bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmental Changes in EEG Phase Amplitude Coupling and Phase Preference over the First Three Years After Birth
Authors: Mariscal Michael G. , Levin April R. , Gabard-Durnam Laurel J. , Tager-Flusberg Helen , Nelson Charles A.
Published: October 2019

The coupling of the phase of slower electrophysiological oscillations with the amplitude of faster oscillations, termed phase-amplitude coupling (PAC), is thought to facilitate dynamic connectivity in the brain. Though the brain undergoes dramatic changes in connectivity during the first few years of life, how PAC changes through this developmental period has not been studied. Here, we examined PAC through electroencephalography (EEG) data collected longitudinally during an awake, eyes-open EEG collection paradigm in 98 children between the ages of 3 months and 3 years. We implement a novel technique developed for capturing both PAC strength and phase preference (i.e., where in the slower oscillation waveform the faster oscillation shows increased amplitude) simultaneously, and employed non-parametric clustering methods to evaluate our metrics across a range of frequency pairs and electrode locations. We found that frontal and occipital PAC, primarily between the alpha-beta and gamma frequencies, increased from early infancy to early childhood (p = 1.35 x 10-5). Additionally, we found frontal gamma coupled with the trough of the alpha-beta waveform, while occipital gamma coupled with the peak of the alpha-beta waveform. This opposing trend may reflect each region’s specialization towards feedback or feedforward processing, respectively.

Significance Statement

The brain undergoes significant changes in functional connectivity during infancy and early childhood, enabling the emergence of higher-level cognition. Phase-amplitude coupling (PAC) is thought to support the functional connectivity of the brain. Here, we find PAC increases from 3 months to 3 years of age. We additionally report the frontal and occipital brain areas show opposing forms of PAC; this difference could facilitate each region’s tendency towards bottom-up or top-down processing.
Conserved bacterial genomes from two geographically distinct peritidal stromatolite formations shed light on potential functional guilds
Authors: Waterworth Samantha C. , Isemonger Eric W. , Rees Evan R. , Dorrington Rosemary A. , Kwan Jason C.
Published: October 2019

Stromatolites are complex microbial mats that form lithified layers and ancient forms are the oldest evidence of life on earth, dating back over 3.4 billion years. Modern stromatolites are relatively rare but may provide clues about the function and evolution of their ancient counterparts. In this study, we focus on peritidal stromatolites occurring at Cape Recife and Schoenmakerskop on the southeastern South African coastline. Using assembled shotgun metagenomic data we obtained 183 genomic bins, of which the most dominant taxa were from the Cyanobacteriia class (Cyanobacteria phylum), with lower but notable abundances of bacteria classified as Alphaproteobacteria, Gammaproteobacteria and Bacteroidia. We identified functional gene sets in bacterial species conserved across two geographically distinct stromatolite formations, which may promote carbonate precipitation through the reduction of nitrogenous compounds and possible production of calcium ions. We propose that an abundance of extracellular alkaline phosphatases may lead to the formation of phosphatic deposits within these stromatolites. We conclude that the cumulative effect of several conserved bacterial species drives accretion in these two stromatolite formations.

ORIGINALITY-SIGNIFICANCE

Peritidal stromatolites are unique among stromatolite formations as they grow at the dynamic interface of calcium carbonate-rich groundwater and coastal marine waters. The peritidal space forms a relatively unstable environment and the factors that influence the growth of these peritidal structures is not well understood. To our knowledge, this is the first comparative study that assesses species conservation within the microbial communities of two geographically distinct peritidal stromatolite formations. We assessed the potential functional roles of these communities using genomic bins clustered from metagenomic sequencing data. We identified several conserved bacterial species across the two sites and hypothesize that their genetic functional potential may be important in the formation of pertidal stromatolites. We contrasted these findings against a well-studied site in Shark Bay, Australia and show that, unlike these hypersaline formations, archaea do not play a major role in peritidal stromatolite formation. Furthermore, bacterial nitrogen and phosphate metabolisms of conserved species may be driving factors behind lithification in peritidal stromatolites.
Establishing Rod-Shape from Spherical, Peptidoglycan-Deficient Bacterial Spores
Authors: Zhang Huan , Mulholland Garrett A. , Seef Sofiene , Zhu Shiwei , Liu Jun , Mignot Tâm , Nan Beiyan
Published: October 2019

Chemical-induced spores of the Gram-negative bacterium Myxococcus xanthus are peptidoglycan (PG)-deficient. It is unclear how these spherical spores germinate into rod-shaped, walled cells without preexisting PG templates. We found that germinating spores first synthesize PG randomly on spherical surfaces. MglB, a GTPase-activating protein, forms a cluster that surveys the status of PG growth and stabilizes at one future cell pole. Following MglB, the Ras family GTPase MglA localizes to the second pole. MglA directs molecular motors to transport the bacterial actin homolog MreB and the Rod PG synthesis complexes away from poles. The Rod system establishes rod-shape by elongating PG at nonpolar regions. Thus, the interaction between GTPase, cytoskeletons and molecular motors provides a mechanism for the de novo establishment of rod-shape in bacteria.

Significance

Spheres and rods are among the most common shapes adopted by walled bacteria, in which the peptidoglycan (PG) cell wall largely determines cell shape. When induced by chemicals, rod-shaped vegetative cells of the Gram-negative bacterium Myxococcus xanthus thoroughly degrade their PG and shrink into spherical spores. As these spores germinate, rod-shaped cells are rebuilt without preexisting templates, which provides a rare opportunity to visualize de novo PG synthesis and bacterial morphogenesis. In this study, we investigated how spherical spores germinate into rods and elucidated a system for rod-shape morphogenesis that includes the Rod PG synthesis system, a GTPase-GAP pair, the MreB cytoskeleton and a molecular motor.
Patterns, predictors, and consequences of dominance in hybrids
Authors: Thompson Ken A. , Urquhart-Cronish Mackenzie , Whitney Kenneth D. , Rieseberg Loren H. , Schluter Dolph
Published: October 2019

Are first-generation (F1) hybrids typically intermediate for all traits that differentiate their parents? Or are they similar to one parent for most traits, or even mismatched for divergent traits? Although the phenotype of otherwise viable and fertile hybrids determines their fate, little is known about the general patterns, predictors, and consequences of phenotype expression in hybrids. To address this empirical gap, we compiled data from nearly 200 studies where traits were measured in a common environment for two parent populations and F1hybrids. We find that individual traits are typically halfway between the parental midpoint and one parental value (i.e., hybrid trait values are typically 0.25 or 0.75 if parents’ values are 0 & 1). When considering pairs of traits together, a hybrid’s multivariate phenotype tends to resemble one parent (pairwise parent-bias) about 50 % more than the other while also exhibiting a similar magnitude of trait mismatch due to different traits having dominance in conflicting directions. We detect no phylogenetic signal nor an effect of parental genetic distance on dominance or mismatch. Using data from an experimental field planting of recombinant hybrid sunflowers—where there is among-individual variation in dominance and mismatch due to segregation of divergent alleles—we illustrate that pairwise parent-bias improves fitness while mismatch reduces fitness. Importantly, the effect of mismatch on fitness was stronger than that of pairwise parent-bias. In sum, our study has three major conclusions. First, hybrids between ecologically divergent natural populations are typically not phenotypically intermediate but rather exhibit substantial mismatch while also resembling one parent more than the other. Second, dominance and mismatch are likely determined by population-specific processes rather than general rules. Finally, selection against hybrids likely results from both selection against somewhat intermediate phenotypes and against mismatched trait combinations.
Inhibition of protein synthesis in M1 of monkeys disrupts performance of sequential movements guided by memory
Authors: Ohbayashi Machiko
Published: October 2019

The production of action sequences is a fundamental aspect of human motor skills. To examine whether primary motor cortex (M1) is involved in maintenance of sequential movements, we trained two monkeys (Cebus apella) to perform two sequential reaching tasks. In one task, sequential movements were instructed by visual cues, whereas in the other task, movements were generated from memory after extended practice. After the monkey became proficient with performing the tasks, we injected an inhibitor of protein synthesis, anisomycin, into M1 to disrupt information storage in this area. Injection of anisomycin in M1 had a marked effect on the performance of sequential movements that were guided by memory. In contrast, the anisomycin injection did not have a significant effect on the performance of movements guided by vision. These results suggest that M1 of non-human primates is involved in the maintenance of skilled sequential movements.
Divergent DNA methylation signatures of juvenile seedlings grafts and adult apple trees
Authors: Perrin Adrien , Daccord Nicolas , Roquis David , Celton Jean-Marc , Vergne Emilie , Bucher Etienne
Published: October 2019

Plants are continuously exposed to environmental perturbations. Outcrossing annual plants can adapt rapidly to these changes via sexual mating and DNA mutations. However, perennial and clonally reproducing plants may have developed particular mechanisms allowing them to adapt to these changes and transmit this information to their offspring. It has been proposed that the mechanisms allowing this plasticity of response could come in the form of epigenetic marks that would evolve throughout a plant’s lifetime and modulate gene expression. To study these mechanisms, we used apple (Malus domestica) as a model perennial and clonally propagated plant. First, we investigated the DNA methylation patterns of mature trees compared to juvenile seedlings. While we did not observe a drastic genome-wide change in DNA methylation levels, we found clear changes in DNA methylation patterns localized in regions enriched in genes involved in photosynthesis. Transcriptomic analysis showed that genes involved in this pathway were overexpressed in seedlings. Secondly, we compared global DNA methylation of a newly grafted plant to its mother tree to assess if acquired epigenomic marks were transmitted via grafting. We identified clear changes, albeit showing weaker DNA methylation differences. Our results show that a majority of DNA methylation patterns from the tree are transmitted to newly grafted plants albeit with specific local differences. Both the epigenomic and transcriptomic data indicate that grafted plants are at an intermediate phase between an adult tree and seedling and inherit part of the epigenomic history of their mother tree.
Characteristics of sequential activity in networks with temporally asymmetric Hebbian learning
Authors: Gillett Maxwell , Pereira Ulises , Brunel Nicolas
Published: October 2019

Sequential activity has been observed in multiple neuronal circuits across species, neural structures, and behaviors. It has been hypothesized that sequences could arise from unsupervised learning processes. However, it is still unclear whether biologically plausible synaptic plasticity rules can organize neuronal activity to form sequences whose statistics match experimental observations. Here we investigate temporally asymmetric Hebbian rules in sparsely connected recurrent rate networks, and develop a theory of the transient sequential activity observed after learning. These rules transform a sequence of random input patterns into synaptic weight updates. After learning, recalled sequential activity is reflected in the transient correlation of network activity with each of the stored input patterns. Using mean-field theory, we derive a low-dimensional description of the network dynamics and compute the storage capacity of these networks. Multiple temporal characteristics of the recalled sequential activity are consistent with experimental observations. We find that the degree of sparseness of the recalled sequences can be controlled by non-linearities in the learning rule. Furthermore, sequences maintain robust decoding, but display highly labile dynamics, when synaptic connectivity is continuously modified due to noise or storage of other patterns, similar to recent observations in hippocampus and parietal cortex. Finally, we demonstrate that our results also hold in recurrent networks of spiking neurons with separate excitatory and inhibitory populations.
On the asymptotic equivalence between the radon and the hough transforms of digital images
Authors: Aramini Riccardo , Delbary Fabrice , Beltrametti Mauro C , Estatico Claudio , Piana Michele , Massone Anna Maria
Published: October 2019

Although characterized by different mathematical definitions, both the Radon and the Hough transforms ultimately take an image as input and provide, as output, functions defined on a preassigned parameter space, i.e., the so-called either Radon or Houghsinograms. The parameters in these two spaces describe a family of curves, which represent either the integration domains considered in the Radon transform, or the kind of curves to be detected by the Hough transform.

It is heuristically known that the Hough sinogram converges to the corresponding Radon sinogram when the discretization step in the parameter space tends to zero. By considering generalized functions in multi-dimensional setting, in this paper we give an analytical proof of this heuristic rationale when the input grayscale digital image is described as a set of grayscale points, that is, as a sum of weighted Dirac delta functions. On these grounds, we also show that this asymptotic equivalence may have a valuable impact on the image reconstruction problem of inverting the Radon sinogram recorded by a medical imaging scanner.
Clonal evaluation of prostate cancer molecular heterogeneity in biopsy samples by dual immunohistochemistry and dual RNA in situ hybridization
Authors: Dedigama-Arachchige Pavithra , Carskadon Shannon , Li Jia , Loveless Ian , Alhamar Mohamed , Peabody James O. , Stricker Hans , Chitale Dhananjay A. , Rogers Craig G. , Menon Mani , Bismar Tarek A. , Gupta Nilesh S. , Williamson Sean R. , Palanisamy Nallasivam
Published: October 2019

Prostate cancer is frequently multifocal. Although there may be morphological variation, the genetic underpinnings of each tumor are not clearly understood. To assess the inter and intra tumor molecular heterogeneity in prostate biopsy samples, we developed a combined immunohistochemistry and RNA in situ hybridization method for the simultaneous evaluation of ERG, SPINK1, ETV1, and ETV4. Screening of 601 biopsy cores from 120 consecutive patients revealed multiple alterations in a mutually exclusive manner in 37% of patients, suggesting multifocal tumors with considerable genetic differences. Furthermore, the incidence of molecular heterogeneity was higher in African Americans patients compared to Caucasian American patients. About 47% of the biopsy cores with discontinuous tumor foci showed clonal differences with distinct molecular aberrations. ERG positivity occurred predominantly in low Gleason grade cancer, whereas ETV4 expression was observed mostly in high Gleason grade cancer. Further studies revealed correlation between the incidence of molecular markers and clinical and pathologic findings, suggesting potential implications for diagnostic pathology practice, such as defining dominant tumor nodules and discriminating juxtaposed but molecularly different tumors of different grade patterns.
Circulating glutamine and Alzheimer’s disease: a Mendelian randomization study
Authors: Adams Charleen D.
Published: October 2019

INTRODUCTION

Alzheimer’s disease is a devastating neurodegenerative disorder. Its worldwide prevalence is over 24 million and is expected to double by 2040. Finding ways to prevent its cognitive decline is urgent.

METHODS

A two-sample Mendelian randomization study was performed instrumenting glutamine, which is abundant in blood, capable of crossing the blood-brain barrier, and involved in a metabolic cycle with glutamate in the brain.

RESULTS

The results reveal a protective effect of circulating glutamine (inverse-variance weighted method, odds ratio per 1-SD increase in circulating glutamine = 0.83; 95% CI 0.71, 0.97; P = 0.02).

CONCLUSION

These findings lend credence to the emerging story supporting the modifiability of glutamine/glutamate metabolism for the prevention of cognitive decline. More circulating glutamine might mean that more substrate is available during times of stress, acting as a neuroprotectant. Modifications to exogenous glutamine may be worth exploring in future efforts to prevent and/or treat Alzheimer’s disease.
Neuropeptide relay between SIFa signaling controls the experience-dependent mating duration of male Drosophila
Authors: Wong Kyle , Schweizer Justine , Nguyen Khoi-Nguyen Ha , Atieh Shatha , Kim Woo Jae
Published: October 2019

Drosophila melanogaster is a suitable model for investigating how neuropeptides influence animal behaviours and physiology. We previously reported that two behavioural paradigms control mating duration of male Drosophila, called Longer-Mating-Duration (LMD) and Shorter-Mating-Duration (SMD) that are induced through socio-sexual environment prior to copulation. Understanding the molecular and cellular mechanisms by which males exhibit plasticity to different social cues remains poorly understood. Here, we show that SIFa modulates the neural circuitry for both LMD and SMD. Neuropeptide-to-neuropeptide communication, so called ‘neuropeptide relay’ plays a key role to mediate this control. We identified that 7 neuropeptides expressed in SIFa Receptor-positive cells are functionally important to regulate either LMD and/or SMD. The modulation of two independent mating duration behaviour by the different SIFa-mediated neuropeptide relay will help to further investigate how the neuropeptidergic modulation can control complex behaviours.
RFEX: Simple Random Forest Model and Sample Explainer for non-Machine Learning experts
Authors: Petkovic D. , Alavi A. , Cai D. , Yang J. , Barlaskar S.
Published: October 2019

Machine Learning (ML) is becoming an increasingly critical technology in many areas. However, its complexity and its frequent non-transparency create significant challenges, especially in the biomedical and health areas. One of the critical components in addressing the above challenges is the explainability or transparency of ML systems, which refers to the model (related to the whole data) and sample explainability (related to specific samples). Our research focuses on both model and sample explainability of Random Forest (RF) classifiers. Our RF explainer, RFEX, is designed from the ground up with non-ML experts in mind, and with simplicity and familiarity, e.g. providing a one-page tabular output and measures familiar to most users. In this paper we present significant improvement in RFEX Model explainer compared to the version published previously, a new RFEX Sample explainer that provides explanation of how the RF classifies a particular data sample and is designed to directly relate to RFEX Model explainer, and a RFEX Model and Sample explainer case study from our collaboration with the J. Craig Venter Institute (JCVI). We show that our approach offers a simple yet powerful means of explaining RF classification at the model and sample levels, and in some cases even points to areas of new investigation. RFEX is easy to implement using available RF tools and its tabular format offers easy-to-understand representations for non-experts, enabling them to better leverage the RF technology.
Experimental phasing of MicroED data using radiation damage
Authors: Martynowycz Michael W. , Hattne Johan , Gonen Tamir
Published: October 2019

We present an example of an experimentally phased structure using only MicroED. The structure of a seven-residue peptide is determined starting from differences to the diffraction intensities induced by structural changes due to radiation damage. The same wedge of reciprocal space was recorded twice by continuous rotation MicroED from a set of 11 individual crystals. The data from the first pass were merged to make a “low-dose dataset”. The data from the second pass were similarly merged to form a “damaged dataset.” Differences between these two datasets were used to calculate a Patterson difference map and to identify a single heavy atom site, from which initial phases were generated. The structure was then completed by iterative cycles of modeling and refinement.
Stimulus blanking reveals transsaccadic feature transfer
Authors: Grzeczkowski Lukasz , Deubel Heiner , Szinte Martin
Published: October 2019

Across saccadic eye movements, the visual system receives two successive static images corresponding to the pre- and the postsaccadic projections of the visual field on the retina. The existence of a mechanism integrating the content of these images is today still a matter of debate. Here, we studied the transfer of a visual feature across saccades using a blanking paradigm. Participants moved their eyes to a peripheral grating and discriminated a change in its orientation occurring during the eye movement. The grating was either constantly on the screen or briefly blanked during and after the saccade. Moreover, it either was of the same luminance as the background (i.e., isoluminant) or anisoluminant with respect to it. We found that for anisoluminant grating, the orientation discrimination across saccade was improved when a blank followed the onset of the eye movement. Such effect was however abolished with isoluminant grating. Additionally, performance was also improved when an anisoluminant grating presented before the saccade was followed by an isoluminant one. These results demonstrate that a detailed representation of the presaccadic image was transferred across saccades allowing participants to perform better on the trans-saccadic orientation task. While such a transfer of visual orientation across saccade is masked in real-life anisoluminant conditions, the use of a blank and of isoluminant postsaccadic grating allowed here to reveal its existence.

Significance statement

Static objects are perceived as not moving across eye movements despite their visual projection shifts on our retina. To compensate for such shifts and create a continuous perception of space, our brain may keep track of objects’ visual features across our movements. We found that shortly blanking a contrast-defined object during and after saccades allows to recover a detailed representation of its orientation. We propose that the transfer of visual content across saccades revealed with the use of a simple blank plays an important role in ensuring our continuous and stable perception of the world.
A specialized deceptive pollination system based on elaborate mushroom mimicry
Authors: Kakishima Satoshi , Tuno Nobuko , Hosaka Kentaro , Okamoto Tomoko , Ito Takuro , Okuyama Yudai
Published: October 2019

Despite its potential effectiveness for outcrossing, few examples of pollination via mushroom mimicry have been reported. This may be because the conditions under which the strategy can evolve are limited and/or because demonstrating it is challenging. Arisaema is a plant genus that has been suggested to adopt mushroom mimicry for pollination, although no compelling evidence for this has yet been demonstrated. Here, we report that Arisaema sikokianum utilizes mostly a single genus of obligate mycophagous flies (Mycodrosophila) as pollinators, and that the insect community dominated by Mycodrosophila is strikingly similar to those found on some species of wood-decaying fungi. Comparative chemical analyses of Arisaema spp. and various mushrooms further revealed that only A. sikokianum emits a set of volatile compounds shared with some mushroom species utilized by Mycodrosophila. Meanwhile, other closely related and often sympatric Arisaema species do not possess such typical traits of mushroom mimicry or attract Mycodrosophila, thereby likely achieving substantial reproductive isolation from A. sikokianum. Our finding indicates that mushroom mimicry is an exceptional and derived state in the genus Arisaema, thus providing an unprecedented opportunity to study the mechanisms underlying the coordinated acquisition of mimicry traits that occurred during a recent speciation event.
Genetic profiling ofMycobacterium tuberculosis“modern” Beijing strains from Southwest Colombia
Authors: Nieto Ramirez Luisa Maria , Ferro Beatriz E. , Diaz Gustavo , Anthony Richard M. , de Beer Jessica , van Soolingen Dick
Published: October 2019

Beijing strains ofMycobacterium tuberculosis(lineage2) have been associated with drug-resistance and transmission of tuberculosis worldwide. Most of the Beijing strains identified in the Colombian pacific coast exhibited a multidrug resistant (MDR) phenotype, in contrast with the phenotype observed in Beijing isolates from other South-American countries. We wanted to evaluate the clonality and genetic background of the Beijing strains isolated in Colombia that belong mostly to the spoligo-international type (SIT) 190. Out of 37 Beijing stains characterized in an 8-years period, we identified five Beijing clones; 36 that belong to the SIT190 type and only one to SIT1. Two loci in VNTR typing: MIRU 39 and QUB11b exhibited the highest level of variation among these strains. Out of the 37 Beijing strains, only one was drug susceptible, 28 represented MDR-TB, four extensively drug resistant TB (XDR-TB) and four pre-XDR-TB. The mutationsrpoBS531L andkatGS315T1 were the most common among the MDR strains as reported elsewhere. Whole genome sequencing analysis allowed us to classify them as modern lineage Beijing strains, sharing up to 76 out of the 275 SNPs described in Beijing strains, as identified worldwide by Schürchet al;including 54 non-synonymous SNPs and 23 silent mutations. We were also able to confirm the presence of 8 specific SNPs that were so far only found in the Beijing strains from Colombia. The presence of modern Beijing strains, most of them representing MDR-TB, suggests a different origin of thisM. tuberculosislineage compared to other Beijing strains found in neighboring countries, such as Peru. The specific 8-SNP signature confirmed the identity of these Colombian Beijing MDR strains. This work may serve as a genetic baseline to study the evolution and spread ofM. tuberculosisBeijing strains in Colombia, which play an important role in the control of MDR-TB.
Genetic access to functionally distinct ganglion cell types in the Somatostatin-IRES-Cre mouse retina
Authors: Fransen James W. , Borghuis Bart G.
Published: October 2019

Retinal ganglion cells (GCs) are a functionally diverse neuron population that encodes and transmits distinct representations of the visual image on the retina to target nuclei in the brain. Independent studies of visually-evoked responses, cell morphology, and gene expression each suggest that GCs in mouse may comprise as many as forty distinct cell types. To date, only a subset of these types have been characterized in detail, and for most genetic access is still lacking. Thus, the majority of identified GC types remains inaccessible for targeted electrophysiology and functional imaging, precluding efficient studies of their response properties, and the cell-intrinsic mechanisms and presynaptic circuits that generate these properties. Here we show that an existing mouse line that is commonly used for studies of cortical inhibitory circuits – Somatostatin-IRES-Cre (Sst-Cre), consistently labels an understudied subset of four GC types with distinct visual responses. We characterized these types both anatomically and functionally using Cre-dependent reporter mouse lines and confocal fluorescence imaging, calcium imaging, and whole-cell electrophysiology. We show that one of the labeled GC types is suppressed by luminance contrast, while another matches a recently described orientation-selective GC type. Our results give new information about these two identified GC types, and establish the utility of the Sst-Cre transgenic mouse line for studies of recently identified GC circuits in the mouse retina.
Assortment of Stauntonia hexaphylla and Cornus officinalis protect against testosterone-induced benign prostatic hyperplasia through anti-inflammatory and anti-proliferative activity
Authors: Karunasagara Shanika , Hong Geum-Lan , Jung Da-Young , Kim Kyung-Hyun , Koh Eun-Jeong , Cho Kyoung-won , Park Sung-Sun , Jung Ju-Young
Published: October 2019

Benign prostatic hyperplasia (BPH) is a progressive pathological condition associated with proliferation of prostatic tissues, prostate enlargement, and lower-urinary tract symptoms. However, the mechanism underlying the pathogenesis of BPH is not clear. The aim of this study was to investigate the protective effects of Stauntonia hexaphylla and Cornus officinalis (SC extract) on a testosterone propionate (TP)-induced BPH model. For in vitro experiments, a human prostate adenocarcinoma cell line was used to perform western blotting for androgen receptor (AR), prostate specific antigen (PSA), and 5α-reductase type 2. Male Sprague-Dawley rats were randomly divided into 8 groups as follows for the in vivo experiments: control, BPH, Fina, Saw, SC25, SC50, SC100, and SC200. To induce BPH, all rats, except those in the control group, were daily administered with subcutaneous injections of TP (5 mg/kg), and orally treated with appropriate PBS/drugs for 4 consecutive weeks. Our findings indicated that the SC treatment significantly reduced the prostate size and downregulated the serum testosterone and DHT levels in BPH rats. The histological examination revealed that SC treatment markedly recovered the TP-induced abnormalities and reduced the prostatic hyperplasia. In addition, in vitro and in vivo western blotting indicated that SC treatment significantly downregulated the AR, PSA, and 5α-reductase type 2 expression, while an immunohistochemistry examination revealed that the SC extract significantly reduced the expression of type 2 5α-reductase and proliferating cell nuclear antigen positive cell count. Collectively, our findings demonstrated that SC extract attenuates BPH through anti-proliferative and anti-inflammation activities and might be useful in the clinical treatment of BPH.
Accurate MS-based Rab10 phosphorylation stoichiometry determination as readout for LRRK2 activity in Parkinson’s disease
Authors: Karayel Özge , Tonelli Francesca , Winter Sebastian Virreira , Geyer Phillip E. , Fan Ying , Sammler Esther M. , Alessi Dario R. , Steger Martin , Mann Matthias
Published: October 2019

Pathogenic mutations in the Leucine-rich repeat kinase 2 (LRRK2) are the predominant genetic cause of Parkinson’s disease (PD). They increase its activity, resulting in augmented Rab10-Thr73 phosphorylation and conversely, LRRK2 inhibition decreases pRab10 levels. However, there is no assay to quantify pRab10 levels for drug target engagement or patient stratification. We developed an ultra-sensitive targeted mass spectrometry (MS)-based assay for determining Rab10-Thr73 phosphorylation stoichiometry in human samples. It uses synthetic stable isotope-labeled (SIL) analogues for both phosphorylated and non-phosphorylated tryptic peptides surrounding Rab10-Thr73 to directly derive the percentage of Rab10 phosphorylation from attomole amounts of the endogenous phosphopeptide. We test the reproducibility of our assay by determining Rab10-Thr73 phosphorylation stoichiometry in human neutrophils before and after LRRK2 inhibition. Compared to healthy controls, neutrophils of LRRK2 G2019S and VPS35 D620N carriers robustly display 1.4-fold and 3.7-fold increased pRab10 levels, respectively. Our generic MS-based assay further establishes the relevance of pRab10 as a prognostic PD marker and is a powerful tool for determining LRRK2 inhibitor efficacy and for stratifying PD patients for LRRK2 inhibitor treatment.
A hierarchical framework for segmenting movement paths
Authors: Getz Wayne M.
Published: October 2019

Comparative applications of animal movement path analyses are hampered by the lack of a comprehensive framework for linking structures and processes conceived at different spatio-temporal scales. Although many analyses begin by generating step-length (SL) and turning-angle (TA) distributions from relocation time-series data—some of which are linked to ecological, landscape, and environmental covariates—the frequency at which these data are collected may vary from sub-seconds to several hours, or longer. The kinds of questions that may be asked of these data, however, are very much scale-dependent. It thus behooves us to clarify how the scale at which SL and TA data are collected and relate to one another, as well as the kinds of ecological questions that can be asked. Difficulties arise because the information contained in SL and TA time series is not semantically aligned with the physiological, ecological, and sociological factors that influence the structure of movement paths. I address these difficulties by classifying movement types at salient temporal scales using two different kinds of vocabularies. The first is the language derived from behavioral and ecological concepts. The second is the language derived from mathematically formulated stochastic walks. The primary tools for analyzing these walks are fitting time-series and stochastic-process models to SL and TA statistics (means, variances, correlations, individual-state and local environmental covariates), while paying attention to movement patterns that emerge at various spatial scales. The purpose of this paper is to lay out a more coherent, hierarchical, scale-dependent, appropriate-complexity framework for conceptualizing path segments at different spatio-temporal scales and propose a method for extracting a simulation model, referred to as M3, from these data when at a relatively high frequencies (ideally minute-by-minute). Additionally, this framework is designed to bridge biological and mathematical movement ecology concepts; thereby stimulating the development of conceptually-rooted methods that facilitates the formulation of our M3model for simulating theoretical and analyzing empirical data, which can then be used to test hypothesis regarding mechanisms driving animal movement and make predications of animal movement responses to management and global change.
Kinesin KIF18A is a novel PUM regulated target promoting mitotic progression and survival of human male germ cell line - TCam-2
Authors: Smialek Maciej Jerzy , Kuczynska Bogna , Ilaslan Erkut , Janecki Damian Mikolaj , Sajek Marcin Piotr , Kusz-Zamelczyk Kamila , Jaruzelska Jadwiga
Published: October 2019

Regulation of proliferation, apoptosis and cell cycle is crucial for the physiology of germ cells. Their malfunction contributes to infertility and germ cell tumours. Kinesin KIF18A is an important germ cell specific regulator which downregulates apoptosis while promoting cell proliferation in animal models. Whereas regulation of KIF18A expression was studied at the transcriptional level, its posttranscriptional regulation has not been extensively explored. Due to the presence of two PUM Binding Elements (PBEs) within 3’UTR,KIF18AmRNA is a potential target of PUMs, well known RNA-binding proteins involved in posttranscriptional gene regulation (PTGR). We investigated that possibility in TCam-2 cells originating from seminoma, representing human male germ cells. We conducted RNA co-immunoprecipitation combined with RT-qPCR, as well as luciferase reporter assay by applying appropriate luciferase construct encoding the wild typeKIF18A3’UTR, upon PUM1 and PUM2 overexpression or knockdown. We found that KIF18A is repressed by PUM1 and PUM2. To study how this regulation influences KIF18A function in TCam-2 cells, MTS proliferation assay, apoptosis and cell cycle, analysis using flow cytometry was performed uponKIF18AsiRNA knockdown. We uncovered that KIF18A significantly influences proliferation, apoptosis and cell cycle, these effects being opposite to PUM effects in TCam-2 cells. We propose that repression by PUM proteins may represent one of mechanisms influencing KIF18A level in controlling proliferation, cell cycle and apoptosis in TCam-2 cells. To the best of our knowledge, this paper identifies the first mammalian functionally germ cell specific gene that is regulated by Pum proteins via 3’UTR.
Repetita iuvant: repetition facilitates online planning of sequential movements
Authors: Ariani Giacomo , Kwon Young Han , Diedrichsen Jörn
Published: October 2019

Beyond being essential for long-term motor-skill development, movement repetition has immediate benefits on performance, increasing speed and accuracy of a second execution. While repetition effects have been reported for single reaching movements, it has yet to be determined whether they also occur for movement sequences, and what aspects of sequence production are improved. We addressed these questions in two behavioral experiments using a discrete sequence production (DSP) task in which human volunteers had to perform short sequences of finger movements. In Experiment 1, we presented participants with randomly varying sequences and manipulated 1) whether the same sequence was repeated on successive trials, and 2) whether participants had to execute the sequence (Go), or not (No-Go). We establish that sequence repetition led to immediate improvements in speed without associated accuracy costs. The largest benefit was observed in the middle part of a sequence, suggesting that sequence repetition facilitated online planning. This claim was further supported by Experiment 2, in which we kept a set of sequences fixed throughout the experiment, thus allowing participants to develop sequence-specific learning: once the need for online planning decreased, the benefit of repetition disappeared. Finally, we found that repetition-related improvements only occurred for the trials that had been preceded by sequence production, suggesting that action selection and sequence pre-planning may not be sufficient to reap the benefits of repetition. Together, these results show that repetition can enhance representations at the level of movement sequences (rather than of individual movements) and facilitate online planning.

New & Noteworthy

Even for overlearned motor skills such as reaching, movement repetition improves performance. How brain processes associated with motor planning or execution benefit from repetition, however, remains unclear. Here we report the novel finding of repetition effects for sequential movements. Our results show that repetition benefits are tied to improved online planning of upcoming sequence elements. We also highlight how actual movement experience appears to be more beneficial than mental rehearsal for observing short-term repetition effects.
Simulating the evolutionary trajectories of metabolic pathways for insect symbionts in the Sodalis genus
Authors: Hall Rebecca J. , Thorpe Stephen , Thomas Gavin H. , Wood A. Jamie
Published: October 2019

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Insect-bacterial symbioses are ubiquitous, but there is still much to uncover about how these relationships establish, persist and evolve. The tsetse endosymbiont Sodalis glossinidius displays intriguing metabolic adaptations to its microenvironment, but the process by which this relationship evolved remains to be elucidated. The recent chance discovery of the free-living secies of the Sodalis genus, S. praecaptivus, provides a serendipitous starting point from which to investigate the evolution of this symbiosis. Here, we present a flux balance model for S. praecaptivus. Metabolic modelling is used in combination with a multi-objective evolutionary algorithm to explore the trajectories that S. glossinidius may have undertaken after becoming internalised. The time-dependent loss of key genes is shown to influence the evolved populations, providing possible targets for future in vitro genetic manipulation. This method provides an unusually detailed perspective on possible evolutionary trajectories for S. glossinidius in this fundamental process of evolutionary and ecological change.
Targeting the PI5P4K lipid kinase family in cancer using novel covalent inhibitors
Authors: Sivakumaren Sindhu Carmen , Shim Hyeseok , Zhang Tinghu , Ferguson Fleur M. , Lundquist Mark R. , Browne Christopher M. , Seo Hyuk-Soo , Paddock Marcia N. , Manz Theresa D. , Jiang Baishan , Hao Ming-Feng , Krishnan Pranav , Wang Diana G. , Yang T. Jonathan , Kwiatkowski Nicholas P. , Ficarro Scott B. , Cunningham James M. , Marto Jarrod A. , Dhe-Paganon Sirano , Cantley Lewis C. , Gray Nathanael S.
Published: October 2019

The PI5P4Ks have been demonstrated to be important for cancer cell proliferation and other diseases. However, the therapeutic potential of targeting these kinases is understudied due to a lack of potent, specific small molecules available. Here we present the discovery and characterization of a novel pan-PI5P4K inhibitor, THZ-P1-2, that covalently targets cysteines on a disordered loop in PI5P4Kα/β/γ. THZ-P1-2 demonstrates cellular on-target engagement with limited off-targets across the kinome. AML/ALL cell lines were sensitive to THZ-P1-2, consistent with PI5P4K’s reported role in leukemogenesis. THZ-P1-2 causes autophagosome clearance defects and upregulation in TFEB nuclear localization and target genes, disrupting autophagy in a covalent-dependent manner and phenocopying the effects of PI5P4K genetic deletion. Our studies demonstrate that PI5P4Ks are tractable targets, with THZ-P1-2 as a useful tool to further interrogate the therapeutic potential of PI5P4K inhibition and inform drug discovery campaigns for these lipid kinases in cancer metabolism and other autophagy-dependent disorders.
Contribution of fungal microbiome to intestinal physiology, early-life immune development and mucosal inflammation in mice
Authors: van Tilburg Bernardes Erik , Pettersen Veronika Kuchařová , Gutierrez Mackenzie W. , Laforest-Lapointe Isabelle , Jendzjowsky Nicholas G. , Cavin Jean-Baptiste , Vicentini Fernando A. , Keenan Catherine M. , Ramay Hena R. , Samara Jumana , MacNaughton Wallace K. , Wilson Richard J. A. , Kelly Margaret M. , McCoy Kathy D. , Sharkey Keith A. , Arrieta Marie-Claire
Published: October 2019

Gut microbiomes make major contributions to the physiological and immunological development of the host, but the relative importance of their bacterial and fungal components, and how they interact, remain largely unknown. We applied carefully controlled experiments in gnotobiotic mice colonized with defined communities of bacteria, fungi, or both to differentiate the direct role of fungi on microbiome assembly, host development, and susceptibility to colitis and airway inflammation. Our results revealed that fungal colonization alone was insufficient to promote the intestinal anatomic and physiological changes seen in mice colonized by bacteria, and had limited impact on the fecal metabolome. However, fungal colonization promoted major shifts in bacterial microbiome ecology, and had an independent effect on the innate and adaptive immune development in young mice. Fungi further exacerbated some aspects of the inflammatory effects of the bacterial community during OVA-induced airway inflammation by promoting macrophage infiltration in the airway. Our results demonstrate a dominant ecological and physiological role of bacteria in gut microbiomes, but highlight fungi as an ecological factor shaping the assembly of the bacterial community and a direct capacity to impact immune system and modulate disease susceptibility. These findings demonstrate that studies focused on bacteria alone provide an incomplete portrayal on microbiome ecology and functionality, and prompt for the inclusion of fungi in human microbiome studies.
Cortical contraction drives the 3D patterning of epithelial cell surfaces
Authors: van Loon Aaron P. , Erofeev Ivan S. , Maryshev Ivan V. , Goryachev Andrew B. , Sagasti Alvaro
Published: October 2019

Cellular protrusions create complex cell surface topographies, but biomechanical mechanisms regulating their formation and arrangement are largely unknown. To study how protrusions form, we focused on the morphogenesis of microridges, elongated actin-based structures projecting from the apical surfaces of zebrafish skin cells that are arranged in labyrinthine patterns. Microridges form by accreting simple finger-like precursors. Live imaging demonstrated that microridge morphogenesis is linked to apical constriction. A non-muscle myosin II (NMII) reporter revealed pulsatile contractions of the actomyosin cortex; inhibiting NMII demonstrated that contractions are required for apical constriction and microridge formation. A biomechanical model suggested that contraction reduces surface tension to permit the fusion of precursors into microridges. Indeed, reducing surface tension with hyperosmolar media promoted microridge formation. In anisotropically stretched cells, microridges formed by precursor fusion along the stretch axis, which computational modeling explained as a consequence of stretch-induced cortical flow. Collectively, our results demonstrate how contraction within the 2D plane of the cortex patterns 3D cell surfaces.

Microridges, elongated 3D protrusions arranged in maze-like patterns on zebrafish skin cells, form by the accretion of simple precursor projections. Modeling and in vivo experiments showed that cortical contractions promote the coalescence of precursors into microridges by reducing membrane tension.
The Impact of Cross-Species Gene Flow on Species Tree Estimation
Authors: Jiao Xiyun , Flouris Thomas , Rannala Bruce , Yang Ziheng
Published: October 2019

Recent analyses of genomic sequence data suggest cross-species gene flow is common in both plants and animals, posing challenges to species tree inference. We examine the levels of gene flow needed to mislead species tree estimation with three species and either episodic introgressive hybridization or continuous migration between an outgroup and one ingroup species. Several species tree estimation methods are examined, including the majority-vote method based on the most common gene tree topology (with either the true or reconstructed gene trees used), the UPGMA method based on the average sequence distances (or average coalescent times) between species, and the full-likelihood method based on multi-locus sequence data. Our results suggest that the majority-vote method is more robust to gene flow than the UPGMA method and both are more robust than likelihood assuming a multispecies coalescent (MSC) model with no cross-species gene flow. A small amount of introgression or migration can mislead species tree methods if the species diverged through speciation events separated by short time intervals. Estimates of parameters under the MSC with gene flow suggest theAnopheles gambiaAfrican mosquito species complex is an example where gene flow greatly impacts species phylogeny.