bluuebunny/crossref_metadata_2025 huggingface dataset:
Diaporthe nebulae sp. nov. and First Report of D. cynaroidis, D. novem, and D. serafiniae on Grapevines in South Africa
Authors: Lesuthu Palesa , Mostert Lizel , Spies Christoffel F. J. , Moyo Providence , Regnier Thierry , Halleen Francois
Published: September 2018

Diaporthe species cause Phomopsis cane and leaf spot as well as Phomopsis dieback on grapevines. Symptoms of Phomopsis dieback have increasingly been observed over the past few years. In order to assess the current status of Diaporthe on grapevines in the Western Cape Province of South Africa, isolations were made from dormant grafted nursery vines, dormant rootstock canes, and dying or dead spurs of field vines. Cultures identified as Diaporthe based on morphological features were further identified to species level by sequencing the internal transcribed spacers (ITS) 1 and 2 and 5.8S rRNA and, for a representative subsample of isolates, the partial beta-tubulin (tub2) and translation elongation factor 1-alpha (EF1-α) genes. Phylogenetic analysis of the combined ITS, tub2, and EF1-α data revealed nine Diaporthe species associated with grapevines during this survey. One of these represents a new species, D. nebulae sp. nov., and three other species, namely D. novem, D. cynaroidis, and D. serafiniae, are reported on grapevines in South Africa for the first time. Species-specific primers were designed for PCR identification of D. ampelina, D. ambigua, and D. foeniculina. Pathogenicity studies conducted on detached grapevine shoots indicated D. ampelina, D. novem, and D. nebulae sp. nov. as the most virulent species.
Identification of Resistance to Powdery Mildew in Publicly Available Male Hop Germplasm
Authors: Gent David H. , Claassen Briana J. , Twomey Megan C. , Wolfenbarger Sierra N.
Published: September 2018

Powdery mildew (caused by Podosphaera macularis) is one of the most important diseases of hop in the western United States. Strains of the fungus virulent on cultivars possessing the resistance factor termed R6 and the cultivar Cascade have become widespread in the Pacific Northwestern United States, the primary hop producing region in the country, rendering most cultivars grown susceptible to the disease at some level. In an effort to identify potential sources of resistance in extant germplasm, 136 male accessions of hop contained in the U.S. Department of Agriculture collection were screened under controlled conditions. Iterative inoculations with three isolates of P. macularis with varying race identified 23 (16.9%) accessions with apparent resistance to all known races of the pathogen present in the Pacific Northwest. Of the 23 accessions, 12 were resistant when inoculated with three additional isolates obtained from Europe that possess novel virulences. The nature of resistance in these individuals is unclear but does not appear to be based on known R genes. Identification of possible novel sources of resistance to powdery mildew will be useful to hop breeding programs in the western United States and elsewhere.
Microtubules Gate Tau Condensation to Spatially Regulate Microtubule Functions
Authors: Tan Ruensern , Lam Aileen J. , Tan Tracy , Han Jisoo , Nowakowski Dan W. , Vershinin Michael , Simo Sergi , Ori-McKenney Kassandra M. , McKenney Richard J.
Published: September 2018

Tau is an abundant microtubule-associated protein in neurons. Tau aggregation into insoluble fibrils is a hallmark of Alzheimer’s disease and other dementias, yet the physiological state of tau molecules within cells remains unclear. Using single molecule imaging, we directly observe that the microtubule lattice regulates reversible tau self-association, leading to dynamic condensation of tau molecules on the microtubule surface. Tau condensates form selectively permissible barriers, spatially regulating the activity of MT severing enzymes and the movement of molecular motors through their boundaries. We propose that reversible self-association of tau molecules, controlled by the microtubule, is an important mechanism of tau’s biological functions, and that oligomerization of tau is a common property shared between the physiological and disease forms of the molecule.

One Sentence Summary:

Reversible tau oligomerization regulates microtubule functions.
Effects of altering histone post-translational modifications on mitotic chromosome structure and mechanics
Authors: Biggs Ronald , Liu Patrick , Stephens Andrew D. , Marko John F.
Published: September 2018

During cell division chromatin is compacted into mitotic chromosomes to aid faithful segregation of the genome between two daughter cells. Post-translational modifications (PTM) of histones alter compaction of interphase chromatin, but it remains poorly understood how these modifications affect mitotic chromosome stiffness and structure. Using micropipette-based force measurements and epigenetic drugs, we probed the influence of canonical histone PTMs that dictate interphase euchromatin (acetylation) and heterochromatin (methylation) on mitotic chromosome stiffness. By measuring chromosome doubling force (the force required to double chromosome length), we find that histone methylation, but not acetylation, contributes to mitotic structure and stiffness. We discuss our findings in the context of chromatin gel modeling of the large-scale organization of mitotic chromosomes.
Multiple C2 domains and Transmembrane region Proteins (MCTPs) tether membranes at plasmodesmata
Authors: Brault Marie L. , Petit Jules D. , Immel Françoise , Nicolas William J. , Brocard Lysiane , Gaston Amélia , Fouché Mathieu , Hawkins Timothy J. , Crowet Jean-Marc , Grison Magali S. , Kraner Max , Alva Vikram , Claverol Stéphane , Deleu Magali , Lins Laurence , Tilsner Jens , Bayer Emmanuelle M.
Published: September 2018

Abstract

In eukaryotes, membrane contact sites (MCS) allow direct communication between organelles. Plants have evolved unique MCS, the plasmodesmata intercellular pores, which combine endoplasmic reticulum (ER) - plasma membrane (PM) contacts with regulation of cell-to-cell signalling. The molecular mechanism and function of membrane tethering within plasmodesmata remains unknown.

Here we show that the Multiple C2 domains and Transmembrane region Protein (MCTP) family, key regulators of cell-to-cell signalling in plants, act as ER - PM tethers specifically at plasmodesmata. We report that MCTPs are core plasmodesmata proteins that insert into the ER via their transmembrane region whilst their C2 domains dock to the PM through interaction with anionic phospholipids. A mctp3/4 loss-of-function mutant induces plant developmental defects while MCTP4 expression in a yeast Δtether mutant partially restores ER-PM tethering. Our data suggest that MCTPs are unique membrane tethers controlling both ER-PM contacts and cell-cell signalling.
Modeling neuronal avalanches and long-range temporal correlations at the emergence of collective oscillations: continuously varying exponents mimic M/EEG results
Authors: Porta Leonardo Dalla , Copelli Mauro
Published: September 2018

We revisit the CROS (“CRitical OScillations”) model which was recently proposed as an attempt to reproduce both scale-invariant neuronal avalanches and long-range time correlations. With excitatory and inhibitory stochastic neurons locally connected in a two-dimensional disordered network, the model exhibits a transition from an active to an oscillating state. Precisely at the transition, the fluctuations of the network activity have detrended fluctuation analysis (DFA) exponents close to one, and avalanches (defined as supra-threshold activity) have power law distributions of size and duration. By simulating larger system sizes, we show that, differently from previous results, the exponents governing the distributions of avalanche size and duration are not necessarily those of the mean-field directed percolation universality class (3/2 and 2, respectively). Instead, exponents obtained via a maximum-likelihood estimator vary continuously in a narrow region of parameter space. Around that critical region, moreover, the values of avalanche and DFA exponents display a spread with negative correlations, in qualitative agreement with the interindividual variability that was experimentally observed in M/EEG data.
Early Neural Correlates of an Auditory Pitch - Visual Size Cross-modal Association
Authors: Boyle Stephanie C. , Kayser Christoph , Ince Robin A. A.
Published: September 2018

Research has shown participants associate high pitch tones with small objects, and low pitch tones with large objects. Yet it remains unclear when these associations emerge in neural signals, and whether or not they are likely the result of predictive coding mechanisms being influenced by multisensory priors. Here we investigated these questions using a modified version of the implicit association task, 128-channel human EEG, and two approaches to single-trial analysis (linear discriminant and mutual information). During two interlaced discrimination tasks (auditory high/low tone and visual small/large circle), one stimulus was presented per trial and the auditory stimulus-response assignment was manipulated. On congruent trials preferred pairings (high tone, small circle) were assigned to the same response key, and on incongruent trials non-preferred pairings were (low tone, small circle). The results showed participants (male and female) responded faster during auditory congruent than incongruent trials. The EEG results showed that acoustic pitch and visual size were represented early in the trial (~100 ms and ~220 ms), over temporal and frontal regions. Neural signals were also modulated by congruency early in the trial for auditory (<100ms) and visual modalities (~200ms). For auditory trials, EEG components were predictive of reaction times, but for visual trials they were not. These EEG results were consistent across analysis methods, demonstrating they are robust to the statistical methodology used. Overall, our data support an early origin of cross-modal associations, and suggest that these may originate during early sensory processing potentially due to predictive coding mechanisms.
Coalescent-based phylogenetic inference from genes with unequivocal historical signal suggests a polytomy at the root of the placental mammal tree of life
Authors: Moreira Filipe R. R. , Schrago Carlos G.
Published: September 2018

Finding the correct place of the root of the Placentalia tree of life is an unsolved problem in mammalian systematics. Three major competing hypotheses were proposed, alternating the position of the supraordinal taxa Afrotheria, Xenarthra, or Atlantogenata as sister lineages to the remaining placentals. While all three phylogenetic associations were inferred by studies conducted so far, recent assessments applying heterogeneous models and coalescent-based phylogenetic methods found robust support for the Atlantogenata hypothesis. Current developments in theoretical phylogenetics, such as the demonstration that concatenating genes may bias the likelihood function, and that summary coalescent-based phylogenetic methods are sensitive to errors in gene tree estimation, calls for a reevaluation of the early placental split problem. We investigated the phylogenetic relationships between placental superorders by restricting the analysis to subsets of genes with unequivocal phylogenetic signal. In contrast to previous works, we show that the hypothesis of a polytomy at the placental root could not be rejected under the multispecies coalescent model. This result endorses conclusions from analyses of retroposon insertion patterns. We provide an analytical framework to access empirical polytomies employing summary coalescent methods and topological tests, helping the investigation of poorly resolved nodes in the tree of life.
Kinetically distinct phases of tau on microtubules regulate kinesin motors and severing enzymes
Authors: Siahaan Valerie , Krattenmacher Jochen , Hernandez-Vega Amayra , Hyman Anthony A. , Diez Stefan , Lansky Zdenek , Braun Marcus
Published: September 2018

Tau is an intrinsically disordered protein, which diffuses on microtubules. In neurodegenerative diseases collectively termed tauopathies, tau malfunction and its detachment from axonal microtubules is correlated with microtubule degradation. It is known that tau can protect microtubules from microtubule-degrading enzymes, such as katanin. However, how tau can fulfill such regulative function is still unclear. Using in vitro reconstitution, we here show that tau molecules on microtubules cooperatively form islands of an ordered layer with regulatory qualities distinct from a comparably dense layer of diffusible tau. These islands shield the microtubules from katanin and kinesin-1 but are penetrable by kinesin-8 which causes the islands to disassemble. Our results indicate a new phase of tau, constituting an adjustable protective sheath around microtubules.
GPR17 is an Essential Component of the Negative Feedback Loop of the Sonic Hedgehog Signalling Pathway in Neural Tube Development
Authors: Yatsuzuka Atsuki , Hori Akiko , Kadoya Minori , Matsuo-Takasaki Mami , Kondo Toru , Sasai Noriaki
Published: September 2018

Dorsal-ventral pattern formation of the neural tube is regulated by temporal and spatial activities of extracellular signalling molecules. Sonic hedgehog (Shh) assigns ventral neural subtypes via activation of the Gli transcription factors. Shh activity changes dynamically during neural differentiation, but the mechanisms responsible for regulating this dynamicity are not fully understood. Here we show that the P2Y-type G-protein coupled receptor GPR17 is involved in temporal regulation of the Shh signal. GPR17 was expressed in the ventral progenitor regions of the neural tube and acted as a negative regulator of the Shh signal in chick embryos. While the activation of the GPR17-related signal inhibited ventral identity, perturbation ofGPR17expression led to aberrant expansion of ventral neural domains. Notably, perturbation ofGPR17expression partially inhibited the negative feedback of Gli activity. Moreover, GPR17 increased cAMP activity, suggesting that it exerts its function by inhibiting the processing of Gli3 protein. GPR17 also negatively regulated Shh signalling in neural cells differentiated from mouse embryonic stem cells, suggesting that GPR17 function is conserved among different organisms. Our results demonstrate that GPR17 is a novel negative regulator of Shh signalling in a wide range of cellular contexts.

Author Summary

During neural development, determination of cell fate and the progress of differentiation are regulated by extracellular signal molecules, including Sonic Hedgehog (Shh). Shh forms a gradient within the embryonic organ of the central nervous system, or the neural tube, and a variety of cells are produced corresponding to the concentration. While the signal concentration is critical for cell fate, recent studies have revealed that the intracellular signal intensity does not always correspond to the Shh concentration. Rather, the intracellular signal intensity changes over time. Importantly, the signal intensity peaks and gradually decreases thereafter, and the half-life of the Shh signal contributes to the cell fate determination. However, the mechanisms for this temporal change are not fully understood.

By using chick embryos and mouse embryonic stem cells as model systems, we demonstrate that the G-protein coupled receptor, GPR17, is an essential regulator for the negative feedback of the Shh signal during neural development. WhileGPR17gene expression is induced by the Shh signal, GPR17 perturbs the Shh signalling pathway. This negative function of GPR17 on the Shh signal is conserved among different vertebrate species. The collective data demonstrate that GPR17 is a negative regulator for the Shh signalling pathway in a wide range of the cellular contexts.
Genome-wide identification and expression analysis of the FAR gene family in hexaploid wheat (Triticum aestivum L.)
Authors: Shi Shandang , Chai Guaiqiang , Ren Hui , Nan Wenzhi , Wu Hongqi , Wang Yong , Li Chunlian , Wang Zhonghua
Published: September 2018

Fatty acyl-CoA reductase (FAR) is involved in the biosynthesis of primary alcohols, which are waxy constituents that play an important role in plant stress. Previous studies have shown that primary alcohol is the most important component in the wheat seeding stage and accounts for more than 80% of the total composition. To date, eight FAR genes have been identified in wheat, but there has not been a systematic analysis. In this study, a comprehensive overview of the TaFAR gene family was performed, including analyses of the phylogenetic relationship, the multiple sequence alignment, the conserved motif distribution and the expression pattern. The result showed that a total of 41 wheat FAR genes were identified and designated TaFAR1-A–TaFAR22-D; all FAR genes were divided into six classes according to their phylogenetic relationship, and most of the FAR genes might be related to wheat cuticular wax synthesis. The analysis of the promoter binding site showed that TaFAR genes could be regulated by the MYB transcription factor and could be used as target genes for hormone regulation under adverse conditions, especially during a drought. This study provides a basis for further analyses of the TaFAR gene function and of upstream regulatory genes.
High-throughput targeted long-read single cell sequencing reveals the clonal and transcriptional landscape of lymphocytes
Authors: Singh Mandeep , Al-Eryani Ghamdan , Carswell Shaun , Ferguson James M. , Blackburn James , Barton Kirston , Roden Daniel , Luciani Fabio , Phan Tri , Junankar Simon , Jackson Katherine , Goodnow Christopher C. , Smith Martin A. , Swarbrick Alexander
Published: September 2018

High-throughput single-cell RNA-Sequencing is a powerful technique for gene expression profiling of complex and heterogeneous cellular populations such as the immune system. However, these methods only provide short-read sequence from one end of a cDNA template, making them poorly suited to the investigation of gene-regulatory events such as mRNA splicing, adaptive immune responses or somatic genome evolution. To address this challenge, we have developed a method that combines targeted long-read sequencing with short-read based transcriptome profiling of barcoded single cell libraries generated by droplet-based partitioning. We use Repertoire And Gene Expression sequencing (RAGE-seq) to accurately characterize full-length T cell (TCR) and B cell (BCR) receptor sequences and transcriptional profiles of more than 7,138 lymphocytes sampled from the primary tumour and draining lymph node of a breast cancer patient. With this method we show that somatic mutation, alternate splicing and clonal evolution of T and B lymphocytes can be tracked across these tissue compartments. Our results demonstrate that RAGE-Seq is an accessible and cost-effective method for high-throughput deep single cell profiling, applicable to a wide range of biological challenges.
Middle-way flexible docking: Pose prediction using mixed-resolution Monte Carlo in estrogen receptorα
Authors: Spiriti Justin , Subramanian Sundar Raman , Palli Rohith , Wu Maria , Zuckerman Daniel M.
Published: September 2018

There is a vast gulf between the two primary strategies for simulating protein-ligand interactions. Docking methods significantly limit or eliminate protein flexibility to gain great speed at the price of uncontrolled inaccuracy, whereas fully flexible atomistic molecular dynamics simulations are expensive and often suffer from limited sampling. We have developed a flexible docking approach geared especially for highly flexible or poorly resolved targets based on mixed-resolution Monte Carlo (MRMC), which is intended to offer a balance among speed, protein flexibility, and sampling power. The binding region of the protein is treated with a standard atomistic force field, while the remainder of the protein is modeled at the residue level with a Gō model that permits protein flexibility while saving computational cost. Implicit solvation is used. Here we assess three facets of the MRMC approach with implications for other docking studies: (i) the role of receptor flexibility in cross-docking pose prediction; (ii) the use of non-equilibrium candidate Monte Carlo (NCMC) and (iii) the use of pose-clustering in scoring. We examine 61 co-crystallized ligands of estrogen receptorα, an important cancer target known for its flexibility. We also compare the performance of the MRMC approach with Autodock smina, a docking program. [1] Adding protein flexibility, not surprisingly, leads to significantly lower total energies and stronger interactions between protein and ligand, but notably we document the important role of backbone flexibility in the improvement. The improved backbone flexibility also leads to improved performance relative to smina. Somewhat unexpectedly, our implementation of NCMC leads to only modestly improved sampling of ligand poses. Overall, the addition of protein flexibility improves the performance of docking, as measured by energy-ranked poses, but we do not find significant improvements based on cluster information or the use of NCMC.
Covariate Assisted Principal Regression for Covariance Matrix Outcomes
Authors: Zhao Yi , Wang Bingkai , Mostofsky Stewart H. , Caffo Brian S. , Luo Xi
Published: September 2018

Modeling variances in data has been an important topic in many fields, including in financial and neuroimaging analysis. We consider the problem of regressing covariance matrices on a vector covariates, collected from each observational unit. The main aim is to uncover the variation in the covariance matrices across units that are explained by the covariates. This paper introducesCovariate Assisted Principal(CAP) regression, an optimization-based method for identifying the components predicted by (generalized) linear models of the covariates. We develop computationally efficient algorithms to jointly search the projection directions and regression coefficients, and we establish the asymptotic properties. Using extensive simulation studies, our method shows higher accuracy and robustness in coefficient estimation than competing methods. Applied to a resting-state functional magnetic resonance imaging study, our approach identifies the human brain network changes associated with age and sex.
Cellular senescence is a central response to cytotoxic chemotherapy in high-grade serous ovarian cancer
Authors: Calvo L. , Cheng S. , Skulimowski M. , Clément I. , Portelance L. , Zhan Y. , Carmona E. , Lafontaine J. , de Ladurantaye M. , Rahimi K. , Provencher D. , Mes-Masson A.-M. , Rodier F.
Published: September 2018

High-grade serous ovarian cancer (HGSOC) commonly responds to initial therapy, but this response is rarely durable. Understanding cell fate decisions taken by HGSOC cells in response to treatment could guide new therapeutic opportunities. Here we find that primary HGSOC cultures undergo therapy-induced senescence (TIS) in response to DNA damage induced by chemotherapy. HGSOC-TIS displays most senescence hallmarks including persistent DNA damage, senescence-associated inflammatory secretome, and selective sensitivity to senolytic Bcl-2 family inhibitors, suggesting avenues for preferential synergistic clearance of these cells. Comparison of pre- and post-chemotherapy HGSOC patient tissue samples revealed changes in senescence biomarkers suggestive of post-treatment “in patient” TIS, and a stronger TIS response in post-chemotherapy tissues correlated with better 5-year survival rates for patients. Together, these data suggest that the induction of cellular senescence in HGSOC cells accounts at least in part for beneficial cellular responses to treatment in patients providing a new therapeutic target.

One Sentence Summary

Cellular senescence is a central beneficial response to chemotherapy in high-grade serous ovarian cancer bothin vitroand in patient.
Evolutionary dynamics of recent selection for enhanced social cognition
Authors: Miller Sara E. , Legan Andrew W. , Henshaw Michael , Ostevik Katherine L. , Samuk Kieran , Uy Floria M. K. , Reeve H. Kern , Sheehan Michael J.
Published: September 2018

Cognitive abilities can vary dramatically among species though little is known about the dynamics of cognitive evolution. Here we demonstrate that recent evolution of visual individual recognition in the paper waspPolistes fuscatusis the target of arguably the strongest positive selective pressure in the species’ recent history. The most extreme selective sweeps inP. fuscatusare associated with genes known to be involved in long-term memory formation, mushroom body development and visual processing – all traits that have recently evolved in association with individual recognition. Cognitive evolution appears to have been driven initially by selection on standing variation in perceptual traits followed by both hard and soft sweeps on learning and memory. Evolutionary modeling reveals that intense selection as observed inP. fuscatusis likely the norm during the early stages of cognitive evolution. These data provide insight into the dynamics of cognition evolution demonstrating that social selection for increased intelligence can lead to rapid multi-genic adaptation of enhanced recognition abilities.
Replication stress induces mitotic death through parallel pathways regulated by WAPL and telomere deprotection
Authors: Masamsetti V. Pragathi , Mak Ka Sin , Jie Low Ronnie Ren , Riffkin Chris D. , Lamm Noa , Crabbe Laure , Karlseder Jan , Huang David C.S. , Hayashi Makoto T. , Cesare Anthony J.
Published: September 2018

Mitotic catastrophe is a broad descriptor encompassing unclear mechanisms of cell death. Here we investigate replication stress-driven mitotic catastrophe in human cells and identify that replication stress principally induces mitotic death signalled through two independent pathways. In p53-compromised cells we find that lethal replication stress confers WAPL-dependent centromere cohesion defects that maintain spindle assembly checkpoint-dependent mitotic arrest in the same cell cycle. Mitotic arrest then drives cohesion fatigue and triggers mitotic death through a primary pathway of BAX/BAK-dependent apoptosis. Simultaneously, a secondary mitotic death pathway is engaged through non-canonical telomere deprotection, regulated by TRF2, Aurora B and ATM. Additionally, we find that suppressing mitotic death promotes genome instability in replication stressed cells through diverse mechanisms depending upon how cell death is averted. These data demonstrate how replication stress-induced mitotic catastrophe signals cell death with implications for cancer treatment and genome instability.
Automated leg tracking reveals distinct conserved gait and tremor signatures inDrosophilamodels of Parkinson’s Disease and Spinocerebellar ataxia 3
Authors: Wu Shuang , Tan Kah Junn , Govindarajan Lakshmi Narasimhan , Stewart James Charles , Gu Lin , Hao Ho Joses Wei , Katarya Malvika , Wong Boon Hui , Tan Eng-King , Li Daiqin , Claridge-Chang Adam , Libedinsky Camilo , Cheng Li , Aw Sherry Shiying
Published: September 2018

Genetic models inDrosophilahave made invaluable contributions to our understanding of the molecular mechanisms underlying neurodegeneration. In human patients, some neurodegenerative diseases lead to characteristic movement dysfunctions, such as abnormal gait and tremors. However, it is currently unknown whether similar movement defects occur in the respective fly models, which could be used to model and better understand the pathophysiology of movement disorders. To address this question, we developed a machine-learning image-analysis programme — Feature Learning-based LImb segmentation and Tracking (FLLIT) — that automatically tracks leg claw positions of freely moving flies recorded on high-speed video, generating a series of body and leg movement parameters. Of note, FLLIT requires no user input for learning. We used FLLIT to characterise fly models of Parkinson’s Disease (PD) and Spinocerebellar ataxia 3 (SCA3). Between these models, walking gait and tremor characteristics differed markedly, and recapitulated signatures of the respective human diseases. Selective expression of mutant SCA3 in dopaminergic neurons led to phenotypes resembling that of PD flies, suggesting that the behavioural phenotype may depend on the circuits affected, rather than the specific nature of the mutation. Different mutations produced tremors in distinct leg pairs, indicating that different motor circuits are affected. Almost 190,000 video frames were tracked in this study, allowing, for the first time, high-throughput analysis of gait and tremor features inDrosophilamutants. As an efficient assay of mutant gait and tremor features in an important model system, FLLIT will enable the analysis of the neurogenetic mechanisms that underlie movement disorders.
A systematic review and standardized clinical validity assessment of male infertility genes
Authors: Oud Manon. S. , Volozonoka Ludmila , Smits Roos M. , Vissers Lisenka E.L.M. , Ramos Liliana , Veltman Joris A.
Published: September 2018

Study question

Which genes are confidently linked to human male infertility?

Summary answer

Our systematic literature search and clinical validity assessment reveals that a total of 67 genes are currently confidently linked to 81 human male infertility phenotypes.

What is known already

The discovery of novel male infertility genes is rapidly accelerating with the availability of Next-Generation Sequencing methods, but the quality of evidence for gene-disease relationships varies greatly. In order to improve genetic research, diagnostics and counseling, there is a need for an evidence-based overview of the currently known genes.

Study design, size, duration

We performed a systematic literature search and evidence assessment for all publications in Pubmed until June 2018 covering genetic causes of male infertility and/or defective male genitourinary development.

Participants/materials, setting, methods

Two independent reviewers conducted the literature search and included papers on the monogenic causes of human male infertility and excluded papers on genetic association or risk factors, karyotype anomalies and/or copy number variations affecting multiple genes. Next, the quality and the extent of all evidence supporting selected genes was weighed by a standardized scoring method and used to determine the clinical validity of each gene-disease relationship as expressed by the following six categories: no evidence, limited, moderate, strong, definitive or unable to classify.

Main results and the role of chance

From a total of 23,031 records, we included 1,286 publications about monogenic causes of male infertility leading to a list of 471 gene-disease relationships. The clinical validity of these gene-disease relationships varied widely and ranged from definitive (n=36) to strong (n=12), moderate (n=33), limited (n=86) or no evidence (n=154). A total of 150 gene-disease relationships could not be classified.

Limitations, reasons for caution

Our literature search was limited to Pubmed.

Wider implications of the findings

The comprehensive overview will aid researchers and clinicians in the field to establish gene lists for diagnostic screening using validated gene-disease criteria and identify gaps in our knowledge of male infertility. For future studies, the authors discuss the relevant and important international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility.

Study funding/competing interest(s)

This work was supported by a VICI grant from The Netherlands Organisation for Scientific Research (918-15-667 to JAV).
Collection of continuous rotation MicroED Data from Ion Beam Milled Crystals of Any Size
Authors: Martynowycz Michael W. , Zhao Wei , Hattne Johan , Jensen Grant J. , Gonen Tamir
Published: September 2018

Microcrystal electron diffraction (MicroED) allows for macromolecular structure solution from nanocrystals. To create crystals of suitable size for MicroED data collection, sample preparation typically involves sonication or pipetting a slurry of crystals from a crystallization drop. The resultant crystal fragments are fragile and the quality of the data that can be obtained from them is sensitive to subsequent sample preparation for cryoEM as interactions in the water-air interface can damage crystals during blotting. Here, we demonstrate the use of a focused ion beam to generate lamellae of macromolecular protein crystals for continuous rotation MicroED that are of ideal thickness, easy to locate, and require no blotting optimization. In this manner, crystals of nearly any size may be scooped and milled to ideal dimensions prior to data collection, thus streamlining the methodology for sample preparation for MicroED.
Propagation of orientation selectivity in a spiking network model of layered primary visual cortex
Authors: Merkt Benjamin , Schüßler Friedrich , Rotter Stefan
Published: September 2018

Neurons in different layers of sensory cortex generally have different functional properties. But what determines firing rates and tuning properties of neurons in different layers? Orientation selectivity in primary visual cortex (V1) is an interesting case to study these questions. Thalamic projections essentially determine the preferred orientation of neurons that receive direct input. But how is this tuning propagated though layers, and how can selective responses emerge in layers that do not have direct access to the thalamus? Here we combine numerical simulations with mathematical analyses to address this problem. We find that a large-scale network, which just accounts for experimentally measured layer and cell-type specific connection probabilities, yields firing rates and orientation selectivities matching electrophysiological recordings in rodent V1 surprisingly well. Further analysis, however, is complicated by the fact that neuronal responses emerge in a dynamic fashion and cannot be directly inferred from static neuroanatomy, as some connections tend to have unintuitive effects due to recurrent interactions and strong feedback loops. These emergent phenomena can be understood by linearizing and coarse-graining. In fact, we were able to derive a low-dimensional linear dynamical system effectively describing stimulus-driven activity layer by layer. This low-dimensional system explains layer-specific firing rates and orientation tuning by accounting for the different gain factors of the aggregate system. Our theory can also be used to design novel optogenetic stimulation experiments, thus facilitating further exploration of the interplay between connectivity and function.

Author summary

Understanding the precise roles of neuronal sub-populations in shaping the activity of networks is a fundamental objective of neuroscience research. In complex neuronal network structures like the neocortex, the relation between the connec-tome and the algorithm implemented in it is often not self-explaining. To this end, our work makes three important contributions. First, we show that the connectivity extracted by anatomical and physiological experiments in visual cortex suffices to explain important properties of the various sub-populations, including their selectivity to visual stimulation. Second, we introduce a novel system-level approach for the analysis of input-output relations of recurrent networks, which leads to the observed activity patterns. Third, we present a method for the design of future optogenetic experiments that can be used to devise specific stimuli resulting in a predictable change of neuronal activity. In summary, we introduce a novel frame-work to determine the relevant features of neuronal microcircuit function that can be applied to a wide range of neuronal systems.
An assessment of the interactions between climatic conditions and genetic characteristic on the agricultural performance of soybeans grown in Northeast Asia
Authors: Park Myoung Ryoul , Cai Chunmei , Seo Min-Jung , Yun Hong-Tae , Park Soo-Kwon , Choi Man-Soo , Park Chang-Hwan , Moon Jung Kyung
Published: September 2018

Glycine max, commonly known as soybean or soya bean, is a species of legume native to East Asia. The interactions between climatic conditions and genetic characteristic affect the agricultural performance of soybean. Therefore, an investigation to identify the main elements affecting the agricultural performances of 11 soybeans was conducted in Northeast Asia, China [Harbin (45°12′N) Yanji (42°53′N) Dalian (39°30′N) Qingdao (36°26′N)] Republic of Korea [Suwon (37°16′N) and Jeonju (35°49′N)]. The days to flowering (DTF) of soybeans with the e1-nf and e1-as alleles and the E1e2e3e4 genotype, except Keumgangkong, Tawonkong, and Duyoukong, was relatively short compared to soybeans with other alleles. Although DTF of the soybeans was highly correlated to all climatic conditions, days to maturity (DTM) and 100-seed weight (HSW) of the soybeans showed no significant correlation with any climatic conditions. The soybeans with a dominant Dt1 allele, except Tawonkong, had the longest stem length (STL). Moreover, the STL of the soybeans grown at the test fields showed a positive correlation with only day length (DL) although the results of our chamber test showed that STL of soybean was positively affected by average temperature (AVT) and DL. Soybean yield (YLD) showed positive correlations with latitude and DL (except L62-667, OT89-5, and OT89-6) although the response of YLD to the climatic conditions was cultivar-specific. Our results show that DTF and STL of soybeans grown in Northeast Asia are highly affected by DL although AVT and genetic characteristic also affect DTF and STL. Along with these results, we confirmed that the DTM, HSW, and YLD of the soybeans vary in relation to their genetic characteristic.
Rational Design of Peptide Vaccines for the Highly Lethal Nipah and Hendra Viruses
Authors: Dey Sumanta , Roy Proyasha , Dutta Tathagata , Nandy Ashesh , Basak Subhash C
Published: September 2018

The Nipah virus disease is a lethal infection that has led to 40% to 75% fatalities in Malaysia, Bangladesh and India. The reports of human-to-human transmission documented in Bangladesh has raised the specter of pandemic potential and has caused the World Health Organization to list the Nipah virus as one of the pathogens to be considered for development of drugs and vaccines on urgent basis, neither of which exist against the Nipah virus as of now, although many proposals have been made and trials initiated. Given that there are established country-specific differences in the virus’ effects and fatalities, meeting the sudden need for a vaccine in case of an epidemic will require design, development and preparation for a peptide vaccine. Thus, we propose a protocol for creating peptide vaccines that can be tailor-made for these specific countries, an approach which is being advocated for the first time. Here, we analyze the surface proteins, Fusion protein and Glycoprotein, of the strains currently affecting the three countries on a large scale and determine the specific country-based epitope differences.
A Fully Automated, Faster Noise Reduction Approach to Increasing the Analytical Capability of Chemical Imaging for Digital Histopathology
Authors: Gupta Soumyajit , Mittal Shachi , Kajdacsy-Balla Andre , Bhargava Rohit , Bajaj Chandrajit
Published: September 2018

High dimensional data, for example from infrared spectral imaging, involves an inherent trade-off in the acquisition time and quality of spatial-spectral data. Minimum Noise Fraction (MNF) developed by Green et al. [1] has been extensively studied as an algorithm for noise removal in HSI (Hyper-Spectral Imaging) data. However, there is a speed-accuracy trade-off in the process of manually deciding the relevant bands in the MNF space, which by current methods could become a person month time for analyzing an entire TMA (Tissue Micro Array). We propose three approaches termed ‘Fast MNF’, ‘Approx MNF’ and ‘Rand MNF’ where the computational time of the algorithm is reduced, as well as the entire process of band selection is fully automated. This automated approach is shown to perform at the same level of reconstruction accuracy as MNF with large speedup factors, resulting in the same task to be accomplished in hours. The different approximations of the algorithm, show the reconstruction accuracy vs storage (50×) and runtime speed (60×) trade-off. We apply the approach for automating the denoising of different tissue histology samples, in which the accuracy of classification (differentiating between the different histologic and pathologic classes) strongly depends on the SNR (signal to noise ratio) of recovered data. Therefore, we also compare the effect of the proposed denoising algorithms on classification accuracy. Since denoising HSI data is done without any ground truth, we also use a metric that assesses the quality of denoising in the image domain between the noisy and denoised image in absence of ground truth.
Colloidal quantum dots suitability for long term cell imaging
Authors: Farias Patricia M. A. , Galembeck André , Milani Raquel , Mendonca Wilson S. , Stingl Andreas
Published: September 2018

Fluorescent semiconductor nanoparticles in tree-dimensional quantum confinement, quantum dots (QDs), synthesized in aqueous medium, and functionalized with polyethylene glycol, were used as probes for the long-term imaging of glial cells. In vitro living healthy as well as cancer glial cells were labelled by direct insertion of a small volume of QDs contained in aqueous suspension into the culture wells. A long-term monitoring (over 7 days) of the cells was performed and no evidence of cell fixation and/or damage was observed. Two control groups, healthy and cancer glial cells, were used to compare cell viability. During the observation period, labelled and non labelled cells presented the same dynamics and no difference was observed regarding cell viability. To our knowledge, this is the first report of the viability of hydrophilic prepared quantum dots without any further surface treatment than the polyethylene-glycol coverage for the long-term imaging of living cells. Further, the study also permitted the observation of two distinct interaction mechanisms between cells and QDs. Healthy glial cells were mainly labelled at their surface, while non-healthy glial cells have shown a high rate in the uptake of QDs.
Pptc7 is an essential phosphatase for promoting mammalian mitochondrial metabolism and biogenesis
Authors: Niemi Natalie M. , Wilson Gary M. , Overmyer Katherine A. , Vögtle F.-Nora , Lohman Danielle C. , Schueler Kathryn L. , Attie Alan D. , Meisinger Chris , Coon Joshua J. , Pagliarini David J.
Published: September 2018

Mitochondrial proteins are replete with phosphorylation; however, the origin, abundance, and functional relevance of these modifications are largely unclear. Nonetheless, mitochondria possess multiple resident phosphatases, suggesting that protein dephosphorylation may be broadly important for mitochondrial activities. To explore this, we deleted the poorly characterized matrix phosphatasePptc7from mice using CRISPR-Cas9 technology. Strikingly,Pptc7−/−mice exhibited marked hypoketotic hypoglycemia, elevated acylcarnitines, and lactic acidosis, and died soon after birth.Pptc7−/−tissues had significantly diminished mitochondrial size and protein content despite normal transcript levels, but consistently elevated phosphorylation on select mitochondrial proteins. These putative Pptc7 substrates include the protein translocase complex subunit Timm50, whose phosphorylation reduced import activity. We further find that phosphorylation in or near the mitochondrial targeting sequences of multiple proteins can disrupt their import rates and matrix processing. Overall, our data define Pptc7 as a protein phosphatase essential for proper mitochondrial function and biogenesis during the extrauterine transition.
A large close relative ofC. elegansis slow-developing but not long-lived
Authors: Woodruff Gavin C. , Johnson Erik , Phillips Patrick C.
Published: September 2018

Background

Variation in body size is thought to be a major driver of a wide variety of ecological and evolutionary patterns, including changes in development, reproduction, and longevity.Caenorhabditis inopinatais a recently-discovered fig-associated nematode that is unusually large relative to other members of the genus, including the closely related model systemC. elegans. Here we test whether the dramatic increase in body size has led to correlated changes in key life history and developmental parameters within this species.

Results

Using four developmental milestones,C. inopinatawas found to have a slower rate of development thanC. elegansacross a range of temperatures. Despite this,C. inopinatadid not reveal any differences in adult lifespan fromC. elegansafter accounting for differences in developmental timing and reproductive mode.C. inopinatafecundity was generally lower than that ofC. elegans, but fitness improved under continuous-mating, consistent with sperm-limitation under gonochoristic (male/female) reproduction.C. inopinataalso revealed greater fecundity and viability at higher temperatures.

Conclusion

Consistent with observations in other ectotherms, slower growth inC. inopinataindicates a potential trade-off between body size and developmental timing, whereas its unchanged lifespan suggests that longevity is largely uncoupled from its increase in body size. Additionally, temperature-dependent patterns of fitness inC. inopinataare consistent with its geographic origins in subtropical Okinawa. Overall, these results underscore the extent to which changes in ecological context and body size can shape life history traits.
μ-rhythm extracted with personalized EEG filters correlates with corticospinal excitability in real-time phase-triggered EEG-TMS
Authors: Schaworonkow Natalie , Caldana Gordon Pedro , Belardinelli Paolo , Ziemann Ulf , Ole Bergmann Til , Zrenner Christoph
Published: September 2018

Ongoing brain activity has been implicated in the modulation of cortical excitability. The combination of electroencephalography (EEG) and transcranial magnetic stimulation (TMS) in a real-time triggered setup is a novel method for testing hypotheses about the relationship between spontaneous neuronal oscillations, cortical excitability, and synaptic plasticity. For this method, a reliable real-time extraction of the neuronal signal of interest from scalp EEG with high signal-to-noise ratio (SNR) is of crucial importance. Here we compare individually tailored spatial filters as computed by spatial-spectral decomposition (SSD), which maximizes SNR in a frequency band of interest, against established local C3-centered Laplacian filters for the extraction of the sensorimotor μ-rhythm. Single-pulse TMS over the left primary motor cortex was synchronized with the surface positive or negative peak of the respective extracted signal, and motor evoked potentials (MEP) were recorded with electromyography (EMG) of a contralateral hand muscle. Both extraction methods led to a comparable degree of MEP amplitude modulation by phase of the sensorimotor μ-rhythm at the time of stimulation. This could be relevant for targeting other brain regions with no working benchmark such as the local C3-centered Laplacian filter, as sufficient SNR is an important prerequisite for reliable real-time single-trial detection of EEG features.