bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Alveolar Bone Grafting on Health Quality in Patients With Cleft Lip and Palate
Authors: Sancak Kevser , Eren Hakan , Altug Ayse Tuba , Tezuner Aysegul Mine
Published: July 2019

Introduction:

This study aimed to explore the effect of alveolar bone grafting on the clinical outcomes, health quality, and satisfaction in patients with cleft lip and palate.

Materials and Methods:

Questionnaire review study was done to patients who underwent secondary alveolar bone grafting retrospectively. This study included 28 patients who underwent secondary alveolar bone grafting by harvesting graft from the anterior iliac crest, excluding one, in Oral and Maxillofacial Department, Faculty of Dentistry, Ankara University, Turkey, during the period from January 2012 to March 2016. All patients were operated using the same technique and by the same surgical team. Patients were interviewed to fill Short-Form Health Survey (SF-12) and Postsurgical Patient Satisfaction Questionnaire (PSPSQ) 6 months postoperatively. The questionnaires were used to assess the relationship between health quality and patient satisfaction. Also, grafted sites were evaluated with respect to fistula, presence of cleft palate.

Results:

The sample consisted of 28 patients (19 females and 9 males), including 13 with bilateral clefts and 15 with unilateral clefts. The mean Physical Component Summary (PCS) and Mental Component Summary (MCS) of SF-12 scores were 54.5718 and 44.6436, respectively. The mean PSPSQ score was 36.7368. PCS scores were found to be significantly correlated with the PSPSQ scores (P ≤0.05). No correlation was found between MCS and PSPSQ scores (P >0.05). A precise and good planned surgery resulted in good satisfaction among patients with cleft lip and palate who underwent alveolar bone grafting. The patient satisfaction was correlated with the success of the operation.
Dietetic assessment and intervention in lung cancer
Authors: Phillips Iain , Hug Adele , Allan Lindsey , Ezhil Veni
Published: July 2019

Purpose of review

Systemic therapy for lung cancer is increasing in intensity and duration. European nutrition guidelines suggest screening for weight loss and malnutrition, however acknowledges there is a lack of evidence. We discuss current data round this issue and identify opportunities for further research.

Recent findings

International guidelines now exist to aid the definition of weight loss in cancer, including cachexia, sarcopenia and malnutrition. These allow consistent definition of overlapping, but distinct clinical syndromes. Nutritional status can be assessed in a range of ways including questionnaires, functional assessments, blood markers, physical activity, weight and BMI. Weight loss is commonly associated with a proinflammatory state. Future treatment is likely to be a combination of dietetic support and pharmacological treatment of cachexia.

There is a paucity of data on dietetic intervention. It is potentially quick, inexpensive and patient specific, using a holistic approach to aid patients who are malnourished or at risk of malnutrition. Lung cancer-related weight loss is common, further strategies are needed to effectively assess and intervene. Dietetic intervention has the potential to improve patients’ quality of life and outcomes.
The challenges of diabetic polyneuropathy: a brief update
Authors: Zochodne Douglas W.
Published: July 2019

Purpose of review

The current review addresses one of the most common neurological disorders, diabetic polyneuropathy (DPN). DPN is debilitating, irreversible and dwarfs the prevalence of most other chronic disorders of the nervous system. Its complications include foot ulceration, amputation, falling and intractable neuropathic pain. Moreover, tight control of hyperglycemia reduces the incidence of DPN in type 1 diabetes mellitus but its role in type 2 diabetes mellitus is less clear.

Recent findings

New therapeutic options to reverse the development of DPN or its associated pain have been proposed but none have significantly changed the clinical approach. The cause of DPN remains controversial traditionally focused on the impact of metabolic abnormalities, polyol flux, microvascular changes, mitochondria, oxidative stress, lipid biology and others. In particular, there has been less attention toward how this chronic disorder alters peripheral neurobiology. It is now clear that in chronic models of diabetes mellitus there exists a unique form of neurodegeneration with a range of protein, mRNA and microRNA alterations to consider. How to reconcile these molecular and structural alterations with metabolic mechanisms is a challenge. In sensory neurons alone, a primary target of DPN, both central perikaryal cytoplasmic and nuclear changes and altered distal sensory axon terminal plasticity may be involved.

In this review, the current therapeutic status of DPN is described with greater emphasis on some new but selected thoughts on its neurobiology. New mechanistic understanding will be essential to developing precision therapeutics for DPN.
Update on classification, epidemiology, clinical phenotype and imaging of the nonsystemic vasculitic neuropathies
Authors: Collins Michael P. , Dyck P. James B. , Hadden Robert D.M.
Published: July 2019

Purpose of review

Single-organ vasculitis of the peripheral nervous system (PNS) is often designated nonsystemic vasculitic neuropathy (NSVN). Several variants or subtypes have been distinguished, including migratory sensory neuropathy, postsurgical inflammatory neuropathy, diabetic radiculoplexus neuropathies, skin-nerve vasculitides, and, arguably, neuralgic amyotrophy. NSVN often presents as nondiabetic lumbosacral radiculoplexus neuropathy (LRPN). This review updates classification, clinical features, epidemiology, and imaging of these disorders.

Recent findings

A recent study showed the annual incidence of LRPN in Olmstead County, Minnesota to be 4.16/100 000:2.79/100 000 diabetic and 1.27/100 000 nondiabetic. This study was the first to determine the incidence or prevalence of any vasculitic neuropathy. In NSVN, ultrasonography shows multifocal enlargement of proximal and distal nerves. In neuralgic amyotrophy, MRI and ultrasound reveal multifocal enlargements and focal constrictions in nerves derived from the brachial plexus. Histopathology of these chronic lesions shows inflammation and rare vasculitis. Diffusion tensor imaging of tibial nerves in NSVN revealed decreased fractional anisotropy in one study.

Single-organ PNS vasculitides are the most common inflammatory neuropathies. Neuralgic amyotrophy might result from PNS vasculitis, but further study is necessary. The usefulness of focal nerve enlargements or constrictions in understanding pathological mechanisms, directing biopsies, and monitoring disease activity in NSVN should be further investigated.
Prediagnostic breast milk DNA methylation alterations in women who develop breast cancer
Authors: Salas Lucas A , Lundgren Sara N. , Browne Eva P. , Punska Elizabeth C. , Anderton Douglas L. , Karagas Margaret R , Arcaro Kathleen F. , Christensen Brock C.
Published: July 2019

Background

Prior candidate gene studies have shown tumor suppressor DNA methylation in breast milk related with history of breast biopsy, an established risk factor for breast cancer. To further establish the utility of breast milk as a tissue-specific biospecimen for investigations of breast carcinogenesis we measured genome-wide DNA methylation in breast milk from women with and without a diagnosis of breast cancer in two independent cohorts.

Methods

DNA methylation was assessed using Illumina HumanMethylation450k in 87 breast milk samples. After quality control, 368,171 autosomal CpG loci were analyzed. Cell type proportion estimates from RefFreeCellMix were calculated and adjusted for in this Epigenome Wide Association Study using linear mixed effects models adjusted for history of breast biopsy, age, time of delivery, cell type proportion estimates, array chip, and subject as random effect.

Results

Epigenome-wide analyses identified 58 differentially methylated CpG sites associated with a breast cancer diagnosis in the prospectively collected milk samples from the breast that would develop cancer compared with women without a diagnosis of breast cancer (q-value < 0.05). Nearly all CpG sites associated with a breast cancer diagnosis were hypomethylated in cases compared with controls, and were enriched for CpG islands. In addition, inferred repeat element methylation was lower in breast milk DNA from cases compared to controls, and cases exhibited increased estimated epigenetic mitotic tick rate as well as DNA methylation age compared with controls.

Conclusion

Breast milk has utility as a biospecimen for prospective assessment of disease risk, for understanding the underlying molecular basis of breast cancer risk factors, and improving primary and secondary prevention of breast cancer.
Increased functional connectivity of thalamic subdivisions in patients with Parkinson’s disease
Authors: Owens-Walton Conor , Jakabek David , Power Brian D. , Walterfang Mark , Velakoulis Dennis , van Westen Danielle , Looi Jeffrey C.L. , Shaw Marnie , Hansson Oskar
Published: July 2019

Parkinson’s disease (PD) affects 2-3% of the population over the age of 65 with loss of dopaminergic neurons in the substantia nigra impacting the functioning of basal ganglia-thalamocortical circuits. The precise role played by the thalamus is unknown, despite its critical role in the functioning of the cerebral cortex, and the abnormal neuronal activity of the structure in PD. Our objective was to more clearly elucidate how functional connectivity and morphology of the thalamus are impacted in PD (n= 32) compared to Controls (n= 20). To investigate functional connectivity of the thalamus we subdivided the structure into two important regions-of-interest, the first with putative connections to the motor cortices and the second with putative connections to prefrontal cortices. We then investigated potential differences in the size and shape of the thalamus in PD, and how morphology and functional connectivity relate to clinical variables. Our data demonstrate that PD is associated with increases in functional connectivity between motor subdivisions of the thalamus and the supplementary motor area, and between prefrontal thalamic subdivisions and nuclei of the basal ganglia, anterior and dorsolateral prefrontal cortices, as well as the anterior and paracingulate gyri. These results suggest that PD is associated with increased functional connectivity of subdivisions of the thalamus which may be indicative alterations to basal ganglia-thalamocortical circuitry.
Enhancing single-cell cellular state inference by incorporating molecular network features
Authors: Dong Ji , Zhou Peijie , Wu Yichong , Wang Wendong , Chen Yidong , Zhou Xin , Xie Haoling , Gao Yuan , Lu Jiansen , Yang Jingwei , Zhang Xiannian , Wen Lu , Fu Wei , Li Tiejun , Tang Fuchou
Published: July 2019

In biological systems, genes function in conjunction rather than in isolation. However, traditional single-cell RNA-seq (scRNA-seq) analyses heavily rely on the transcriptional similarity of individual genes, ignoring the inherent gene-gene interactions. Here, we present SCORE, a network-based method, which incorporates the validated molecular network features to infer cellular states. Using real scRNA-seq datasets, SCORE outperforms existing methods in accuracy, robustness, scalability, data integration and removal of batch effect. When applying SCORE to a newly generated human ileal scRNA-seq dataset, we identified several novel stem/progenitor clusters, including a Cripto-1+ cluster. Moreover, two distinct groups of goblet cells were identified and only one of them tended to secrete mucus. Besides, we found that the recently identified BEST4+OTOP2+ microfold cells also highly expressed CFTR, which is different from their colonic counterparts. In summary, SCORE enhances cellular state inference by simulating the dynamic changes of molecular networks, providing more biological insights beyond statistical interpretations.
Liver fluke granulin promotes exosome-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinoma
Authors: Arunsan Patpicha , Chaidee Apisit , Cochan Christina J. , Mann Victoria H. , Tanno Toshihiko , Kumkhaek Chutima , Smout Michael J. , Karinshak Shannon E. , Rodpai Rutchanee , Sotillo Javier , Loukas Alex , Laha Thewarach , Brindley Paul J. , Ittiprasert Wannaporn
Published: July 2019

Crosstalk between malignant and neighboring cells contributes to tumor growth. In East Asia, infection with fish-borne liver flukes is a major risk factor for cholangiocarcinoma (CCA). The parasite secretes a growth factor termed liver fluke granulin (Ov-GRN-1), a homologue of the human progranulin (huPGRN), which contributes significantly to biliary tract fibrosis and morbidity during infection. Here, exosome-mediated transfer of mRNAs from the human cholangiocyte cell line (H69) was investigated following exposure to Ov-GRN-1, to naïve recipient H69 cells. To minimize the influence of endogenous huPGRN, the gene encoding huPGRN was inactivated using CRISPR/Cas9-based gene knock-out. Several huPGRN-depleted cell lines, termed ΔhuPGRN-H69, were established. These lines exhibited >80% reductions in levels of huPGRN transcripts and protein, both in gene-edited cells and within exosomes released by these cells. Profiles of exosomal RNAs (exRNA) from ΔhuPGRN-H69 for CCA-associated characteristics revealed a paucity of transcripts for estrogen- and Wnt-signaling pathways, peptidase inhibitors and tyrosine phosphatase related to cellular processes including oncogenic transformation. Several CCA-specific mRNAs including MAPK/AKT pathway members were induced by exposure to Ov-GRN-1. By comparison, estrogen, Wnt/PI3K and TGF signaling and other CCA pathway mRNAs were upregulated in wild type H69 exposed to Ov-GRN-1. Of these, CCA-associated exRNAs modified the CCA microenvironment in naïve recipient cells co-cultured with exosomes from ΔhuPGRN-H69 exposed to Ov-GRN-1, and induced translation of MAPK phosphorylation related-protein in naïve recipient cells comparing with control recipient cells. Exosome-mediated crosstalk in response to liver fluke granulin promoted a CCA-specific program through MAPK pathway which, in turn, established a CCA-conducive disposition.
Functional connectivity predicts changes in attention over minutes, days, and months
Authors: Rosenberg Monica D. , Scheinost Dustin , Greene Abigail S. , Avery Emily W. , Kwon Young Hye , Finn Emily S. , Ramani Ramachandran , Qiu Maolin , Constable R. Todd , Chun Marvin M.
Published: July 2019

The ability to sustain attention differs across people and changes within a single person over time. Although recent work has demonstrated that patterns of functional brain connectivity predict individual differences in sustained attention, whether these same patterns capture fluctuations in attention in single individuals remains unclear. Here, across five independent studies, we demonstrate that the sustained attention connectome-based predictive model (CPM), a validated model of sustained attention function, generalizes to predict attention changes across minutes, days, weeks, and months. Furthermore, the sustained attention CPM is sensitive to within-subject state changes induced by propofol as well as sevoflurane, such that individuals show functional connectivity signatures of stronger attentional states when awake than when under deep sedation and light anesthesia. Together these results demonstrate that fluctuations in attentional state reflect variability in the same functional connectivity patterns that predict individual differences in sustained attention.
Alternative splicing modulation by G-quadruplexes
Authors: Georgakopoulos-Soares Ilias , Parada Guillermo E. , Wong Hei Yuen , Miska Eric A. , Kwok Chun Kit , Hemberg Martin
Published: July 2019

Alternative splicing is central to metazoan gene regulation but the regulatory mechanisms involved are only partially understood. Here, we show that G-quadruplex (G4) motifs are enriched ~3-fold both upstream and downstream of splice junctions. Analysis of in vitro G4-seq data corroborates their formation potential. G4s display the highest enrichment at weaker splice sites, which are frequently involved in alternative splicing events. The importance of G4s in RNA as supposed to DNA is emphasized by a higher enrichment for the non-template strand. To explore if G4s are involved in dynamic alternative splicing responses, we analyzed RNA-seq data from mouse and human neuronal cells treated with potassium chloride. We find that G4s are enriched at exons which were skipped following potassium ion treatment. We validate the formation of stable G4s for three candidate splice sites by circular dichroism spectroscopy, UV-melting and fluorescence measurements. Finally, we explore G4 motifs across eleven representative species, and we observe that strong enrichment at splice sites is restricted to mammals and birds.
Self-assembled primary tumor clusters for precision cancer therapy
Authors: Yin Shenyi , Xi Ruibin , Wu Aiwen , Ji Jia-Fu , Xi Jianzhong Jeff
Published: July 2019

Several patient-derived tumor models emerged recently as robust preclinical models. However, their potential to guide clinical therapy remained unclear. We report a novel model for personalized drug testing called patient-derived tumor-like cell clusters (PTC) that enabled us to accomplish personalized drug tests within 10-20 days. Mechanistically, PTCs result from the migration and aggregation of CD8+/CD44+ primary epithelial cells in a mixture of fibroblasts and macrophages, and form spheroid cultures. Phenotypic and genotypic profiling of PTCs showed a high degree of similarity with the original patient tumors, indicating that PTC structurally and functionally recapitulated original tumors. Over 200 PTC models have been established from at least six cancer types and diverse sampling approaches. Given its seamless integration with current clinical sampling approaches, the PTC platform will revolutionize chemotherapy programs for cancer patients.
Pivotal involvement of the CX3CL1-CX3CR1 axis for the recruitment of M2-TAMs in skin carcinogenesis
Authors: Ishida Yuko , Kuninaka Yumi , Yamamoto Yuki , Nosaka Mizuho , Kimura Akihiko , Furukawa Fukumi , Mukaida Naofumi , Kondo Toshikazu
Published: July 2019

We previously revealed the crucial roles of CX3CL1-CX3CR1 axis in skin wound healing. Although repeated wounds frequently develop into skin cancer, the roles of CX3CL1 in skin carcinogenesis remain elusive. Here, we proved that CX3CL1 protein expression and CX3CR1+ macrophages were observed in human skin cancer tissues. Similarly, we observed the enhancement of CX3CL1 expression and the abundant accumulation of CX3CR1+ tumor-associated macrophages (TAMs) with M2 phenotypes in the skin carcinogenesis process induced by the combined treatment with 7,12-dimethylbenz-(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). In this mouse skin carcinogenesis process, CX3CR1+ TAMs exhibited M2 phenotypes with the expression of Wnt3a and angiogenic molecules including vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9. Compared to wild-type mice, CX3CR1-deficient mice showed fewer numbers of skin tumors with a lower incidence. Concomitantly, M2-macrophage numbers and neovascularization reduced with the depressed expression of angiogenic factors and Wnt3a. Thus, the CX3CL1-CX3CR1 axis can crucially contribute to skin carcinogenesis by regulating the accumulation and functions of TAMs. Thus, this axis can be a good target for preventing and/or treating skin cancers.
DIscBIO: a user-friendly pipeline for biomarker discovery in single-cell transcriptomics
Authors: Ghannoum Salim , Netto Waldir Leoncio , Fantini Damiano , Ragan-Kelley Benjamin , Parizadeh Amirabbas , Jonasson Emma , Ståhlberg Anders , Farhan Hesso , Köhn-Luque Alvaro
Published: July 2019

The growing attention toward the benefits of single-cell RNA sequencing (scRNA-seq) is leading to a myriad of computational packages for the analysis of different aspects of scRNA-seq data. For researchers without advanced programing skills, it is very challenging to combine several packages in order to perform the desired analysis in a simple and reproducible way. Here we present DIscBIO, an open-source, multi-algorithmic pipeline for easy, efficient and reproducible analysis of cellular sub-populations at the trasncriptomic level. The pipeline integrates multiple scRNA-seq packages and allows biomarker discovery with decision trees and gene enrichment analysis in network context using single-cell sequencing read counts through clustering and differential analysis. DIscBIO is freely available as an R package. It can be run either in command-line mode or through a computational pipeline using Jupyter notebooks. We also provide a user-friendly, cloud version of the notebook for researchers with very limited programming skills. We showcase all pipeline features using two scRNA-seq datasets. The first dataset consists of circulating tumor cells from patients with breast cancer. The second one is a cell cycle regulation datatset in myxoid liposarcoma. All analyses are available as notebooks that integrate in a sequential narrative R code with explanatory text and output data and images. These notebooks can be used as tutorials for training purposes and will guide researchers to explore their scRNA-seq data.
Isothermal digital detection of microRNA using background-free molecular circuit
Authors: Gines Guillaume , Menezes Roberta , Nara Kaori , Kirstetter Anne-Sophie , Taly Valérie , Rondelez Yannick
Published: July 2019

MicroRNA, a class of transcripts involved in the regulation of gene expression, are emerging as promising disease-specific biomarkers accessible from tissues or bodily fluids. However, their accurate quantification from biological samples remains challenging. We report a sensitive and quantitative microRNA method using an isothermal amplification chemistry adapted to a droplet digital readout. Building on molecular programming concepts, we design DNA circuit that converts, threshold, amplifies and report the presence of a specific microRNA, down to the femtomolar concentration. Using a leak-absorption mechanism, we were able to suppress non-specific amplification, classically encountered in other exponential amplification reactions. As a result, we demonstrate that this isothermal amplification scheme is adapted to digital counting of microRNA: by partitioning the reaction mixture into water-in-oil droplets, resulting in single microRNA encapsulation and amplification, the method provides absolute target quantification. The modularity of our approach enables to repurpose the assay for various microRNA sequences.
Variation in cephalic neuromasts surface and cave-dwelling fishes of the family Amblyopsidae (Teleostei: Percopsiformes)
Authors: Soares Daphne , Niemiller Matthew L.
Published: July 2019

Cave adaptation has led to unique sensory specializations to compensate for the lack of visual cues in aphotic subterranean habitats. As the role of vision is reduced or disappears, other sensory modalities become hypertrophied allowing cave-adapted organisms to successfully detect and interact their surrounding environment. The array of aquatic subterranean habitats, from fast-flowing streams and waterfalls, to quiet phreatic pools, presents a diverse palette to examine what possible sensory solutions have evolved against a backdrop of complete darkness. Mechanosensation is enhanced in many subterranean animals to such an extent that a longer appendage is recognized as a prominent troglomorphic adaptation in many metazoans. Fishes, however, not only interact with the environment using their fins, but also with specialized sensory organs to detect hydrodynamic events. We hypothesize that subterranean adaptation drives the hypertrophy of the mechanosensory lateral line, but that other environmental forces dictate the specific neuromast phenotype. To this end, we studied differences in the cephalic lateral line of the fishes in the North American family Amblyopsidae, which includes surface, cave-facultative, and cave-obligate species. None of the taxa we examined possessed canal neuromasts on the head. Primarily surface-dwelling species,Chologaster cornutaandForbesichthys agassizii, possessed receded neuromasts throughout most of the head, with a few on papillae located in front of the nostrils and on ventral grooves on each side of the mouth. The cavefishesAmyblopsis spelaeaandTyphlichthys subterraneouspossessed papillate superficial neuromasts all over the head. We speculate that the change from the surface to the cave environment has led to papillate neuromasts in this group, which are likely shaped to detect the hydrodynamic characteristics of the boundary layer created by the swimming fish. Moving sensory organs from the surface of the body out into the boundary layer could increase sensitivity to high frequency stimuli created by prey, predators, and conspecifics.
LSM2-8 and XRN-2 contribute to the silencing of H3K27me3-marked genes through targeted RNA decay
Authors: Mattout Anna , Gaidatzis Dimos , Padeken Jan , Schmid Christoph , Aeschlimann Florian , Kalck Véronique , Gasser Susan M.
Published: July 2019

In fission yeast and plants, RNA-processing pathways contribute to constitutive and facultative heterochromatin silencing, complementing well-characterized pathways of transcriptional repression. However, it was unclear whether this additional level of regulation occurs in metazoans. Here we describe a pathway of silencing in C. elegans somatic cells, in which the highly conserved, RNA binding complex LSM2-8 selectively silences heterochromatic reporters and endogenous genes bearing the Polycomb mark H3K27me3. Importantly, the LSM2-8 complex works cooperatively with XRN-2, a 5’-3’ exoribonuclease, and disruption of the pathway leads to mRNA stabilization. This selective LSM2-8-mediated RNA degradation does not target nor depend on H3K9me2/me3, unlike previously described pathways of heterochromatic RNA degradation. Intriguingly, the loss of LSM2-8 coincides with a localized drop in H3K27me3 levels on lsm-8-sensitive loci only. Together this defines a mechanism of RNA degradation that selectively targets a subset of H3K27me3-marked genes, revealing an unrecognized layer of regulation for facultative heterochromatin in animals.
RNA-Bloom provides lightweight reference-free transcriptome assembly for single cells
Authors: Nip Ka Ming , Chiu Readman , Yang Chen , Chu Justin , Mohamadi Hamid , Warren René L. , Birol Inanc
Published: July 2019

We present RNA-Bloom, ade novoRNA-seq assembly algorithm that leverages the rich information content in single-cell transcriptome sequencing (scRNA-seq) data to reconstruct cell-specific isoforms. We benchmark RNA-Bloom’s performance against leading bulk RNA-seq assembly approaches, and illustrate its utility in detecting cell-specific gene fusion events using sequencing data from HiSeq-4000 and BGISEQ-500 platforms. We expect RNA-Bloom to boost the utility of scRNA-seq data, expanding what is informatically accessible now.
Presynaptic Gαo(GOA-1) signals to depress command neuron excitability and allow stretch-dependent modulation of egg laying inCaenorhabditis elegans
Authors: Ravi Bhavya , Zhao Jian , Chaudhry Sana , Bartole Mattingly , Kopchock Richard J. , Guijarro Christian , Kang Lijun , Collins Kevin M.
Published: July 2019

Egg laying in the nematode wormCaenorhabditis elegansis a two-state behavior modulated by internal and external sensory input. We have previously shown that homeostatic feedback of embryo accumulation in the uterus regulates bursting activity of the serotonergic HSN command neurons that sustains the egg-laying active state. How sensory feedback of egg release signals to terminate the egg-laying active state is less understood. We find that Gαo, a conserved Pertussis Toxin-sensitive G protein, signals within HSN to inhibit egg-laying circuit activity and prevent entry into the active state. Gαosignaling hyperpolarizes HSN, reducing HSN Ca2+activity and input onto the postsynaptic vulval muscles. Loss of inhibitory Gαosignaling uncouples presynaptic HSN activity from a postsynaptic, stretch-dependent homeostat, causing precocious entry into the egg-laying active state when only a few eggs are present in the uterus. Feedback of vulval opening and egg release activates the uv1 neuroendocrine cells which release NLP-7 neuropeptides which signal to inhibit egg laying through Gαo-independent mechanisms in the HSNs and Gαo-dependent mechanisms in cells other than the HSNs. Thus, neuropeptide and inhibitory Gαosignaling maintains a bi-stable state of electrical excitability that dynamically controls circuit activity in response to both external and internal sensory input to drive a two-state behavior output.
Individual variation in dispersal and fecundity increases rates of spatial spread
Authors: Schreiber Sebastian J. , Beckman Noelle G.
Published: July 2019

Abstract

Dispersal and fecundity are two fundamental traits underlying the spread of populations. Using integral difference equation models, we examine how individual variation in these fundamental traits and the heritability of these traits influence rates of spatial spread of populations along a one-dimensional transect. Using a mixture of analytic and numerical methods, we show that individual variation in dispersal rates increases spread rates and the more heritable this variation, the greater the increase. In contrast, individual variation in lifetime fecundity only increases spread rates when some of this variation is heritable. The highest increases in spread rates occurs when variation in dispersal positively covaries with fecundity. Our results highlight the importance of estimating individual variation in dispersal rates, dispersal syndromes in which fecundity and dispersal co-vary positively, and heritability of these traits to predict population rates of spatial spread.
FINE GRAINED LONGITUDINAL ANALYSIS OF COCOA BEAN FERMENTATION PROVIDES INSIGHTS INTO THE DYNAMICS OF MICROBIAL POPULATIONS
Authors: Pacheco-Montealegre M. E. , Dávila-Mora L. L. , Botero-Rute L. M. , Reyes A. , Caro-Quintero A.
Published: July 2019

Cocoa bean fermentation is an important microbial driven process where metabolites that affect chocolate quality and aroma are produced. Although considerable research has been devoted to the yeast and bacteria species involved in this process, less attention has been paid to the role of populations and strains, which hinders its selection, monitoring and use. Here we present a study that evaluates the microbial diversity associated to the tools and bean mass during spontaneous cocoa fermentation and in two distinct agro-ecological zones in Colombia. Using high-throughput sequencing of molecular markers for bacteria and yeast, we established the dynamics at the species-level (OTUs) and strains-level (oligotypes). Our results show that cocoa bean fermentation is catalyzed by a composite of strains within each OTU and not by one single strain. Eventhough we found only a few bacterial OTUs, one Enterobacter, three of Lactic Acid Bacteria and two of Acetic Acid Bacteria, these could be further split into 6, 23 and 19 oligotypes, respectively. Only two fungal OTUs were found. Comparison between fermentations suggest that local protocols generated a specific footprint in the dynamics of the microbial communities and that tools are reservoirs of some of those groups. The population analysis shows that the oligotypes that become most dominant are the same in the two locations, coupling co-abundance and dominance analysis we suggest that a combination of Enterobacter and Acetobacter oligotypes seem more optimal for the starter cultures. In conclusion, the results presented here show that exploring the fine level dynamics of microbial fermentation is necessary to understand the patterns of the dominance of specific populations and can be used as a valuable approach to select and monitor specific bacteria for the design of starter cultures in the food industry.

IMPORTANCE

In Colombia, the lack of tools to validate and standardize fermentation protocols are one of the principal reasons why Colombian cocoa beans are not recognized as “fine-flavor” and widely marketed. Because of the large influence of the microbial fermentation in cocoa quality, the present study explores the microbial dynamics using high-throughput sequencing of molecular markers in two of the most important producer regions in Colombia. The results show that the identification of dominant and transitive strains can be used to select, design and monitor starter cultures and/or the effect of adjustments in the fermentation protocols.
Planar polarization of cilia in the zebrafish floor-plate involves Par3-mediated posterior localization of highly motile basal bodies
Authors: Donati Antoine , Schneider-Maunoury Sylvie , Vesque Christine
Published: July 2019

To produce a directional flow, ciliated epithelia display a uniform orientation of ciliary beating. Oriented beating requires planar cell polarity (PCP), which leads to planar orientation and asymmetric positioning of the ciliary basal body (BB) along the polarity axis. We took advantage of the polarized mono-ciliated epithelium of the embryonic zebrafish floor plate to investigate by live-imaging the dynamics and mechanisms of BB polarization. We showed that BBs, although bearing a cilium, were highly motile along the antero-posterior axis. BBs contacted both the anterior and the posterior membranes, with a bias towards posterior contacts from early somitogenesis on. Contacts exclusively occurred at junctional Par3 local enrichments or “patches” and were often preceded by transient membrane digitations extending towards the BB, suggesting focused cortical pulling forces. Accordingly, BBs and Par3 patches were linked by dynamic microtubules. We showed that Par3 became posteriorly enriched prior to BB posterior positioning and that floor plate polarization was impaired upon Par3 patches disruption triggered by Par3 or aPKC overexpression. In the PCP mutant Vangl2, where floor plate cells fail to polarize, we observed that BB were still motile but presented behavioral defects, such as ectopic contacts with lateral membranes that correlated with Par3 patch fragmentation and spreading to lateral membranes. Our data lead us to propose an unexpected function for posterior local Par3 enrichment in controlling BB asymmetric positioning downstream of the PCP pathway via a microtubule capture/shrinkage mechanism.
Hemibiotrophic fungal pathogen induces systemic susceptibility and systemic shifts in wheat metabolome and microbiome composition
Authors: Seybold Heike , Demetrowitsch Tobias , Hassani M. Amine , Szymczak Silke , Reim Ekaterina , Haueisen Janine , Rühlemann Malte , Franke Andre , Schwarz Karin , Stukenbrock Eva H.
Published: July 2019

Yield losses caused by fungal pathogens represent a major threat to global food production. One of the most devastating fungal wheat pathogens is Zymoseptoria tritici. Despite the importance of this fungus and wheat as main staple food crop the underlying mechanisms of plant-pathogen interactions are poorly understood. Here we present a conceptual framework based on coinfection assays, comparative metabolomics, and microbiome profiling to study the interaction of Z. tritici in susceptible and resistant wheat. We demonstrate that Z. tritici suppresses the production of immune-related metabolites in a susceptible cultivar. Remarkably, this fungus-induced immune suppression spreads within the leaf and even to other leaves, a previously undescribed phenomenon that we term “systemic induced susceptibility”. Using a comparative metabolomics approach, we identified defense-related biosynthetic pathways that are suppressed and induced in susceptible and resistant cultivars, respectively. We show that these fungus-induced changes also dramatically affect the wheat leaf microbiome. Our findings emphasize that immune suppression by this hemibiotrophic pathogen impacts specialized plant metabolism, alters its associated microbial communities, and renders wheat vulnerable to further infections.
Systematic assessment of commercially available low-input miRNA library preparation kits
Authors: Heinicke Fatima , Zhong Xiangfu , Zucknick Manuela , Breidenbach Johannes , Sundaram Arvind , Flåm Siri T. , Leithaug Magnus , Dalland Marianne , Farmer Andrew , Henderson Jordana M. , Hussong Melanie A. , Moll Pamela , Nguyen Loan , McNulty Amanda , Shaffer Jonathan M. , Shore Sabrina , Yip HoiChong Karen , Vitkovska Jana , Rayner Simon , Lie Benedicte A , Gilfillan Gregor D.
Published: July 2019

High-throughput sequencing is increasingly favoured to assay the presence and abundance of micro RNAs (miRNAs) in biological samples, even from low RNA amounts, and a number of commercial vendors now offer kits that allow miRNA sequencing from sub-nanogram (ng) inputs. However, although biases introduced during library preparation have been documented, the relative performance of current reagent kits has not been investigated in detail. Here, six commercial kits capable of handling <100ng total RNA input were used for library preparation, performed by kit manufactures, on synthetic miRNAs of known quantities and human biological total RNA samples. We compared the performance of miRNA detection sensitivity, reliability, titration response and the ability to detect differentially expressed miRNAs. In addition, we assessed the use of unique molecular identifiers sequence (UMI) tags in one kit. We observed differences in detection sensitivity and ability to identify differentially expressed miRNAs between the kits, but none were able to detect the full repertoire of expected miRNAs. The reliability within the replicates of all kits was good, while larger differences were observed between the kits, although none could accurately quantify the majority of miRNAs. UMI tags, at least within the input ranges tested, offered little advantage to improve data utility. In conclusion, biases in miRNA abundance are heavily influenced by the kit used for library preparation, suggesting that comparisons of datasets prepared by different procedures should be made with caution. This article is intended to assist researchers select the most appropriate kit for their experimental conditions.
Modulation of Actin network and Tau phosphorylation by HDAC6 ZnF UBP domain
Authors: Balmik Abhishek Ankur , Sonawane Shweta Kishor , Chinnathambi Subashchandrabose
Published: July 2019

Microtubule-associated protein Tau undergoes aggregation in Alzheimer’s disease and a group of other related diseases collectively known as Tauopathies. In AD, Tau forms aggregates, which are deposited intracellularly as neurofibrillary tangles. HDAC6 plays an important role in aggresome formation where it recruits polyubiquitinated aggregates to the motor protein dynein. Here, we have studied the effect of HDAC6 ZnF UBP on Tau phosphorylation, ApoE localization, GSK-3β regulation and cytoskeletal organization in neuronal cells by immunocytochemistry. Immunocytochemistry reveals that HDAC6 ZnF UBP can modulate Tau phosphorylation and actin cytoskeleton organization when the cells are exposed to the domain. HDAC6 ZnF UBP treatment to cells does not affect their viability and resulted in enhanced neurite extension and formation of structures similar to podosomes, lamellipodia and podonuts suggesting its role in actin re-organization. Also, HDAC6 treatment showed increased nuclear localization of ApoE and tubulin localization in microtubule organizing centre. Our studies suggest the regulatory role of this domain in different aspects of neurodegenerative diseases.
Defining the emergence of myeloid-derived suppressor cells in breast cancer using single-cell transcriptomics
Authors: Alshetaiwi Hamad , Pervolarakis Nicholas , McIntyre Laura Lynn , Ma Dennis , Nguyen Quy , Rath Jan Akara , Nee Kevin , Hernandez Grace , Evans Katrina , Torosian Leona , Silva Anushka , Walsh Craig , Kessenbrock Kai
Published: July 2019

Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses during cancer. It remains elusive how MDSCs differ from their normal myeloid counterparts, which limits our ability to specifically detect and therapeutically target MDSCs during cancer. Here, we used single-cell RNAseq to compare MDSC-containing splenic myeloid cells from breast tumor-bearing mice to wildtype controls. Our computational analysis of 14,646 single-cell transcriptomes reveals that MDSCs emerge through a previously unrealized aberrant neutrophil maturation trajectory in the spleen giving rise to a unique chemokine-responsive, immunosuppressive cell state that strongly differs from normal myeloid cells. We establish the first MDSC-specific gene signature and identify novel surface markers for improved detection and enrichment of MDSCs in murine and human samples. Our study provides the first single-cell transcriptional map defining the development of MDSCs, which will ultimately enable us to specifically target these cells in cancer patients.

One Sentence Summary

We used single cell transcriptomics to identify the unique molecular features distinguishing myeloid-derived suppressor cells (MDSCs) from their normal, myeloid counterparts, which enabled us to reveal distinct transitory gene expression changes during their maturation in the spleen, and to identify novel cell surface markers for improved detection and isolation of MDSCs.
A custom genotyping array reveals population-level heterogeneity for the genetic risks of prostate cancer and other cancers in Africa
Authors: Harlemon Maxine , Ajayi Olabode , Kachambwa Paidamoyo , Kim Michelle S. , Simonti Corinne N. , Quiver Melanie H. , Petersen Desiree C. , Mittal Anuradha , Fernandez Pedro , Hsing Ann W. , Baichoo Shakuntala , Agalliu Ilir , Jalloh Mohamed , Gueye Serigne M. , Snyper Nana Yaa , Adusei Ben , Mensah James E. , Abrahams Afua O.D. , Adebiyi Akindele O. , Orunmuyi Akin , Aisuodionoe-Shadrach Oseremen I. , Nwegbu Maxwell M. , Joffe Maureen , Chen Wenlong C. , Irusen Hayley , Neugut Alfred I. , Quintana Yuri , Seutloali Moleboheng , Fadipe Mayowa , Warren Christopher , Woehrmann Marcos H. , Zhang Peng , Ongaco Chrissie , Mawhinney Michelle , McBride Jo , Andrews Caroline , Adams Marcia , Pugh Elizabeth , Rebbeck Timothy R. , Petersen Lindsay , Lachance Joseph
Published: July 2019

Although prostate cancer is the leading cause of cancer mortality for African men, the vast majority of known disease associations have been detected in European study cohorts. Furthermore, most genome-wide association studies have used genotyping arrays that are hindered by SNP ascertainment bias. To overcome these disparities in genomic medicine, the Men of African Descent and Carcinoma of the Prostate (MADCaP) Network has developed a genotyping array that is optimized for African populations. The MADCaP Array contains more than 1.5 million markers and an imputation backbone that successfully tags over 94% of common genetic variants in African populations. This array also has a high density of markers in genomic regions associated with cancer susceptibility, including 8q24. We assessed the effectiveness of the MADCaP Array by genotyping 399 prostate cancer cases and 403 controls from seven urban study sites in sub-Saharan Africa. We find that samples from Ghana and Nigeria cluster together, while samples from Senegal and South Africa yield distinct ancestry clusters. Using the MADCaP array, we identified cancer-associated loci that have large allele frequency differences across African populations. Polygenic risk scores were also generated for each genome in the MADCaP pilot dataset, and we found that predicted risks of CaP are lower in Senegal and higher in Nigeria.

Significance

We have developed an Africa-specific genotyping array which enables investigators to identify novel disease associations and to fine-map genetic loci that are associated with prostate and other cancers.
Quantitative real-time PCR assay for the rapid identification of the multidrug-resistant bacterial pathogen Stenotrophomonas maltophilia
Authors: Fraser Tamieka A. , Bell Mikaela G. , Harris Patrick N.A. , Bell Scott C. , Bergh Haakon , Nguyen Thuy-Khanh , Kidd Timothy J. , Nimmo Graeme R. , Sarovich Derek S. , Price Erin P.
Published: July 2019

Stenotrophomonas maltophilia is emerging as an important cause of disease in nosocomial and community-acquired settings, including bloodstream, wound and catheter-associated infections. Cystic fibrosis airways also provide optimal growth conditions for various opportunistic pathogens with high antibiotic tolerance, including S. maltophilia. Currently, there is no rapid, cost-effective, and accurate molecular method for detecting this potentially life-threatening pathogen, particularly in polymicrobial specimens, suggesting that its true prevalence may be underestimated. Here, we used large-scale comparative genomics to identify a specific genetic target for S. maltophilia, with subsequent development and validation of a real-time PCR assay for its detection. Analysis of 165 Stenotrophomonas spp. genomes identified a 4kb region specific to S. maltophilia, which was targeted for Black Hole Quencher assay design. Our assay yielded the positive detection of 89 of 89 (100%) clinical S. maltophilia strains, and no amplification of 23 non-S. maltophilia clinical isolates. S. maltophilia was detected in 10/16 CF sputa, demonstrating the utility for direct detection in respiratory specimens. The assay demonstrated good sensitivity, with limits of detection and quantitation on pure culture of ~10 and ~100 genome equivalents, respectively. Our assay provides a highly specific, sensitive, and cost-effective method for the accurate identification of S. maltophilia, and will improve the diagnosis and treatment of this under-recognized pathogen by enabling its accurate and rapid detection from polymicrobial clinical and environmental samples.