cell types. Users can build phenotype trees and interact with the resulting hierarchical structures of both high-dimensional feature and image spaces. We report on use-cases in which domain scientists explore various large-scale fluorescence imaging datasets. We demonstrate how Facetto assists users in steering the clustering and classification process, inspecting analysis results, and gaining new scientific insights into cancer biology.
A neural network for online spike classification that improves decoding accuracy
Authors: Issar Deepa , Williamson Ryan C. , Khanna Sanjeev B. , Smith Matthew A.
Published: August 2019

Separating neural signals from noise can improve brain-computer interface performance and stability. However, most algorithms for separating neural action potentials from noise are not suitable for use in real time and have shown mixed effects on decoding performance. With the goal of removing noise that impedes online decoding, we sought to automate the intuition of human spike-sorters to operate in real time with an easily tunable parameter governing the stringency with which spike waveforms are classified. We trained an artificial neural network with one hidden layer on neural waveforms that were hand-labeled as either spikes or noise. The network output was a likelihood metric for each waveform it classified, and we tuned the network’s stringency by varying the minimum likelihood value for a waveform to be considered a spike. Using the network’s labels to exclude noise waveforms, we decoded remembered target location during a memory-guided saccade task from electrode arrays implanted in prefrontal cortex of rhesus macaque monkeys. The network classified waveforms in real time, and its classifications were qualitatively similar to those of a human spike-sorter. Compared to decoding with threshold crossings, in most sessions we improved decoding performance by removing waveforms with low spike likelihood values. Furthermore, decoding with our network’s classifications became more beneficial as time since array implantation increased. Our classifier serves as a feasible preprocessing step, with little risk of harm, that could be applied to both offline neural data analyses and online decoding.

New & Noteworthy

While there are many spike-sorting methods that isolate well-defined single units, these methods typically involve human intervention and have inconsistent effects on decoding. We used human classified neural waveforms as training data to create an artificial neural network that could be tuned to separate spikes from noise that impaired decoding. We found that this network operated in real time and was suitable for both offline data processing and online decoding.
Experimental Determination of Evolutionary Barriers to Horizontal Gene Transfer
Authors: Kirit Hande Acar , Lagator Mato , Bollback Jonathan P.
Published: August 2019

Horizontal gene transfer, the acquisition of genes across species boundaries, is a major source of novel phenotypes. Several barriers have been suggested to impede the likelihood of horizontal transmission; however experimental evidence is scarce. We measured the fitness effects of genes transferred fromSalmonella entericaserovar Typhimurium toEscherichia coli, and found that most result in strong fitness costs. Previously identified evolutionary barriers — gene function and the number of protein-protein interactions — did not predict the fitness effects of transferred genes. In contrast, dosage sensitivity, gene length, and the intrinsic protein disorder significantly impact the likelihood of a successful horizontal transfer. While computational approaches have been successful in describing long-term barriers to horizontal gene transfer, our experimental results identified previously underappreciated barriers that determine the fitness effects of newly transferred genes, and hence their short-term eco-evolutionary dynamics.
The Human Motor Cortex Contributes to Gravity Compensation to Maintain Posture and During Reaching
Authors: Hardesty R. L. , Ellaway P. H. , Gritsenko V.
Published: August 2019

How the neural motor system recruits muscles to support the arm against gravity is a matter of active debate. It is unknown how the neural motor system compensates for the changing gravity-related joint moments either when holding a steady-state posture or during movement between postural steady states, e.g., during reaching. Here we used single-pulse transcranial magnetic stimulation to compare the roles that the human primary motor cortex plays in the muscle recruitment to compensate for gravity. We hypothesized that the motor cortex contributes to muscle recruitment to both maintain posture and to compensate for changes in gravitational passive joint moments during movement. To test this hypothesis, we used visual targets in virtual reality to instruct five postures and three movements with or against gravity. We then measured the amplitude and gain of motor evoked potentials in multiple muscles of the arm at several phases of the reaching motion and during posture maintenance. Stimulation below the resting motor threshold, calibrated to the biceps muscle, caused motor evoked potentials in all muscles during all postural and reaching tasks. The amplitude of motor evoked potentials was proportional to the motoneuronal excitability measured as muscle activity. The coefficient of proportionality was positively correlated with the postural component of muscle moment during posture and movement. Altogether our results support the hypothesis. The observed contribution of the motor cortex to the recruitment of multiple antagonistic muscles suggests a whole-limb strategy for overcoming passive gravity-related moments with both active muscle moments and muscle co-activation that modulates limb impedance.

New & Noteworthy

Maintaining static posture and producing motion appear to be contradictory tasks for the nervous system. In contrast to this seeming dichotomy, our results show that the motorcortical control signals play the same role in both tasks when it is framed in biomechanical terms, i.e., muscle contractions needed to compensate for gravity.
An efficient method to clone TAL effector genes fromXanthomonas oryzaeusing Gibson assembly
Authors: Li Chenhao , Ji Chonghui , Huguet-Tapia José C. , White Frank F. , Dong Hansong , Yang Bing
Published: August 2019

TALes (Transcription Activator-Like effectors) represent the largest family of type III effectors among pathogenic bacteria and play a critical role in the process of infection. Strains ofXanthomonas oryzaepv. oryzae (Xoo) and some strains of otherXanthomonaspathogens contain large numbers of TALe genes. Previous techniques to clone individual or a complement of TALe genes through conventional strategies are inefficient and time-consuming due to multiple genes (up to 29 copies) in a given genome and technically challenging due to the repetitive sequences (up to 33 nearly identical 102-nucleotide repeats) of individual TALe genes. Thus, only a limited number of TALe genes have been molecularly cloned and characterized, and the functions of most TALe genes remain unknown. Here, we present an easy and efficient cloning technique to clone TALe genes selectively throughin vitrohomologous recombination and single strand annealing and demonstrate the feasibility of this approach with four different Xoo strains. Based on the Gibson assembly strategy, two complementary vectors with scaffolds that can preferentially capture all TALe genes from a pool of genomic fragments were designed. Both vector systems enabled cloning of a full complement of TALe genes from each of four Xoo strains and functional analysis of individual TALes in rice in approximately one month compared to three months by previously used methods. The results demonstrate a robust tool to advance TALe biology and a potential for broad usage of this approach to clone multiple copies of highly competitive DNA elements in any genome of interest.
Humans can navigate complex graph structures acquired during latent learning
Authors: Rmus Milena , Ritz Harrison , Hunter Lindsay E , Bornstein Aaron M , Shenhav Amitai
Published: August 2019

Humans appear to represent many forms of knowledge in associative networks whose nodes are multiply connected, including sensory, spatial, and semantic. Recent work has shown that explicitly augmenting artificial agents with such graph-structured representations endows them with more human-like capabilities of compositionality and transfer learning. An open question is how humans acquire these representations. Previously, it has been shown that humans can learn to navigate graph-structured conceptual spaces on the basis of direct experience with trajectories that intentionally draw the network contours (Schapiro et al., 2012;2016), or through direct experience with rewards that covary with the underlying associative distance (Wu et al., 2018). Here, we provide initial evidence that this capability is more general, extending to learning to reason about shortest-path distances across a graph structure acquired across disjoint experiences with randomized edges of the graph - a form of latent learning. In other words, we show that humans can infer graph structures, assembling them from disordered experiences. We further show that the degree to which individuals learn to reason correctly and with reference to the structure of the graph corresponds to their propensity, in a separate task, to use model-based reinforcement learning to achieve rewards. This connection suggests that the correct acquisition of graph-structured relationships is a central ability underlying forward planning and reasoning, and may be a core computation across the many domains in which graph-based reasoning is advantageous.
Pervasive differential splicing in Marek’s Disease Virus can discriminate CVI-988 vaccine strain from RB-1B virulent strain in chicken embryonic fibroblasts
Authors: Sadigh Yashar , Tahiri-Alaoui Abdessamad , Spatz Stephen , Nair Venugopal , Ribeca Paolo
Published: August 2019

Marek’s disease is a major scourge challenging poultry health worldwide. It is caused by the highly contagious Marek’s disease virus (MDV), an alphaherpesvirus. Here we show that, similar to other members of itsHerpesviridaefamily, MDV also presents a complex landscape of splicing events, most of which are uncharacterised and/or not annotated. Quite strikingly, and although the biological relevance of this fact is unknown, we found that a number of viral splicing isoforms are strain-specific despite the close sequence similarity of the strains considered, virulent RB-1B and vaccine CVI-988. We validated our findings by devising an assay that discriminates infections caused by the two strains in chicken embryonic fibroblasts based on the presence of some RNA species. To our knowledge, this study is the first ever to accomplish such a result, emphasizing how important a comprehensive knowledge of the viral transcriptome can be to understand viral pathogenesis.

Importance

Marek’s disease virus (MDV) causes an agro-economically important disease of chickens worldwide. Although commercial poultry are vaccinated against MDV, it is not possible to achieve sterilising immunity, and available vaccines can only protect chickens against the symptoms of the disease. Vaccinated chicken often become superinfected with virulent strains, shedding virus into the environment. The most effective MDV vaccine strain, CVI-988, shares >99% sequence identity with the prototype virulent virus strain RB-1B. Interestingly, our work shows that despite their almost identical sequences MDV strains CVI-988 and RB-1B have significantly different splicing profiles, and hence transcriptomes. We independently validated this discovery by detecting with real-time PCR some splicing isoforms expressed by MDV strain CVI-988 and absent in the transcriptome of the RB-1B strain. These results indicate that the coding potential of MDV might be much larger than previously thought, and suggest a likely underestimation of the role of the viral transcriptome in the pathogenesis and prevention of MDV.
Tick-borne pathogens in ticks (Acari: Ixodidae) collected from various domestic and wild hosts in Corsica (France), a Mediterranean island environment
Authors: Grech-Angelini Sébastien , Stachurski Frédéric , Vayssier-Taussat Muriel , Devillers Elodie , Casabianca François , Lancelot Renaud , Uilenberg Gerrit , Moutailler Sara
Published: August 2019

Corsica is a touristic mountainous French island in the north-west of the Mediterranean Sea presenting a large diversity of natural environments where many interactions between humans, domestic animals and wild fauna occur. Despite this favourable context, tick-borne pathogens (TBPs) have not systematically been investigated. In this study, a large number of TBPs were screened in ticks collected during one year from domestic and wild hosts in Corsica. More than 1,500 ticks belonging to nine species and five genera (Rhipicephalus,Hyalomma,Dermacentor,IxodesandHaemaphysalis) were analysed individually or pooled (by species, gender, host and locality). A real-time microfluidic PCR was used for high-throughput screening of TBPs DNA. This advanced methodology permitted the simultaneous detection of 29 bacterial and 12 parasitic species (includingBorrelia,Anaplasma,Ehrlichia,Rickettsia,Bartonella,CandidatusNeoehrlichia,Coxiella,Francisella,BabesiaandTheileria). CCHF virus was investigated individually in tick species known to be vectors or carriers of this virus. In almost half of the tick pools (48%), DNA from at least one pathogen was detected and eleven species of TBPs from six genera were reported. TBPs were found in ticks from all collected hosts and were present in more than 80% of the investigated area. The detection of some pathogens DNA confirmed their previous identification in Corsica, such asRickettsia aeschlimannii(23% of pools),Rickettsia slovaca(5%),Anaplasma marginale(4%) andTheileria equi(0.4%), but most TBPs DNA was not reported before in Corsican ticks. This includedAnaplasma phagocytophilum(16%),Rickettsia helvetica(1%), Borrelia afzelii(0.7%), Borrelia miyamotoi(1%), Bartonella henselae(2%),Babesia bigemina(2%) andBabesia ovis(0.5%). The important tick infection rate and the diversity of TBPs reported in this study highlight the probable role of animal reservoir hosts for zoonotic pathogens and human exposure to TBPs on Corsica.
Loss of intermediate filament IFB-1 reduces mobility, density and physiological function of mitochondria in C. elegans sensory neurons
Authors: Barmaver Syed Nooruzuha , Shanmugam Muniesh Muthaiyan , Chang Yen , Bhan Prerana , Wu Gong-Her , Wagner Oliver I.
Published: August 2019

Mitochondria and intermediate filament (IF) accumulations often occur during imbalanced axonal transport leading to various types of neurological diseases. It is still poorly understood whether a link between neuronal IFs and mitochondrial mobility exist. In C. elegans, among the 11 cytoplasmic IF family proteins, IFB-1 is of particular interest as it is expressed in a subset of sensory neurons. Depletion of IFB-1 leads to mild dye-filling and significant chemotaxis defects as well as reduced life span. Sensory neuron development is affected and mitochondria transport is slowed down leading to reduced densities of these organelles. Mitochondria tend to cluster in neurons of IFB-1 mutants likely dependent on fission but independent of fusion events. Oxygen consumption and mitochondrial membrane potential is measurably reduced in worms carrying mutations in the ifb-1 gene. Membrane potential also seems to play a role in transport such as FCCP treatment led to increased directional switching of mitochondria. Mitochondria colocalize with IFB-1 in worm neurons and appear in a complex with IFB-1 in pull-down assays. In summary, we propose a model in which neuronal intermediate filaments may serve as critical (transient) anchor points for mitochondria during their long-range transport in neurons for steady and balanced transport.

Abstract Figure

Synopsis

Various neurological diseases are both associated with abnormal accumulations of neuronal intermediate filaments as well as mitochondria. Here, we report a link between these two phenomena employing the model organisms C. elegans. Depletion of neuronal intermediate filament IFB-1 impairs the transport of mitochondria in sensory neurons leading to clustered and accumulated mitochondria affecting neuronal growth and oxygen consumption in nematodes.
Structural Basis for CAL1-Mediated Centromere Maintenance
Authors: Medina-Pritchard Bethan , Lazou Vasiliki , Zou Juan , Byron Olwyn , Rappsilber Juri , Heun Patrick , Jeyaprakash A. Arockia
Published: August 2019

Centromeres are microtubule attachment sites on chromosomes defined by the enrichment of CENP-A-containing nucleosomes. To preserve centromere identity, CENP-A must be escorted to centromeres by a CENP-A-specific chaperone for deposition. Despite this essential requirement, many eukaryotes differ in the composition of players involved in centromere maintenance highlighting the plasticity of this process. In humans, CENP-A recognition and centromere targeting is achieved by HJURP and the Mis18 complex, respectively. Here, using crystal structures, we show how Drosophila CAL1, an evolutionarily distinct CENP-A chaperone, targets CENP-A to the centromere receptor CENP-C without the requirement of the Mis18 complex: while the N-terminal CAL1 fragment (CAL11-160) wraps around CENP-A/H4 through multiple physical contacts, the C-terminal CAL1 fragment (CAL1893-914) directly binds CENP-C cupin dimer. Our work shows CAL1, though divergent at the primary structure, employs evolutionarily conserved and adaptive structural principles to recognise CENP-A/H4 and CENP-C providing insights into the minimalistic principles underlying centromere maintenance.
Stimulating stopping? Investigating the effects of tDCS over the inferior frontal gyri and visual cortices
Authors: Thunberg Christina N. , Messel Mari S. , Raud Liisa , Huster René J.
Published: August 2019

The ability to cancel an already initiated response is central to flexible behavior. While several different behavioral and neural markers have been suggested to quantify the latency of the stopping process, it remains unclear if they quantify the stopping process itself, or other supporting mechanisms such as visual and/or attentional processing. The present study sought to investigate the contributions of inhibitory and sensory processes to stopping latency markers by combining transcranial direct current stimulation (tDCS), electroencephalography (EEG) and electromyography (EMG) recordings in a within-subject design. Active and sham tDCS were applied over the inferior frontal gyri (IFG) and visual cortices (VC), combined with both online and offline EEG and EMG recordings. We found evidence that neither of the active tDCS condition affected stopping latencies relative to sham stimulation. Our results challenge previous findings suggesting that anodal tDCS over the IFG can reduce stopping latency and demonstrates the necessity of adequate control conditions in tDCS research. Additionally, while the different putative markers of stopping latency showed generally positive correlations with each other, they also showed substantial variation in the estimated latency of inhibition, making it unlikely that they all capture the same construct exclusively.
Nutrient-dependent mTORC1 signaling in coral-algal symbiosis
Authors: Voss Philipp A. , Gornik Sebastian G. , Jacobovitz Marie R. , Rupp Sebastian , Dörr Melanie S. , Maegele Ira , Guse Annika
Published: August 2019

To coordinate development and growth with nutrient availability, animals must sense nutrients and acquire food from the environment once energy is depleted. A notable exception are reef-building corals that form a stable symbiosis with intracellular photosynthetic dinoflagellates (family Symbiodiniaceae (LaJeunesse et al., 2018)). Symbionts reside in ‘symbiosomes’ and transfer key nutrients to support nutrition and growth of their coral host in nutrient-poor environments (Muscatine, 1990; Yellowlees et al., 2008). To date, it is unclear how symbiont-provided nutrients are sensed to adapt host physiology to this endosymbiotic life-style. Here we use the symbiosis model Exaiptasia pallida (hereafter Aiptasia) to address this. Aiptasia larvae, similar to their coral relatives, are naturally non-symbiotic and phagocytose symbionts anew each generation into their endodermal cells (Bucher et al., 2016; Grawunder et al., 2015; Hambleton et al., 2014). Using cell-specific transcriptomics, we find that symbiosis establishment results in downregulation of various catabolic pathways, including autophagy in host cells. This metabolic switch is likely triggered by the highly-conserved mTORC1 (mechanistic target of rapamycin complex 1) signaling cascade, shown to integrate lysosomal nutrient abundance with animal development (Perera and Zoncu, 2016). Specifically, symbiosomes are LAMP1-positive and recruit mTORC1 kinase. In symbiotic anemones, mTORC1 signaling is elevated when compared to non-symbiotic animals, resembling a feeding response. Moreover, symbiosis establishment enhances lipid content and cell proliferation in Aiptasia larvae. Challenging the prevailing belief that symbiosomes are early arrested phagosomes (Mohamed et al., 2016), we propose a model in which symbiosomes functionally resemble lysosomes as core nutrient sensing and signaling hubs that have co-opted the evolutionary ancient mTORC1 pathway to promote growth in endosymbiotic cnidarians.
Simulating bipedal walking using a translating center of pressure
Authors: Potwar Karna , Lee Dongheui
Published: August 2019

During walking, foot orientation and foot placement allow humans to stabilize their gait and to move forward. Consequently the upper body adapts to the ground reaction force (GRF) transmitted through the feet. The foot-ground contact is often modeled as a fixed pivot in bipedal models for analysis of locomotion. The fixed pivot models, however, cannot capture the effect of shift in the pivot point from heel to toe. In this study, we propose a novel bipedal model, called SLIPCOP, which employs a translating center of pressure (COP) in a spring loaded inverted pendulum (SLIP) model. The translating COP has two modes: one with a constant speed of translation and the other as the weighted function of the GRF in the fore aft direction. We use the relation between walking speed and touchdown (TD) angle as well as walking speed and COP speed, from existing literature, to restrict steady state solutions within the human walking domain. We find that with these relations, SLIPCOPprovides steady state solutions for very slow to very fast walking speeds unlike SLIP. SLIPCOPfor normal to very fast walking speed shows good accuracy in estimating COM amplitude and swing stance ratio. SLIPCOPis able to estimate the distance traveled by the COP during stance with high precision.
Genome-wide development of miRNA-based SSR markers in Cleistogenes songorica with their transferability analysis to gramineae and non- gramineae species
Authors: Kanzana Gisele , Zhang Yufei , Ma Tiantian , Liu Wenxian , Wu Fan , Yan Qi , Min Xueyang , Yan Zhuanzhuan , Pascal Muvunyi Blaise , Li Jie , Zhang Zhengshe , Zhao Yufeng , Zhang Jiyu
Published: August 2019

SSR markers are commonly used for many genetic applications, such as map construction, fingerprinting and genetic diversity analysis due to their high reproducibility, levels of polymorphism and abundance. As endogenous, small RNAs, miRNAs have essential roles in plant development and gene expression under diverse stress conditions, including various biotic and abiotic stress conditions. In the present study, we predicted 110 pre-miRNAs sequences from 287 precursor miRNAs and used them as queries for SSR marker development. Among 110 primer pairs, 85 were successfully amplified and examined for transferability to other gramineae and non-gramineae species. The results showed that all 82 primer pairs yielded unambiguous and strong amplification, and across the 23 studied Cleistogenes accessions, a total of 385 alleles were polymorphic. The number of alleles produced per primer varied from 3 to 11, with an average of 4.69 per locus. The expected heterozygosity (He) ranged from 0.44 to 0.88, with an average of 0.74 per locus, and the PIC (Polymorphism Information Content) values ranged from 0.34 to 0.87, with an average of 0.69 per locus. In this study, 1422 miRNA target genes were predicted and analyzed using the GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) databases. The results showed that this miRNA-based microsatellite marker system can be very useful for genetic diversity and marker-assisted breeding studies.
Distribution and abundance of bottlenose dolphin (Tursiops truncatus) over the French Mediterranean continental shelf
Authors: Labach Hélène , Azzinari Caroline , Barbier Maxime , Cesarini Cathy , Daniel Boris , David Léa , Dhermain Frank , Di-Méglio Nathalie , Guichard Benjamin , Jourdan Julie , Robert Nicolas , Roul Marine , Tomasi Nicolas , Gimenez Olivier
Published: August 2019

The Mediterranean bottlenose dolphin (Tursiops truncatus) sub-population is listed as vulnerable by the International Union for Conservation of Nature. This species is strictly protected in France and the designation of Special Areas of Conservation (SAC) is required under the European Habitat Directive. However, little information is available about the structure, dynamic and distribution of the population in the French Mediterranean waters. We collected photo-identification data over the whole French Mediterranean continental shelf all year round between 2013 and 2015. We sighted 151 groups of bottlenose dolphins allowing the individually photo-identification of 1,060 animals. The encounter rate distribution showed the presence of bottlenose dolphins over the whole continental shelf all year round. Using capture-recapture methods, we estimated for the first time the size of the bottlenose dolphin resident population at 557 individuals (95% confidence interval: 216-872) along the French Mediterranean continental coast. Our results were used in support of the designation of a new dedicated SAC in the Gulf of Lion and provide a reference state for the bottlenose dolphin monitoring in the French Mediterranean waters in the context of the Marine Strategy Framework Directive.
The generation of plasma cells and CD27−IgD−B cells during Hantavirus infection are associated with distinct pathological findings
Authors: Kerkman PF , Dernstedt A , Tadala L , Mittler E , Dannborg M , Sundling C , Maleki KT , Tauriainen J , Tuiskunen-Bäck A , Wigren Byström J , Ocaya P , Thunberg T , Jangra R , Román-Sosa G , Guardado-Calvo P , Rey FA , Klingström J , Chandran K , Puhar A , Ahlm C , Forsell MNE
Published: August 2019

Human hantavirus infections can cause hemorrhagic fever with renal syndrome (HFRS), major signs of the disease being thrombocytopenia and transient kidney dysfunction. By a comprehensive and longitudinal study of circulating B cells, we demonstrate that these two pathologies associate with distinct effects on the humoral immune system during HFRS. Low thrombocyte counts strongly associated with an abnormal frequency of plasmablasts in circulation, whereas kidney dysfunction was indicative of an accumulation of CD27−B cells and plasmablasts. Finally, we provide evidence that high levels of extracellular ATP in circulation during HFRS correlates with shedding of surface CD27 on B cells via a metallomatrix proteinase-8-mediated mechanism. Since extracellular ATP is known to regulate kidney function, our study reveals a link between kidney dysfunction and the generation of CD27−IgD−B cells, and a potential molecular target for treatment of the symptomatic phase of HFRS.
Structural diversity of oligomeric β-propellers with different numbers of identical blades
Authors: Afanasieva Evgenia , Chaudhuri Indronil , Martin Jörg , Hertle Eva , Ursinus Astrid , Alva Vikram , Hartmann Marcus D. , Lupas Andrei N.
Published: August 2019

β-Propellers arise through the amplification of a supersecondary structure element called a blade. This process produces toroids of between four and twelve repeats, which are almost always arranged sequentially in a single polypeptide chain. We found that new propellers evolve continuously by amplification from single blades. We therefore investigated whether such nascent propellers can fold as homo-oligomers before they have been fully amplified within a single chain. One-to six-bladed building blocks derived from two seven-bladed WD40 propellers yielded stable homo-oligomers with six to nine blades, depending on the size of the building block. High-resolution structures for tetramers of two blades, trimers of three blades, and dimers of four and five blades, respectively, show structurally diverse propellers and include a novel fold, highlighting the inherent flexibility of the WD40 blade. Our data support the hypothesis that subdomain-sized fragments can provide structural versatility in the evolution of new proteins.
Discovering the shared biology of cognitive traits determined by genetic overlap
Authors: Guimaraes JPOFT , Bralten J , Greven CU , Franke B , Sprooten E , Beckmann CF
Published: August 2019

Investigating the contribution of biology to human cognition has assumed a bottom-up causal cascade where genes influence brain systems that activate, communicate, and ultimately drive behavior. Yet few studies have directly tested whether cognitive traits with overlapping genetic underpinnings also rely on overlapping brain systems. Here, we report a step-wise exploratory analysis of genetic and functional imaging overlaps among cognitive traits. We used twin-based genetic analyses in the human connectome project (HCP) dataset (N=486), in which we quantified the heritability of measures of cognitive functions, and tested whether they were driven by common genetic factors using pairwise genetic correlations. Subsequently, we derived activation maps associated with cognitive tasks via functional imaging meta-analysis in BrainMap (N=4484), and tested whether cognitive traits that shared genetic variation also exhibited overlapping brain activation. Our genetic analysis determined that six cognitive measures (card sorting, no-go continuous performance, fluid intelligence, processing speed, reading decoding and vocabulary comprehension) were heritable (0.3<h2<0.5), and genetically correlated with at least one other heritable cognitive measure (0.2<ρg<0.35). The meta-analysis showed that two genetically-correlated traits, card sorting and fluid intelligence (ρg=0.24), also had a significant brain activation overlap (ρperm=0.29). These findings indicate that fluid intelligence and executive functioning rely on overlapping biological features, both at the neural systems level and at the molecular level. The cross-disciplinary approach we introduce provides a concrete framework for data-driven quantification of biological convergence between genetics, brain function, and behavior in health and disease.
MMP2 As An Independent Prognostic Stratifier In Oral Cavity Cancers
Authors: Hoffmann Caroline , Vacher Sophie , Sirven Philémon , Lecerf Charlotte , Massenet Lucile , Moreira Aurélie , Surun Aurore , Schnitzler Anne , Klijanienko Jerzy , Mariani Odette , Jeannot Emmanuelle , Badois Nathalie , Lesnik Maria , Choussy Olivier , Le Tourneau Christophe , Guillot-Delost Maude , Kamal Maud , Bieche Ivan , Soumelis Vassili
Published: August 2019

Background

Around 25% of oral cavity squamous cell carcinoma (OCSCC) are not controlled by standard of care. Identifying those patients could offer them possibilities for intensified and personalized regimen. However, there is currently no validated biomarker for OCSCC patient selection in a pre-treatment setting.

Patients and methods

Our objectives were to determine a robust and independent predictive biomarker for disease related death in OCSCC treated with standard of care. Tumor and juxtatumor secretome were analyzed in a prospective discovery cohort of 37 OCSCC treated by primary surgery. Independent biomarker validation was performed by RTqPCR in a retrospective cohort of 145 patients with similar clinical features. An 18-gene signature (18G) predictive of the response to PD-1 blockade was evaluated in the same cohort..

Results

Among 29 deregulated molecules in a secretome analysis, we identified soluble MMP2 as a prognostic biomarker. In our validation cohort (n=145), high levels ofMMP2andCD276, and low levels ofCXCL10andSTAT1mRNA were associated with poor prognosis in univariate analysis (Kaplan-Meier).MMP2(p = 0.001) and extra-nodal extension (ENE) (p = 0.006) were independent biomarkers of disease-specific survival (DSS) in multivariate analysis, and defined prognostic groups with 5-year DSS ranging from 36% (MMP2highENE+) to 88% (MMP2lowENE-). The expression of 18G was similar in the different prognostic groups, suggesting comparable responsiveness to anti-PD-1.

Conclusion

High levels of MMP2 was an independent and validated prognostic biomarker, which may be used to select poor prognosis patients for intensified neoadjuvant or adjuvant regimens.