bluuebunny/crossref_metadata_2025 huggingface dataset:
Sophisticated suction organs from insects living in raging torrents: Morphology and ultrastructure of the attachment devices of net-winged midge larvae (Diptera: Blephariceridae)
Authors: Kang Victor , Johnston Richard , van de Kamp Thomas , Faragó Tomáš , Federle Walter
Published: June 2019

2.

Suction organs provide powerful yet dynamic attachments for many aquatic animals, including octopus, squid, remora, and clingfish. While the functional morphology of suction organs from various cephalopods and fishes has been investigated in detail, there are only few studies on such attachment devices in insects. Here we characterise the morphology, ultrastructure, andin vivomovements of the suction attachment organs of net-winged midge larvae (genusLiponeura) – aquatic insects that live on rocks in rapid alpine waterways where flow rates can reach 3 m s-1– using scanning electron microscopy, laser confocal scanning microscopy, and X-ray computed micro-tomography (micro-CT). We identified structural adaptations important for the function of the suction attachment organs fromL. cinerascensandL. cordata. First, a dense array of spine-like microtrichia covering each suction disc comes into contact with the substrate upon attachment. Similar hairy structures have been found on the contact zones of suction organs from octopus, clingfish, and remora fish. These structures are thought to contribute to the seal and to provide increased shear force resistance in high-drag environments. Second, specialised rim microtrichia at the suction disc periphery form a continuous ring in close contact with a surface and may serve as a seal on a variety of surfaces. Third, a V-shaped cut on the suction disc (the V-notch) is actively peeled open via two cuticular apodemes inserting into its flanks. The apodemes are attached to dedicated V-notch opening muscles, thereby providing a unique detachment mechanism. The complex cuticular design of the suction organs, along with specialised muscles that attach to them, allows blepharicerid larvae to generate powerful attachments which can withstand strong hydrodynamic forces and quickly detach for locomotion. Our findings could be applied to bio-inspired attachment devices that perform well on a wide range of surfaces.
A proteogenomic resource enabling integrated analysis ofListeriagenotype-proteotype-phenotype relationships
Authors: Varadarajan Adithi R. , Pavlou Maria P. , Goetze Sandra , Grosboillot Virginie , Shen Yang , Loessner Martin J. , Ahrens Christian H. , Wollscheid Bernd
Published: June 2019

Listeria monocytogenesis an opportunistic foodborne pathogen responsible for listeriosis, a potentially fatal foodborne disease. Many differentListeriastrains and serotypes exist, but a proteogenomic resource that bridges the gap in our molecular understanding of the relationships between theListeriagenotypes and phenotypes via proteotypes is still missing. Here we devised a next-generation proteogenomics strategy that enables the community to rapidly proteotypeListeriastrains and relate this information back to the genotype. Based on sequencing andde novoassembly of the two most commonly usedListeriamodel strains, EGD-e and ScottA, we established two comprehensiveListeriaproteogenomic databases. A genome comparison established core- and strain-specific genes potentially responsible for virulence differences. Next, we established a DIA/SWATH-based proteotyping strategy, including a new and robust sample preparation workflow, that enables the reproducible, sensitive, and relative quantitative measurement ofListeriaproteotypes. This reusable and publically available DIA/SWATH library covers 70% of open reading frames ofListeriaand represents the most extensive spectral library forListeriaproteotype analysis to date. We used these two new resources to investigate theListeriaproteotype in states mimicking the upper gastrointestinal passage. Exposure ofListeriato bile salts at 37 °C, which simulates conditions encountered in the duodenum, showed significant proteotype perturbations including an increase of FlaA, the structural protein of flagella. Given thatListeriais known to lose its flagella above 30 °C, this was an unexpected finding. The formation of flagella, which might have implications on infectivity, was validated by parallel reaction monitoring and light and scanning electron microscopy.flaAtranscript levels were not significantly different with and without exposure to bile salts at 37 °C, suggesting regulation at the post-transcriptional level. Together, these analyses provide a comprehensive proteogenomic resource and toolbox for theListeriacommunity enabling the analysis ofListeriagenotype-proteotype-phenotype relationships.
Phylogenetic and structural diversity of aromatically dense pili from environmental metagenomes
Authors: Bray M. S. , Wu J. , Padilla C.C. , Stewart F. J. , Fowle D. A. , Henny C. , Simister R. L. , Thompson K. J. , Crowe S. A. , Glass J. B.
Published: June 2019

Electroactive type IV pili, or e-pili, are used by some microbial species for extracellular electron transfer. Recent studies suggest that e-pili may be more phylogenetically and structurally diverse than previously assumed. Here, we used updated aromatic density thresholds (≥9.8% aromatic amino acids, ≤22-aa aromatic gaps, and aromatic amino acids at residues 1, 24, 27, 50 and/or 51, and 32 and/or 57) to search for putative e-pilin genes in metagenomes from diverse ecosystems with active microbial metal cycling. Environmental putative e-pilins were diverse in length and phylogeny, and included truncated e-pilins inGeobacterspp., as well as longer putative e-pilins in Fe(II)-oxidizingBetaproteobacteriaandZetaproteobacteria.

Originality and Significance

Electroactive pili (e-pili) are used by microorganisms to respire solid metals in their environment through extracellular electron transfer. Thus, e-pili enable microbes to occupy specific environmental niches. Additionally, e-pili have important potential for biotechnological applications. Currently the repertoire of known e-pili is small, and their environmental distribution is largely unknown. Using sequence analysis, we identified numerous genes encoding putative e-pili from diverse anoxic, metal-rich ecosystems. Our results expand the diversity of putative e-pili in environments where metal oxides may be important electron acceptors for microbial respiration.
Stress Resets Transgenerational Small RNA Inheritance
Authors: Houri-Ze’evi Leah , Teichman Guy , Gingold Hila , Rechavi Oded
Published: June 2019

Transgenerational inheritance of small RNAs is challenging basic concepts of heredity and achieving control over such responses is of great interest. InC. elegansnematodes, small RNAs are transmitted across generations to establish a transgenerational memory trace of ancestral environments and distinguish self from non-self genes. Inheritance of small RNAs is regulated by dedicated machinery and carryover of aberrant heritable small RNA responses was shown to be maladaptive and to induce sterility. Here we show that various types of stress (starvation, high temperatures, and high osmolarity) but not non-stressful changes in cultivation conditions, lead to resetting of small RNA inheritance. We found that stress leads to a genome-wide reduction in heritable small RNA levels and that mutants defective in different stress pathways exhibit irregular RNAi inheritance dynamics. Moreover, we discovered that resetting of heritable RNAi is orchestrated by MAPK pathway factors, the transcription factor SKN-1, and the MET-2 methyltransferase. Termination of small RNA inheritance, and the fact that this process depends on stress, could protect from run-on of environment-irrelevant heritable gene regulation.
Early-Stage Ocular Hypertension Alters Retinal Ganglion Cell Synaptic Transmission in the Visual Thalamus
Authors: Bhandari Ashish , Smith Jennie C. , Zhang Yang , Reid Lisa , Goeser Toni , Fan Shan , Ghate Deepta , Hook Matthew J. Van
Published: June 2019

Axonopathy is a hallmark of many neurodegenerative diseases including glaucoma, where elevated intraocular pressure (ocular hypertension, OHT) stresses retinal ganglion cell (RGC) axons as they exit the eye and form the optic nerve. OHT causes early changes in the optic nerve such as axon atrophy, transport inhibition, and gliosis. Importantly, many of these changes appear to occur prior to irreversible neuronal loss, making them promising points for early diagnosis of glaucoma. It is unknown whether OHT has similarly early effects on the function of RGC output to the brain. To test this possibility, we elevated eye pressure in mice by anterior chamber injection of polystyrene microbeads. 5 weeks post-injection, bead-injected eyes showed a modest RGC loss in the peripheral retina, as evidenced by RBPMS antibody staining. Additionally, we observed reduced dendritic complexity and lower spontaneous spike rate of On-αRGCs, targeted for patch clamp recording and dye filling using aOpn4-cre reporter mouse line. To determine the influence of OHT on retinal projections to the brain, we expressed Channelrhodopsin-2 (ChR2) in melanopsin-expressing retinal ganglion cells by crossing theOpn4-cre mouse line with a ChR2-reporter mouse line and recorded post-synaptic responses in thalamocortical relay neurons in the dorsal lateral geniculate nucleus (dLGN) of the thalamus evoked by stimulation with 460 nm light. The use of aOpn4-cre reporter system allowed for expression of ChR2 in a narrow subset of RGCs responsible for image-forming vision in mice. Five weeks following OHT induction, paired pulse and high-frequency stimulus train experiments revealed that presynaptic vesicle release probability at retinogeniculate synapses was elevated. Additionally, miniature synaptic current frequency was slightly reduced in brain slices from OHT mice and proximal dendrites of post-synaptic dLGN relay neurons, assessed using a Sholl analysis, showed a reduced complexity. Strikingly, these changes occurred prior to major loss of RGCs labeled with theOpn4-Cre mouse, as indicated by immunofluorescence staining of ChR2-expressing retinal neurons. Thus, OHT leads to pre- and post-synaptic functional and structural changes at retinogeniculate synapses. Along with RGC dendritic remodeling and optic nerve transport changes, these retinogeniculate synaptic changes are among the earliest signs of glaucoma.
Cohort profile: The LipidCardio Study - Role of Lipoproteins in Cardiovascular Disease
Authors: König Maximilian , Joshi Samita , Leistner David M. , Landmesser Ulf , Sinning David , Steinhagen-Thiessen Elisabeth , Demuth Ilja
Published: June 2019

Purpose

The LipidCardio Study was established for in-depth analyses of cardiovascular risk factors, providing well-defined cardiovascular and metabolic phenotypes. Particularly the role of lipoproteins in the pathobiological process and treatment of cardiovascular disease will be a main focus.

Participants

1.005 individuals aged 21 years and older undergoing cardiac catheterization during 17 months at a tertiary academic cardiology center were enrolled. The baseline data set contains detailed phenotyping, broad biochemical parameters, genetic data, but also standardized personal and family history, a screening test for cognitive impairment, pulse wave analysis and measurements of hand grip strength, amongst others. Blood samples were stored in a biobank for future analyses.

Findings to date

The mean age of the participants at enrolment was 70.9±11.1 years (70% male). Coronary angiography provided evidence of obstructive coronary artery disease (CAD) in 69.9% of participants. Those with evidence of CAD were significantly more likely to be male, inactive, diabetic and with a family history of cardiovascular disease than participants without CAD.

20% of patients had lipoprotein(a) [Lp(a)] concentrations above 106.9 nmol/L (fifth quintile). These patients had significantly increased odds of obstructive CAD compared to participants in quintiles 1-4 (OR 1.70, 95% CI 1.17 to 2.48, p=0.005). There was reasonable evidence that with increasing severity of CAD the odds of having elevated Lp(a) increased. We were able to replicate the established strong association between specified single nucleotide polymorphisms (SNPs) in the LPA gene (rs10455872, rs3798220 and rs186696265) and the APOE gene (rs7412), and the concentration of Lp(a), validating our phenotype database and biobank.

Future plans

Mortality information will be obtained in two-year intervals. Follow-up phone interviews will be conducted at 3, and 6 years after enrolment. We seek to cooperate with other researchers in the field, e.g. by sharing data and biobank samples.

Registration

not applicable, purely observational study
Efficient and adaptive sensory codes
Authors: Młynarski Wiktor , Hermundstad Ann M.
Published: June 2019

The ability to adapt to changes in stimulus statistics is a hallmark of sensory systems. Here, we develop a theoretical framework that can account for the dynamics of adaptation from an information-processing perspective. We use this framework to optimize and analyze adaptive sensory codes, and we show that codes optimized for stationary environments can suffer from prolonged periods of poor performance when the environment changes. To mitigate the adversarial effects of these environmental changes, sensory systems must navigate tradeoffs between the ability to accurately encode incoming stimuli, and the ability to rapidly detect and adapt to changes in the distribution of these stimuli. We derive families of codes that balance these objectives, and we demonstrate their close match to experimentally-observed neural dynamics during mean and variance adaptation. Our results provide a unifying perspective on adaptation across a range of sensory systems, environments, and sensory tasks.
Compensating for a shifting world: evolving reference frames of visual and auditory signals across three multimodal brain areas
Authors: Caruso Valeria C. , Pages Daniel S. , Sommer Marc A. , Groh Jennifer M.
Published: June 2019

Stimulus locations are detected differently by different sensory systems, but ultimately they yield similar percepts and behavioral responses. How the brain transcends initial differences to compute similar codes is unclear. We quantitatively compared the reference frames of two sensory modalities, vision and audition, across three interconnected brain areas involved in generating saccades, namely the frontal eye fields (FEF), lateral and medial parietal cortex (M/LIP), and superior colliculus (SC). We recorded from single neurons in head-restrained monkeys performing auditory- and visually-guided saccades from variable initial fixation locations, and evaluated whether their receptive fields were better described as eye-centered, head-centered, or hybrid (i.e. not anchored uniquely to head- or eye-orientation). We found a progression of reference frames across areas and across time, with considerable hybrid-ness and persistent differences between modalities during most epochs/brain regions. For both modalities, the SC was more eye-centered than the FEF, which in turn was more eye-centered than the predominantly hybrid M/LIP. In all three areas and temporal epochs from stimulus onset to movement, visual signals were more eye-centered than auditory signals. In the SC and FEF, auditory signals became more eye-centered at the time of the saccade than they were initially after stimulus onset, but only in the SC at the time of the saccade did the auditory signals become predominantly eye-centered. The results indicate that visual and auditory signals both undergo transformations, ultimately reaching the same final reference frame but via different dynamics across brain regions and time.

New and Noteworthy

Models for visual-auditory integration posit that visual signals are eye-centered throughout the brain, while auditory signals are converted from head-centered to eye-centered coordinates. We show instead that both modalities largely employ hybrid reference frames: neither fully head-nor eye-centered. Across three hubs of the oculomotor network (intraparietal cortex, frontal eye field and superior colliculus) visual and auditory signals evolve from hybrid to a common eye-centered format via different dynamics across brain areas and time.
Activation of a nerve injury transcriptional signature in airway-innervating sensory neurons after LPS induced lung inflammation
Authors: Kaelberer Melanie Maya , Caceres Ana Isabel , Jordt Sven-Eric
Published: June 2019

The lungs, the immune and nervous systems functionally interact to respond to respiratory environmental exposures and infections. The lungs are innervated by vagal sensory neurons of the jugular and nodose ganglia, fused together in smaller mammals as the jugular-nodose complex (JNC). While the JNC shares properties with the other sensory ganglia, the trigeminal (TG) and dorsal root ganglia (DRG), these sensory structures express differential sets of genes that reflect their unique functionalities. Here, we used RNAseq in mice to identify the differential transcriptomes of the three sensory ganglia types. Using a fluorescent retrograde tracer and fluorescence-activated cell sorting we isolated a defined population of airway-innervating JNC neurons and determined their differential transcriptional map after pulmonary exposure to lipopolysaccharide (LPS), a major mediator of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) after infection with Gram-negative bacteria or inhalation of organic dust. JNC neurons activated an injury response program leading to increased expression of gene products such as the G-protein coupled receptors, Cckbr, inducing functional changes in neuronal sensitivity to peptides, and Gpr151, also rapidly induced upon neuropathic nerve injury in pain models. Unique JNC-specific transcripts, present at only minimal levels in TG, DRG and other organs, were identified. These included TMC3, encoding for a putative mechanosensor, and Urotensin 2B, a hypertensive peptide. These findings highlight the unique properties of the JNC and reveal that ALI/ARDS rapidly induce a nerve-injury related state changing vagal excitability.

SIGNIFICANCE STATEMENT

The lungs are innervated by sensory neurons of the jugular-nodose ganglia complex (JNC) that detect toxic exposures and interact with lung-resident cells and the immune system to respond to pathogens and inflammation. Here we report the expression of specific genes that differentiate these neurons from neurons in the other sensory ganglia, the trigeminal (TG) and dorsal root ganglia (DRG). Through nerve tracing we identified and isolated airway innervating JNC neurons and determined their differential transcriptional map after lung inflammation induced by a bacterial product, lipopolysaccharide (LPS). We observed the rapid activation of a nerve injury transcriptional program that increased nerve sensitivity to inflammation. This mechanism may result in more permanent nerve injury associated with chronic cough and other respiratory complications.
The thalamic basis of outcome and cognitive impairment in traumatic brain injury
Authors: Lutkenhoff Evan S. , Wright Matthew J. , Shrestha Vikesh , Real Courtney , McArthur David L. , Buitrago-Blanco Manuel , Vespa Paul M. , Monti Martin M.
Published: June 2019

Objective

To understand how, biologically, the acute event of traumatic brain injury gives rise to a long-term disease, we address the relationship between evolving cortical and subcortical brain damage and measures of functional outcome and cognitive functioning at six months post-injury.

Methods

Longitudinal analysis of clinical and MRI data collected, in a tertiary neurointensive care setting, in a continuous sample of 157 patients surviving moderate to severe traumatic brain injury between 2000 and 2018. For each patient we collected T1- and T2-weighted MRI data, acutely and at a six-months follow-up, as well as acute measures of injury severity (Glasgow Coma Scale) and follow-up measures of functional impairment (Glasgow Outcome Scale extended), and, in a subset of patients, neuropsychological measures of attention, executive functions, and episodic memory.

Results

In the final cohort of 113 subcortical and 92 cortical datasets that survived (blind) quality control, extensive atrophy was observed over the first six months post-injury across the brain. Nonetheless, only atrophy within subcortical regions, particularly in left thalamus, were associated with functional outcome and neuropsychological measures of attention, executive functions, and episodic memory. Furthermore, when brought together in an analytical model, longitudinal brain measurements could distinguish good versus bad outcome with 90% accuracy, whereas acute brain and clinical measurements alone could only achieve 20% accuracy.

Interpretation

Despite great injury heterogeneity, secondary thalamic pathology is a measurable minimum common denominator mechanism directly relating biology to clinical measures of outcome and cognitive functioning, potentially linking the acute “event” and the long(er)-term “disease” of TBI.
Resting state functional connectivity in early post-anesthesia recovery is characterized by globally reduced anticorrelations
Authors: Nir Tommer , Jacob Yael , Huang Kuang-Han , Schwartz Arthur E. , Brallier Jess W. , Ahn Helen , Kundu Prantik , Tang Cheuk Y. , Delman Bradley N. , McCormick Patrick J. , Sano Mary , Deiner Stacie G. , Baxter Mark G. , Mincer Joshua S.
Published: June 2019

Though a growing body of literature is addressing the possible longer-term cognitive effects of anesthetics, to date no study has delineated the normal trajectory of neural recovery due to anesthesia alone in older adults. We obtained resting state functional magnetic resonance imaging scans on 62 healthy human volunteers between ages forty and eighty before, during, and after sevoflurane (general) anesthesia, in the absence of surgery, as part of a larger study on cognitive function post-anesthesia. Resting state networks expression decreased consistently one hour after emergence from anesthesia. This corresponded to a global reduction in anticorrelated functional connectivity post-anesthesia, seen across individual regions-of-interest. Positively correlated functional connectivity remained constant across peri-anesthetic states. All measures returned to baseline 1 day later, with individual regions-of-interest essentially returning to their pre-anesthesia connectivity levels. These results define normal peri-anesthetic changes in resting state connectivity in healthy older adults.
Batch Effect Correction of RNA-seq Data through Sample Distance Matrix Adjustment
Authors: Fei Teng , Yu Tianwei
Published: June 2019

Batch effect is a frequent challenge in deep sequencing data analysis that can lead to misleading conclusions. We present scBatch, a numerical algorithm that conducts batch effect correction on the count matrix of RNA sequencing (RNA-seq) data. Different from traditional methods, scBatch starts with establishing an ideal correction of the sample distance matrix that effectively reflect the underlying biological subgroups, without considering the actual correction of the raw count matrix itself. It then seeks an optimal linear transformation of the count matrix to approximate the established sample pattern. The benefit of such an approach is the final result is not restricted by assumptions on the mechanism of the batch effect. As a result, the method yields good clustering and gene differential expression (DE) results. We compared the new method, scBatch, with leading batch effect removal methods ComBat and mnnCorrect on simulated data, real bulk RNA-seq data, and real single-cell RNA-seq data. The comparisons demonstrated that scBatch achieved better sample clustering and DE gene detection results.
Circuit-Specific Early Impairment of Proprioceptive Sensory Neurons in the SOD1G93AMouse Model for ALS
Authors: Seki Soju , Yamamoto Toru , Quinn Kiara , Spigelman Igor , Pantazis Antonios , Olcese Riccardo , Wiedau-Pazos Martina , Chandler Scott H. , Venugopal Sharmila
Published: June 2019

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which motor neurons degenerate resulting in muscle atrophy, paralysis and fatality. Studies using mouse models of ALS indicate a protracted period of disease development with progressive motor neuron pathology, evident as early as embryonic and postnatal stages. Key missing information includes concomitant alterations in the sensorimotor circuit essential for normal development and function of the neuromuscular system. Leveraging unique brainstem circuitry, we showin vitroevidence for reflex circuit-specific postnatal abnormalities in the jaw proprioceptive sensory neurons in the well-studied SOD1G93Amouse. These include impaired and arrhythmic action potential burst discharge associated with a deficit in Nav1.6 Na+channels. However, the mechanoreceptive and nociceptive trigeminal ganglion neurons and the visual sensory retinal ganglion neurons were resistant to excitability changes in age matched SOD1G93Amice. Computational modeling of the observed disruption in sensory patterns predicted asynchronous self-sustained motor neuron discharge suggestive of imminent reflexive defects such as muscle fasciculations in ALS. These results demonstrate a novel reflex circuit-specific proprioceptive sensory abnormality in ALS.

Significance Statement

Neurodegenerative diseases have prolonged periods of disease development and progression. Identifying early markers of vulnerability can therefore help devise better diagnostic and treatment strategies. In this study, we examined postnatal abnormalities in the electrical excitability of muscle spindle afferent proprioceptive neurons in the well-studied SOD1G93Amouse model for neurodegenerative motor neuron disease, ALS. Our findings suggest that these proprioceptive sensory neurons are exclusively afflicted early in the disease process relative to sensory neurons of other modalities. Moreover, they presented Nav1.6 Na+channel deficiency which contributed to arrhythmic burst discharge. Such sensory arrhythmia could initiate reflexive defects such as muscle fasciculations in ALS as suggested by our computational model.
Single Cell Analysis Reveals Immune Cell-Adipocyte Crosstalk Regulating the Transcription of Thermogenic Adipocytes
Authors: Rajbhandari Prashant , Arneson Douglas , Feng An-Chieh , Ahn In Sook , Diamante Graciel , Zaghari Nima , Thomas Brandon J. , Vergnes Laurent , Lee Stephen D. , Reue Karen , Smale Stephen T. , Yang Xia , Tontonoz Peter
Published: June 2019

Immune cells are vital constituents of the adipose microenvironment that influence both local and systemic lipid metabolism. Mice lacking IL10 have enhanced thermogenesis, but the roles of specific cell types in the metabolic response to IL10 remain to be defined. We demonstrate here that selective loss of IL10 receptor α in adipocytes recapitulates the beneficial effects of global IL10 deletion, and that local crosstalk between IL10-producing immune cells and adipocytes is a determinant of thermogenesis and systemic energy balance. Single Nuclei Adipocyte RNA-sequencing (SNAP-seq) of subcutaneous adipose tissue defined a metabolically-active mature adipocyte subtype characterized by robust expression of genes involved in thermogenesis whose transcriptome was selectively responsive to IL10Rα deletion. Furthermore, single-cell transcriptomic analysis of adipose stromal populations identified lymphocytes as a key source of IL10 production in response to thermogenic stimuli. These findings implicate adaptive immune cell-adipocyte communication in the maintenance of adipose subtype identity and function.
Mycobacteria fecal shedding in wild boars (Sus scrofa), South-eastern France
Authors: Fellag Mustapha , Drancourt Michel , Marié Jean-Lou , Davoust Bernard
Published: June 2019

The recent recrudescence of tuberculosis in cattle has implicated wild boar as a reservoir and vector of this disease, which led to the investigation of fecal shedding of the causativeMycobacterium bovis. In the Provence region of France, wild boars are very abundant, and the current study was carried out to assess the presence of tuberculous and nontuberculous mycobacteria in feces of wild boar population. W e developed an original protocol allowing the fast isolation of mycobacteria by combining a 1%-chlorhexidine decontamination of fecal matter with culture on MOD9 medium. Colonies were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, combined with DNA sequencing. This protocol yielded no tuberculous mycobacteria among ninety-nine wild boar fecal samples collected in the Provence region. However, non-tuberculous mycobacteria were isolated from five samples (5.05%), includingMycobacterium peregrinum, Mycobacterium vaccaeandMycobacterium setense, the last species being previously unreported in the wild boar; in addition to two positive samples forNocardiaspp. In conclusion, wild boars in southeastern France are not shedding tuberculosis agents, but they could constitute a reservoir of human non-tuberculous mycobacteriosis in selected populations directly exposed to wild boars.
Distinct Contribution of DNA Methylation and Histone Acetylation to the Genomic Occupancy of Transcription Factors
Authors: Cusack Martin , King Hamish W. , Spingardi Paolo , Kessler Benedikt M. , Klose Robert J. , Kriaucionis Skirmantas
Published: June 2019

Epigenetic modifications on chromatin play important roles in regulating gene expression. While chromatin states are often governed by multi-layered structure, how individual pathways contribute to gene expression remains poorly understood. For example, DNA methylation is known to regulate transcription factor binding but also to recruit methyl-CpG binding proteins that affect chromatin structure through the activity of histone deacetylase complexes (HDACs). Both of these mechanisms can potentially affect gene expression, but the importance of each, and whether these activities are integrated to achieve appropriate gene regulation, remains largely unknown. To address this important question, we measured gene expression, chromatin accessibility, and transcription factor occupancy in wild-type or DNA methylation-deficient mouse embryonic stem cells following HDAC inhibition. Interestingly, we observe widespread increases in chromatin accessibility at repeat elements when HDACs are inhibited, and this is magnified when cells also lack DNA methylation. A subset of these elements have elevated binding of the YY1 and GABPA transcription factors and increased expression. The pronounced additive effect of HDAC inhibition in DNA methylation deficient cells demonstrate that DNA methylation and histone deacetylation act largely independently to suppress transcription factor binding and gene expression.
Potential of host serum protein biosignatures in the diagnosis of tuberculous meningitis in children
Authors: Manyelo Charles M , Solomons Regan S , Snyders Candice I , Stanley Kim , Walzl Gerhard , Chegou Novel N
Published: June 2019

Background

Tuberculous meningitis (TBM) is the most severe form of tuberculosis and results in high morbidity and mortality in children. Diagnostic delay contributes to the poor outcome. There is an urgent need for new tools for the rapid diagnosis of TBM, especially in children.

Methods

We collected serum samples from children in whom TBM was suspected at a tertiary hospital in Cape Town, South Africa. Children were subsequently classified as having TBM or no TBM using a published uniform research case-definition. Using a multiplex cytokine array platform, we investigated the concentrations of serum biomarkers comprising 7-markers that were previously found to be of value in the diagnosis of adult pulmonary TB (CRP, SAA, CFH, IFN-γ, IP-10, Apo-AI and transthyretin) plus other potentially useful host biomarkers as diagnostic candidates for TBM.

Findings

Of 47 children included in the study, 23 (48.9%) had a final diagnosis of TBM of which six had HIV co-infection. A modified version of the adult 7-marker biosignature in which transthyretin was replaced by NCAM1, diagnosed TBM in children with AUC of 0.80 (95% CI, 0.67-0.92), sensitivity of 73.9% (95% CI, 51.6-89.8%) and specificity of 66.7% (95% CI, 44.7-84.4%). A new childhood TBM specific 3-marker biosignature (adipsin, Aβ42 and IL-10) showed potential in the diagnosis of TBM, with AUC of 0.84 (95% CI, 0.73-0.96), sensitivity of 82.6% (95 CI, 61.2-95.0%) and specificity of 75.0% (95% CI, 53.3-90.2%) after leave-one-out cross validation.

Conclusion

An adult 7-marker serum protein biosignature showed potential in the diagnosis of TBM in children. However, a smaller childhood TBM-specific biosignature demonstrated improved performance characteristics. Our data indicates that blood-based biomarkers may be useful in the diagnosis of childhood TBM and require further investigation.
Phylogenomic analysis ofClostridium perfringensidentifies isogenic strains in gastroenteritis outbreaks, and novel virulence-related features
Authors: Kiu Raymond , Caim Shabhonam , Pickard Derek , Painset Anais , Swift Craig , Dougan Gordon , Mather Alison E , Amar Corinne , Hall Lindsay J
Published: June 2019

Clostridium perfringensis a major enteric pathogen known to cause gastroenteritis in human adults. Although major outbreak cases are frequently reported, limited Whole Genome Sequencing (WGS) based studies have been performed to understand the genomic epidemiology and virulence gene content ofC. perfringens-associated outbreak strains. We performed both genomic and phylogenetic analysis on 109C. perfringensstrains (human and food) isolated from disease cases in England and Wales between 2011-2017. Initial findings highlighted the enhanced discriminatory power of WGS in profiling outbreakC. perfringensstrains, when compared to the current Public Health England referencing laboratory technique of Fluorescent Amplified Fragment Length Polymorphism (fAFLP). Further analysis identified that isogenicC. perfringensstrains were associated with nine distinct care home-associated outbreaks over the course of a 5-year interval, indicating a potential common source linked to these outbreaks or transmission over time and space. As expected the enterotoxin CPE gene was encoded in all but 4 isolates (96.4%; 105/109), with virulence plasmids encodingcpe(particularly pCPF5603- and pCPF4969-family plasmids) extensively distributed (82.6%;90/109). Genes encoding accessory virulence factors, such as beta-2 toxin, were commonly detected (46.7%; 50/109), and genes encoding phage proteins were also frequently identified, with additional analysis indicating their contribution to increased virulence determinants within the genomes of gastroenteritis-associatedC. perfringens. Overall this large-scale genomic study of gastroenteritis-associatedC. perfringenssuggested that 3 major sub-types underlie these outbreaks: strains carrying (1) pCPF5603 plasmid, (2) pCPF4969 plasmid, and (3) strains carryingcpeon transposable element Tn5565(usually integrated into chromosome). Our findings indicate that further studies will be required to fully probe this enteric pathogen, particularly in relation to developing intervention and prevention strategies to reduce food poisoning disease burden in vulnerable patients, such as the elderly.
Ecological and dietary differences between Ugandan chimpanzee communities with possible implications on tool use
Authors: Berger Iris , Hobaiter Catherine , Bell Matthew , De Moor Delphine , Gruber Thibaud
Published: June 2019

Some East African chimpanzee (Pan troglodytes schweinfurthii) communities, such as the Sonso chimpanzees, display an unusually limited range of tool-use, but it remains unclear whether this is due to ecological and/or cultural factors. Information on ecological conditions and the diet of the Sonso chimpanzees in relation to neighbouring communities is needed. Here, we studied three adjacent communities in Budongo Forest (Sonso, Waibira, and Kamira), and the presumed core area of an undescribed community (Mwera), in the neighbouring Bugoma Forest. Through line-transects, we investigated (i) whether there were differences in food diversity and abundance between the communities’ home ranges; (ii) whether the home ranges differed in abundance of sticks and insect nests; and (iii) whether Sonso and Mwera chimpanzees differed in their diet (using faecal samples). Across communities, Sonso had the richest food availability and the lowest insect nest abundance. However, food availability in Mwera, Bugoma, was richer than Budongo communities that neighbour the Sonso territory, suggesting that there may be variation within Budongo. Data from faecal samples replicated our direct observations of food availability suggesting that Sonso chimpanzees had a broader diet than Mwera chimpanzees. This difference in foods availability may partially explain the Sonso chimpanzees’ lack of stick-tool-use, and low levels of insectivory. The tool repertoire of the other communities is currently unknown; however, we make predictions based on our ecological data. More detailed knowledge of small-scale variation in ecology within and between forest habitats may be important to advancing our understanding of the drivers of tool-use.

SIGNIFICANCE STATEMENT – HIGHLIGHTED STUDENT PAPER

To advance our knowledge of the role of ecological factors in the emergence of tool use in chimpanzees, a nuanced understanding of the ecological conditions different chimpanzee communities experience is needed. We studied four Ugandan chimpanzee communities in two forests. One of these communities, Sonso, in the Budongo Forest, is well-known for its restricted range of tool types, including a total absence of stick use. Food diversity and abundance were highest, and stick tool use opportunities (abundance of sticks and insect nests) were lowest for the core-habitat of the Sonso chimpanzees in contrast to the other communities. We argue that ecological factors play a role in their unusual pattern of tool use, and make predictions about the expected types of tool use in the other communities based on their ecology. Thus, our study provides information that may help advance our understanding of how tool use arises under varied socioecological circumstances.
Long non-coding RNA GAS5 acts as proliferation “brakes” in CD133+ cells responsible for tumor recurrence
Authors: Sharma Nikita S , Gnamlin Prisca , Durden Brittany , Gupta Vineet K , Kesh Kousik , Garrido Vanessa T , Hadad Roey , Dudeja Vikas , Saluja Ashok , Banerjee Sulagna
Published: June 2019

Presence of quiescent, therapy evasive population often described as cancer stem cells (CSC) or tumor initiating cells (TIC) is often attributed to extreme metastasis and tumor recurrence. This population is typically enriched in a tumor as a result of microenvironment or chemotherapy induced stress. The TIC population adapts to this stress by turning on cell cycle arrest programs that is a “fail-safe” mechanism to prevent expansion of malignant cells to prevent further injury. Upon removal of the “stress” conditions, these cells restart their cell cycle and regain their proliferative nature thereby resulting in tumor relapse. Growth Arrest Specific 5 (GAS5) is a long-noncoding RNA that plays a vital role in this process. In pancreatic cancer, CD133+ population is a typical representation of the TIC population that is responsible for tumor relapse. In this study, we show for the first time that emergence of CD133+ population coincides with upregulation of GAS5, that reprograms the cell cycle to slow proliferation by inhibiting GR mediated cell cycle control. The CD133+ population further routed metabolites like glucose to shunt pathways like pentose phosphate pathway, that were predominantly biosynthetic in spite of being quiescent in nature but did not use it immediately for nucleic acid synthesis. Upon inhibiting GAS5, these cells were released from their growth arrest and restarted the nucleic acid synthesis and proliferation. Our study thus showed that GAS5 acts as a molecular switch for regulating quiescence and growth arrest in CD133+ population, that is responsible for aggressive biology of pancreatic tumors.
Strength of species interactions determines biodiversity and stability in microbial communities
Authors: Ratzke Christoph , Barrere Julien , Gore Jeff
Published: June 2019

Organisms – especially microbes – tend to live in complex communities. While some of these ecosystems are very bio-diverse, others aren’t1–3, and while some are very stable over time others undergo strong temporal fluctuations4,5. Despite a long history of research and a plethora of data it is not fully understood what sets biodiversity and stability of ecosystems6,7. Theory as well as experiments suggest a connection between species interaction, biodiversity, and stability of ecosystems8–13, where an increase of ecosystem stability with biodiversity could be observed in several cases7,9,14. However, what causes these connections remains unclear. Here we show in microbial ecosystems in the lab that the concentrations of available nutrients can set the strength of interactions between bacteria. At high nutrient concentrations, extensive microbial growth leads to strong chemical modifications of the environment, causing more negative interactions between species. These stronger interactions exclude more species from the community – resulting in a loss of biodiversity. At the same time, these stronger interactions also decrease the stability of the microbial communities, providing a mechanistic link between species interaction, biodiversity and stability.
Interferometric Fluorescent Cross Correlation Spectroscopy
Authors: Saha Ipsita , Saffarian Saveez
Published: June 2019

We present a method utilizing single photon interference and fluorescence correlation spectroscopy (FCS) to simultaneously measure transport of fluorescent molecules within aqueous samples. Our method, within seconds, measures transport in thousands of homogenous voxels (100 nm)3 and eliminates photo-physical artifacts associated with blinking of fluorescent molecules. A comprehensive theoretical framework is presented and validated by measuring transport of quantum dots, associated with VSV-G receptor along cellular membranes as well as within viscous gels.
Apolipoprotein L9 interacts with LC3/GABARAP and is a microtubule-associated protein with a widespread subcellular distribution
Authors: Thekkinghat Arvind A. , Yadav Kamlesh K. , Rangarajan Pundi N.
Published: June 2019

Mouse Apolipoprotein L9 is a 34-kDa phosphatidylethanolamine (PE)-binding protein. The gene is present only in mouse and rat genomes; hence it is taxonomically restricted. To understand why, it is essential to uncover details about its functions in cellular processes. Here we show that ApoL9 interacts with the proteins of the LC3 and GABARAP subfamilies, which are key players in macroautophagy. In amino-acid starved cells it preferentially interacts with lipidated LC3B, likely by binding to its PE moiety. On treatment with autophagy inhibitors bafilomycin A1 and chloroquine, ApoL9 is found near swollen mitochondria and on lysosomes/LAMP1-positive compartments. However, ApoL9 itself does not seem to be degraded as a result of autophagy, suggesting that it is not an autophagy cargo receptor. Deletions in a putative transmembrane region between amino acids 110 and 145 abolish PE-binding. In addition, ApoL9 can redistribute to stress granules, can homooligomerize, and is a microtubule-associated protein. In short, its distribution in the cell is quite widespread, suggesting that it could have functions at the intersection of membrane binding and reorganization, autophagy, cellular stress and intracellular lipid transport.

Summary statement

This article is about how Apolipoprotein L9, a lipid-binding protein, has versatile properties and influences a variety of processes taking place inside an animal cell.
The endonuclease Cue2 cleaves mRNAs at stalled ribosomes during No Go Decay
Authors: D’Orazio Karole N. , Wu Colin Chih-Chien , Sinha Niladri , Loll-Krippleber Raphael , Brown Grant W. , Green Rachel
Published: June 2019

Translation of problematic sequences in mRNAs leads to ribosome collisions that trigger a sequence of quality control events including ribosome rescue, degradation of the stalled nascent polypeptide via the Ribosome-mediated Quality control Complex (RQC), and targeting of the mRNA for decay (No Go Decay or NGD). Previous studies provide strong evidence for the existence of an endonuclease involved in the process of NGD though the identity of the endonuclease and the extent to which it contributes to mRNA decay remain unknown. Using a reverse genetic screen in yeast, we identify Cue2 as the conserved endonuclease that is recruited to stalled ribosomes to promote NGD. Ribosome profiling and biochemistry provide strong evidence that Cue2 cleaves mRNA within the A site of the colliding ribosome. Finally, we show that NGD primarily proceeds via Xrn1-mediated exonucleolytic decay. Cue2-mediated endonucleolytic decay normally constitutes a secondary decay pathway, but becomes a major contributor in cells depleted of factors required for the resolution of stalled ribosome complexes (the RQT factors including Slh1). Together these results provide insights into how multiple decay processes converge to process problematic mRNAs in eukaryotic cells.

One Sentence Summary

Cue2 is the endonuclease that cleaves mRNA at ribosome stall sites.
E2F1 Drives Breast Cancer Metastasis by Regulating the Target Gene FGF13 and Altering Cell Migration
Authors: Hollern Daniel P. , Swiatnicki Matthew R. , Rennhack Jonathan P. , Misek Sean A. , Matson Brooke C. , McAuliff Andrew , Gallo Kathleen A. , Caron Kathleen M. , Andrechek Eran R.
Published: June 2019

In prior work we demonstrated that loss of E2F transcription factors inhibits metastasis. Here we address the mechanisms for this phenotype and identify the E2F regulated genes that coordinate tumor cell metastasis. Transcriptomic profiling of E2F1 knockout tumors identified a role for E2F1 as a master regulator of a suite of pro-metastatic genes, but also uncovered E2F1 target genes with an unknown role in pulmonary metastasis. High expression of one of these genes, Fgf13, is associated with early human breast cancer metastasis in a clinical dataset. Together these data led to the hypothesis that Fgf13 is critical for breast cancer metastasis, and that upregulation of Fgf13 may partially explain how E2F1 promotes breast cancer metastasis. To test this hypothesis we ablated Fgf13 via CRISPR. Deletion of Fgf13 in a MMTV-PyMT breast cancer cell line reduces the frequency of pulmonary metastasis. In addition, loss of Fgf13 reducedin vitrocell migration, suggesting that Fgf13 may be critical for tumor cells to invade out of and escape the primary tumor. The significance of this work is twofold: we have both uncovered genomic features by which E2F1 regulates metastasis and we have identified new pro-metastatic functions for the E2F1 target gene Fgf13.