bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuropeptide F receptor acts in theDrosophilaprothoracic gland to regulate growth and developmental timing
Authors: Kannangara Jade R. , Henstridge Michelle A. , Parsons Linda M. , Kondo Shu , Mirth Christen K. , Warr Coral G.
Published: December 2019

As juvenile animals grow, their behaviour, physiology, and development need to be matched to environmental conditions to ensure they survive to adulthood. However, we know little about how behaviour and physiology are integrated with development to achieve this outcome. Neuropeptides are prime candidates for achieving this due to their well-known signalling functions in controlling many aspects of behaviour, physiology and development in response to environmental cues. In the growingDrosophilalarva, while several neuropeptides have been shown to regulate feeding behaviour, and a handful to regulate growth, it is unclear if any of these play a global role in coordinating feeding behaviour with developmental programs. Here, we demonstrate that Neuropeptide F Receptor (NPFR), best studied as a conserved regulator of feeding behaviour from insects to mammals, also regulates development inDrosophila. Knocking downNPFRin the prothoracic gland, which produces the steroid hormone ecdysone, generates developmental delay and an extended feeding period, resulting in increased body size. We show that these effects are due to decreased ecdysone production, as these animals have reduced expression of ecdysone biosynthesis genes and lower ecdysone titres. Moreover, these phenotypes can be rescued by feeding larvae food supplemented with ecdysone. Further, we show that NPFR negatively regulates the insulin signalling pathway in the prothoracic gland to achieve these effects. Taken together, our data demonstrate that NPFR signalling plays a key role in regulating animal development and may thus play a global role in integrating feeding behaviour and development inDrosophila.
Structural clusters of histone H3 and H4 residues regulate chronological lifespan inSaccharomyces cerevisiae
Authors: Ngubo Mzwanele , Reid Jessica , Patterton Hugh -G
Published: December 2019

We have performed a comprehensive analysis of the involvement of histone H3 and H4 residues in the regulation of chronological lifespan in yeast, and identify four structural groups in the nucleosome that influence lifespan. We also identify residues where substitution with an epigenetic mimic extends lifespan, providing evidence that a simple epigenetic switch, without possible additional background modifications, causes longevity. Residues where substitution result in the most pronounced lifespan extension are all on the exposed face of the nucleosome, with the exception of H3E50, which is present on the lateral surface, between two DNA gyres. Other residues that have a more modest effect on lifespan extension are concentrated at the extremities of the H3-H4 dimer, suggesting a role in stabilizing the dimer in its nucleosome frame. Residues that reduce lifespan are buried in the histone handshake motif, suggesting that these mutations destabilize the octamer structure.

All residues exposed on the nucleosome disk face and that cause lifespan extension are known to interact with Sir3. We find that substitution of H4K16 and H4H18 cause Sir3 to redistribute from telomeres and silent mating loci to secondary positions, often enriched for Rap1, Abf1 or Reb1 binding sites, whereas H3E50 does not. The redistribution of Sir3 in the genome can be reproduced by an equilibrium model based on primary and secondary binding sites with different affinities for Sir3. The redistributed Sir3 cause transcriptional repression at most of the new loci, including of genes where null mutants were previously shown to extend chronological lifespan. The transcriptomic profiles of H4K16 and H4H18 mutant strains are very similar, and compatible with a DNA replication stress response. This is distinct from the transcriptomic profile of H3E50, which matches strong induction of oxidative phosphorylation. We propose that the different groups of residues are involved in binding to heterochromatin proteins, in destabilizing the association of the nucleosome DNA, disrupting binding of the H3-H4 dimer in the nucleosome, or disrupting the structural stability of the octamer, each category impacting on chronological lifespan by a different mechanism.
A sulfoglycolytic Entner-Doudoroff pathway inRhizobium leguminosarumbv.trifoliiSRDI565
Authors: Li Jinling , Epa Ruwan , Scott Nichollas E. , Skoneczny Dominic , Sharma Mahima , Snow Alexander J.D. , Lingford James P. , Goddard-Borger Ethan D. , Davies Gideon J. , McConville Malcolm J. , Williams Spencer J.
Published: December 2019

Rhizobia are nitrogen fixing bacteria that engage in symbiotic relationships with plant hosts but can also persist as free-living bacteria with the soil and rhizosphere. Here we show that free livingRhizobium leguminosarumSRDI565 can grow on the sulfosugar sulfoquinovose (SQ) using a sulfoglycolytic Entner-Doudoroff (sulfo-ED) pathway resulting in production of sulfolactate (SL) as the major metabolic end-product. Comparative proteomics supports the involvement of a sulfo-ED operon encoding an ABC transporter cassette, sulfo-ED enzymes and an SL exporter. Consistent with an oligotrophic lifestyle, proteomics data revealed little change in expression of the sulfo-ED proteins during growth on SQ versus mannitol, a result confirmed through biochemical assay of sulfoquinovosidase activity in cell lysates (data are available via ProteomeXchange with identifier PXD015822). Metabolomics analysis showed that growth on SQ involves gluconeogenesis to satisfy metabolic requirements for glucose-6-phosphate and fructose-6-phosphate. Metabolomics analysis also revealed the unexpected production of small amounts of sulfofructose and 2,3-dihydroxypropanesulfonate, which are proposed to arise from promiscuous activities of the glycolytic enzyme phosphoglucose isomerase and a non-specific aldehyde reductase, respectively. This work shows that rhizobial metabolism of the abundant sulfosugar SQ may contribute to persistence of the bacteria in the soil and to mobilization of sulfur in the pedosphere.
Yeast ATM and ATR use different mechanisms to spread histone H2A phosphorylation around a DNA double-strand break
Authors: Li Kevin , Bronk Gabriel , Kondev Jane , Haber James E.
Published: December 2019

One of the hallmarks of DNA damage is the rapid spreading of phosphorylated histone H2A (γ-H2AX) around a DNA double-strand break (DSB). In the budding yeastS. cerevisiae, nearly all H2A isoforms can be phosphorylated, either by Mec1ATRor Tel1ATMcheckpoint kinases. We induced a site-specific DSB with HO endonuclease at theMATlocus on chromosome III and monitored the formation of γ-H2AX by ChIP-qPCR in order to uncover the mechanisms by which Mec1ATRand Tel1ATMpropagate histone modifications across chromatin. With either kinase, γ-H2AX spreads as far as ∼50 kb on both sides of the lesion within 1 h; but the kinetics and distribution of modification around the DSB are significantly different. The total accumulation of phosphorylation is reduced by about half when either of the two H2A genes is mutated to the nonphosphorylatable S129A allele. Mec1 activity is limited by the abundance of its ATRIP partner, Ddc2. Moreover, Mec1 is more efficient than Tel1 at phosphorylating chromatin intrans– at distant undamaged sites that are brought into physical proximity to the DSB. We compared experimental data to mathematical models of spreading mechanisms to determine whether the kinases search for target nucleosomes by primarily moving in three dimensions through the nucleoplasm or in one dimension along the chromatin. Bayesian model selection indicates that Mec1 primarily uses a 3D diffusive mechanism, whereas Tel1 undergoes directed motion along the chromatin.
The tempest in a cubic millimeter: Image-based refinements necessitate the reconstruction of 3D microvasculature from a large series of damaged alternately-stained histological sections
Authors: Lobachev Oleg
Published: December 2019

This work presents two methods that facilitate a 3D reconstruction of microscopic blood vessels in the volume slightly larger than 1 mm3. The source of the data are histological serial sections, i.e., microscopic images of probes, stained with immunohistochemistry. Odd and even sections have different stainings in our primary data set. Thus, firstly, an approach to register an alternately-stained series is presented. With image filtering and a feature-detection-based registration we obtain a registered stack of 148 serial sections. The series has missing sections, locally damaged sections, artifacts from acquisition. All these hinder correct connectivity of blood vessels. With our second approach we interpolate the missing information while maintaining the connectivity. We achieve this with deformations based on dense optical flow. The presented methodology is applicable to further histological series. A combination of both approaches allows us to reconstruct more than 76% larger volumes. An important detail was the composition mode of images. Summarizing, we use methods from image processing and computer vision to create large-scale 3D models from immunostained histological serial sections.
Bifidobacterium breveUCC2003 exopolysaccharide modulates the early life microbiota by acting as a dietary substrate
Authors: Puengel D , Treveil A , Dalby MJ , Caim S , Colquhoun IJ , Booth C , Ketskemety J , Korcsmaros T , van Sinderen D , Lawson MAE , Hall LJ
Published: December 2019

Members of the genusBifidobacteriumrepresent an important bacterial group for promoting health during early life. Previous studies have indicated that bifidobacterial exopolysaccharides (EPS) are involved in host interactions, with purified EPS also suggested to modulate microbe-microbe interactions by acting as a nutrient substrate. To further explore the role of EPS as a potential dietary component, we determined the longitudinal effects of bifidobacterial EPS on microbial communities and metabolite profiles using an infant model colon system.Bifidobacterium breveUCC2003 was utilised as a representative early life bifidobacterial strain, and a corresponding isogenic EPS-deletion mutant (B. breveUCC2003 EPS-). Initial transcriptomics analysis of the EPS mutant vs. parentB. breveUCC2003 strain highlighted differential expression in a discrete number of genes, including theepsbiosynthetic cluster, though overall growth dynamics between the two strains were unaffected. Model colon vessels were inoculated withB. brevestrains and microbiome dynamics were monitored using metataxonomic (via 16S rRNA sequencing) and metabolomic (via1H NMR) approaches. Baseline early life microbiota profiles were similar between vessels, with persistence ofB. breve(EPS+ and EPS-) observed between 0-36h. Within the EPS-positive vessel there was a significant shift in microbiome and metabolite profiles until the end of the study (405h); we observed increases ofEscherichiaandTyzzerella, and short-chain fatty acids including acetate, propionate and formate, including further correlations between taxa and metabolites which were not observed in the EPS-negative vessel. These data indicate that theB. breveUCC2003 EPS is potentially being metabolised by members of the infant microbial community, leading to differential microbial metabolism and altered metabolite by-products. Overall, these findings may allow for development of EPS-specific strategies to beneficially alter the early life microbiota to promote infant health.
14-3-3β paralog is inhibited by acetylation during differentiation to the osteogenic lineage
Authors: Frontini-Lopez Yesica R , Gojanovich Aldana D , Uhart Marina , Bustos Diego M
Published: December 2019

14-3-3 protein family binds and regulate hundred of serine/threonine phosphorylated proteins. Considered as redundant, ubiquitous and constantly expressed this protein family was treated as an accessory for many signaling systems. Here we studied the reversible inhibition by acetylation of its essential N-ε-lysine 49/51 residue during the osteogenic differentiation of human adipose-derived stem cells (ASC). We found that during the differentiation of ASC the levels of 14-3-3 acK49/51 increase showing that inhibition of 14-3-3 is necessary for this process. Among the 7 paralogs of this family, the inhibition by this posttranslational modification occurs mostly on the paralog β located specifically in the nucleus where 14-3-3 was described to binds to H3 histone and many transcription factors. Short hairpin RNA silencing of 14-3-3β gene but not 14-3-3γ increases significantly the osteogenic potential of the cells. These results show that specifically 14-3-3β is a negative regulator of osteogenesis and its inhibition by acetylation on lysine 51 is the cellular mechanism to regulate it.
Sexual Differences in Mitochondrial Proteins in Rat Cerebral Microvessels: A Proteomic Approach
Authors: Cikic Sinisa , Chandra Partha K. , Harman Jarrod C. , Rutkai Ibolya , Katakam Prasad V.G. , Guidry Jessie J. , Gidday Jeffrey M. , Busija David W.
Published: December 2019

Sex differences in mitochondrial numbers and function are present in large cerebral arteries, but it is unclear whether these differences extend to the microcirculation. We performed an assessment of mitochondria-related proteins in cerebral microvessels (MVs) isolated from young, male and female, Sprague-Dawley rats. MVs composed of arterioles, capillaries, and venules were isolated from the cerebrum and used to perform a 3 vs. 3 quantitative, multiplexed proteomics experiment utilizing tandem mass tags (TMT), coupled with liquid chromatography/mass spectrometry (LC/MS). MS data and bioinformatic analyses were performed using Proteome Discoverer version 2.2 and Ingenuity Pathway Analysis. We identified a total of 1,969 proteins, of which 1,871 were quantified by TMT labels. Sixty-four proteins were expressed significantly (p < 0.05) higher in female samples compared with male samples. Females expressed more mitochondrial proteins involved in energy production, mitochondrial membrane structure, anti-oxidant enzyme proteins, and those involved in fatty acid oxidation. Conversely, males had higher expression levels of mitochondria-destructive proteins. We validated our key Proteomics results with western blotting. Our findings reveal, for the first time, the full extent of sexual dimorphism in the mitochondrial metabolic protein profiles of MVs, which may contribute to sex-dependent cerebrovascular and neurological pathologies.

Synopsis

Energy-producing proteins in the cerebral microvessels (MVs) of male and female rats were examined by quantitative discovery-based proteomics to gain insight into the sex-dependent etiology of cardiovascular and neurological diseases. Females expressed more mitochondrial proteins involved in energy production, membrane structure, anti-oxidant activity, and fatty acid oxidation. In contrast, males exhibited more mitochondria-destructive proteins such as mitochondrial eating protein. Our findings reveal for the first time the sexual dimorphism of mitochondria-related proteins in cerebral MVs, which may explain functional sex-related differences in MVs during health and in the etiology of neurological pathologies of cerebrovascular origin.
Transcriptome sequencing and screening of genes related to sex determination ofTrichosanthes kirilowiiMaxim
Authors: Hu Xiuqin , Zhu Jinkai , Ji Guanjie , Wang Zhen , Xin Jie
Published: December 2019

Trichosanthes kirilowiiMaxim. (TK) is a dioecious plant in the Cucurbitaceae for which different sexes have separate medicinal uses. In order to study the genes related to sex determination, transcriptome sequencing was performed on flower buds and leaves of male and female plants using the high-throughput sequencing technology. A total of 145,975 unigenes and 7110 DEGs were obtained. There were 6776 DEGs annotated to 1234 GO terms and enriched to 18 functional groups, including five biological processes related to sugar metabolism. KEGG pathway analysis indicated genes involved in hormone transduction, hormone synthesis and carbohydrate metabolism. The sex determination genes ofTKare different from known sex determination mechanisms (ACS11, ACS7(2), WIP1). Many DEGs ofTKare involved in reproductive organ formation, hormone signal transduction and regulatory networks. In combination with the previous study of sex differentiation of Cucurbitaceae, the results of GO, KEGG and the expression of related genes in male and female plants, 18 candidate genes for sex determining ofTKwere screened from 151 hormone-related differentially expressed genes. The genes includedMYB80, MYB108andMYB21of the MYB family,CER1, CBL, ABCB199, SERK1andHSP81-3. The results provide a foundation for the study of sex differentiation inTK.
Accuracy of a deep convolutional neural network in the detection of myopic macular diseases using swept-source optical coherence tomography
Authors: Sogawa Takahiro , Tabuchi Hitoshi , Nagasato Daisuke , Masumoto Hiroki , Ikuno Yasushi , Ohsugi Hideharu , Ishitobi Naofumi , Mitamura Yoshinori
Published: December 2019

This study examined and compared outcomes of deep learning (DL) in identifying swept-source optical coherence tomography (OCT) images without myopic macular lesions [i.e., no high myopia (nHM) vs. high myopia (HM)], and OCT images with myopic macular lesions [e.g., myopic choroidal neovascularization (mCNV) and retinoschisis (RS)]. A total of 796 SS-OCT images were included in the study as follows and analyzed by k-fold cross-validation (k = 5) using DL’s renowned model, Visual Geometry Group-16: nHM, 107 images; HM, 456 images; mCNV, 122 images; and RS, 111 images (n = 796). The binary classification of OCT images with or without myopic macular lesions; the binary classification of HM images and images with myopic macular lesions (i.e., mCNV and RS images); and the ternary classification of HM, mCNV, and RS images were examined. Additionally, sensitivity, specificity, and the area under the curve (AUC) for the binary classifications as well as the correct answer rate for ternary classification were examined.

The classification results of OCT images with or without myopic macular lesions were as follows: AUC, 0.983; sensitivity, 0.953; specificity, 0.940. The classification results of HM images and images with myopic macular lesions were as follows: AUC, 0.976; sensitivity, 0.940; specificity, 0.941. The correct answer rate in the ternary classification of HM images, mCNV images, and RS images were as follows: HM images, 93.7%; mCNV images, 82.4%; and RS, 92.3% with mean, 91.4%. Using noninvasive, easy-to-obtain swept-source OCT images, the DL model was able to classify OCT images without myopic macular lesions and OCT images with myopic macular lesions such as mCNV and RS with high accuracy. The study results suggest the possibility of conducting highly accurate screening of ocular diseases using artificial intelligence, which may improve the prevention of blindness and reduce workloads for ophthalmologists.
Clinical correlates of sarcopenia and falls in Parkinson’s disease
Authors: Lima Danielle Pessoa , de Almeida Samuel Brito , de Carvalho Bonfadini Janine , de Luna João Rafael Gomes , de Alencar Madeleine Sales , Pinheiro-Neto Edilberto Barreira , Viana-Júnior Antonio Brazil , Veras Samuel Ranieri Oliveira , Sobreira-Neto Manoel Alves , de Sá Roriz-Filho Jarbas , Braga-Neto Pedro
Published: December 2019

Background

Sarcopenia is a complex and multifactorial geriatric condition seen in several chronic degenerative diseases. This study aimed to screen for sarcopenia and fall risk in a sample of Parkinson’s disease (PD) patients and to investigate demographic and clinical factors associated.

Methods

This is a cross-sectional study. We evaluated 218 PD patients at the Movement Disorders Clinic in Fortaleza, Brazil, and collected clinical data including experiencing falls in the six months prior to their medical visit. Probable sarcopenia diagnosis was confirmed by using a sarcopenia screening tool (SARC-F questionnaire) and the presence of low muscle strength.

Results

One hundred and twenty-one patients (55.5%) were screened positive for sarcopenia using the SARC-F and 103 (47.4%) met the criteria for probable sarcopenia. Disease duration, modified Hoehn and Yahr stage, Schwab and England Activities of Daily Living Scale score, levodopa equivalent dose, probable sarcopenia and positive SARC-F screening were all associated with experiencing falls in the prior six months. Disease duration, lower quality of life and female gender were independently associated with sarcopenia. Experiencing falls in the prior six months was significantly more frequent among patients screened positive in the SARC-F compared to those screened negative.

Conclusions

Sarcopenia and PD share common pathways and may affect each other’s prognosis and patients’ quality of life. Since sarcopenia is associated with lower quality of life and increased risk of falls, active case finding, diagnosis and proper management of sarcopenia in PD patients is essential.
Automatic and fast encoding of representational uncertainty underlies probability distortion
Authors: Ren Xiangjuan , Luo Huan , Zhang Hang
Published: December 2019

Humans do not have an accurate representation of probability information in the environment but distort it in a surprisingly stereotyped way (“probability distortion”), as shown in a wide range of judgment and decision-making tasks. Many theories hypothesize that humans automatically compensate for the uncertainty inherent in probability information (“representational uncertainty”) and probability distortion is a consequence of uncertainty compensation. Here we examined whether and how the representational uncertainty of probability is quantified in the human brain and its relevance to probability distortion behavior. Human subjects kept tracking the relative frequency of one color of dot in a sequence of dot arrays while their brain activity was recorded by magnetoencephalography (MEG). We found converging evidence from both neural entrainment and time-resolved decoding analysis that a mathematically- derived measure of representational uncertainty is automatically computed in the brain, despite it is not explicitly required by the task. In particular, the encodings of relative frequency and its representational uncertainty respectively occur at latencies of approximately 300 ms and 400 ms. The relative strength of the brain responses to these two quantities correlates with the probability distortion behavior. The automatic and fast encoding of the representational uncertainty provides neural basis for the uncertainty compensation hypothesis of probability distortion. More generally, since representational uncertainty is closely related to confidence estimation, our findings exemplify how confidence might emerge prior to perceptual judgment.
Deciphering the mechanism of inhibition of SERCA1a by sarcolipin using molecular simulations
Authors: Barbot T. , Beswick V. , Montigny C. , Quiniou E. , Jamin N. , Mouawad L.
Published: December 2019

SERCA1a is an ATPase calcium pump that transports Ca2+from the cytoplasm to the sarco/endoplasmic reticulum lumen. Sarcolipin (SLN), a transmembrane peptide, regulates the activity of SERCA1a by decreasing its Ca2+transport rate, but its mechanism of action is still not well understood. To decipher this mechanism, we have performed normal modes analysis in the all-atom model, with the SERCA1a-SLN complex or the isolated SERCA1a embedded in an explicit membrane. The comparison of the results allowed us to provide an explanation for the action of SLN that is in good agreement with experimental observations. In our analyses, the presence of SLN locally perturbs the TM6 transmembrane helix and as a consequence modifies the position of D800, one of the key metal-chelating residues. Additionally, it reduces the flexibility of the gating residues, V304 and E309 in TM4, at the entrance of the Ca2+binding sites, which would decrease the affinity for Ca2+. Unexpectedly, SLN has also an effect on the ATP binding site more than 35 Å away, due to the straightening of TM5, a long helix considered as the spine of the protein. The straightening of TM5 modifies the structure of the P-N linker that sits above it, and which comprises the351DKTG354conserved motif, resulting in an increase of the distance between ATP and the phosphorylation site. As a consequence, the turn-over rate could be affected. All this gives SERCA1a the propensity to go toward a Ca2+-deprived E2-like state in the presence of SLN and toward a Ca2+high-affinity E1-like state in the absence of SLN, although the SERCA1a-SLN complex was crystallized in an E1-like state. In addition to a general mechanism of inhibition of SERCA1a regulatory peptides, this study also provides an insight in the conformational transition between the E2 and E1 states.

Statement of Significance

The role of sarco/endoplasmic reticulum calcium ATPase in muscle relaxation is essential. Impairment of its function may result in either cardiac diseases, or myopathies, and also thermogenesis defects. Inhibition of the ATPase by regulatory peptide such as sarcolipin remains unclear. The structure of the ATPase in complex with this peptide was studied by all-atom normal modes analysis, an in silico technique which allows us to decipher the mechanism of inhibition of calcium transport by sarcolipin at a molecular level. Our results open the way to understanding the impact of in vivo misregulation of the ATPase activity by sarcolipin. Development of tools enhancing or preventing interaction between the ATPase and its regulatory peptide could be considered as new therapeutic approaches.
Control of assembly of extra-axonemal structures: the paraflagellar rod of trypanosomes
Authors: Alves Aline A. , Bezerra Maria J. R. , de Souza Wanderley , Vaughan Sue , Cunha-e-Silva Narcisa L. , Sunter Jack D.
Published: December 2019

Eukaryotic flagella are complex microtubule based organelles and in many organisms there are extra-axonemal structures present, including the outer dense fibres of mammalian sperm and the paraflagellar rod (PFR) of trypanosomes. Flagellum assembly is a complex process occurring across three main compartments, the cytoplasm, the transition fibre-transition zone, and the flagellum. It begins with translation of protein components, followed by their sorting and trafficking into the flagellum, transport to the assembly site and then incorporation. Flagella are formed from over 500 proteins; the principles governing axonemal component assembly are relatively clear. However, the coordination and sites of extra-axonemal structure assembly processes are less clear.

We have discovered two cytoplasmic proteins inT. bruceithat are required for PFR formation, PFR assembly factors 1 and 2. Deletion of either PFR-AF1 or PFR-AF2 dramatically disrupted PFR formation and caused a reduction in the amount of major PFR proteins. The presence of cytoplasmic factors required for PFR formation aligns with the concept of processes occurring across multiple compartments to facilitate axoneme assembly and this is likely a common theme for extra-axonemal structure assembly.

Summary statement

Eukaryotic flagella are complex organelles. In many organisms there are extra-axonemal structures including the trypanosome paraflagellar rod. We have discovered two cytoplasmic proteins that are required for paraflagellar rod formation.
To mock or not: a comprehensive comparison of mock IP and DNA input for ChIP-seq
Authors: Xu Jinrui , Kudron Michelle M. , Victorsen Alec , Gao Jiahao , Ammouri Haneen N. , Navarro Fabio C. P. , Gevirtzman Louis , Waterston Robert H. , White Kevin P. , Reinke Valerie , Gerstein Mark
Published: December 2019

Chromatin immunoprecipitation (IP) followed by sequencing (ChIP-seq) is the gold standard to detect genome-wide DNA-protein binding. The binding sites of transcription factors facilitate many biological studies. Of emerging concern is the abundance of spurious sites in ChIP-seq, which are mainly caused by uneven genomic sonication and nonspecific interactions between chromatin and antibody. A “mock” IP is designed to correct for both factors, whereas a DNA input control corrects only for uneven sonication. However, a mock IP is more susceptible to technical noise than a DNA input, and empirically, these two controls perform similarly for ChIP-seq. Therefore, DNA input is currently being used almost exclusively. With a large dataset, we demonstrate that using a DNA input control results in a definable set of spurious sites, and their abundance is tightly associated with the intrinsic properties of the ChIP-seq sample. For example, compared to human cell lines, samples such as human tissues and whole worm and fly have more accessible genomes, and thus have more spurious sites. The large and varying abundance of spurious sites may impede comparative studies across multiple samples. In contrast, using a mock IP as control substantially removes these spurious sites, resulting in high-quality binding sites and facilitating their comparability across samples. Although outperformed by mock IP, DNA input is still informative and has unique advantages. Therefore, we have developed a method to use both controls in combination to further improve binding site detection.
Association of Sonic Hedgehog with the extracellular matrix requires its zinc-coordination fold
Authors: Jägers Carina , Roelink Henk
Published: December 2019

Sonic Hedgehog (Shh) has a catalytic cleft characteristic for zinc metallopeptidases and has significant sequence similarities with some bacterial peptidoglycan metallopeptidases defining a subgroup within the M15A family that, besides having the characteristic zinc coordination domain, can bind two calcium ions. Extracellular matrix (ECM) components in animals include heparan-sulfate proteoglycans, which are analogs of bacterial peptidoglycan and thus potentially involved in the extracellular distribution of Shh. We found that the zinc-coordination fold of Shh is required for its association with ECM as well as for non-cell autonomous signaling. Association with the ECM requires the presence of at least 0.1 μM zinc and is prevented by mutations affecting critical conserved catalytical residues as well as extracellular calcium. Our results demonstrate that the zinc-coordination fold is required for ECM-association and suggest that the putative intrinsic peptidase activity of Shh is required for non-cell autonomous signaling.
Adaptive shifts in gene regulation underlie a developmental delay in thermogenesis in high-altitude deer mice
Authors: Velotta Jonathan P. , Robertson Cayleih E. , Schweizer Rena M. , McClelland Grant B. , Cheviron Zachary A.
Published: December 2019

Aerobic performance is tied to fitness as it influences an animal’s ability to find food, escape predators, or survive extreme conditions. At high altitude, where low O2availability and persistent cold prevail, maximum metabolic heat production (thermogenesis) is an aerobic performance trait that is intimately linked to survival. Understanding how thermogenesis evolves to enhance survival at high altitude will yield insight into the links between physiology, performance, and fitness. Recent work in deer mice (Peromyscus maniculatus) has shown that adult mice native to high-altitude have higher thermogenic capacities under hypoxia compared to lowland conspecifics, but developing high-altitude pups delay the onset of thermogenesis. This suggests that natural selection on thermogenic capacity varies across life stages. To determine the mechanistic cause of this ontogenetic delay, we analyzed the transcriptomes of thermo-effector organs – brown adipose tissue and skeletal muscle – in developing deer mice native to low- and high-altitude. We demonstrate that the developmental delay in thermogenesis is associated with adaptive shifts in the expression of genes involved in nervous system development, fuel/O2supply, and oxidative metabolism gene pathways. Our results demonstrate that selection has modified the developmental trajectory of the thermoregulatory system at high altitude and has done so by acting on the regulatory systems that control the maturation of thermo-effector tissues. We suggest that the cold and hypoxic conditions of high altitude may force a resource allocation trade-off, whereby limited energy is allocated to developmental processes such as growth, versus active thermogenesis during early development.
Xi rhythms: decoding neural oscillations to create full-brain high-resolution spectra parametric mapping
Authors: Hu Shiang , Valdes-Sosa Pedro A.
Published: December 2019

Neural oscillations excitability shape sensory, motor, and cognitive processes of the brain operation. To quantify the spectrum of brain magnetic and electrical recordings has become the main methodology to study neural oscillations. However, there is still lacking a valid approach, although the literatures on the spectrum decomposition is vast. In this work, we fit the neural spectrum by means of the Expectation Maximization algorithm, where the E step turns into a Winner filtering to separate multiple components and the M step is to fit each component by minimizing the smoothness penalized Whittle likelihood and shape-restricted regression, say, monotonicity, that is able to fit the diverse shape of each component. The decomposition allows characterizing the oscillation amplitude, resonance frequency, bandwidth, skewness, kurtosis, and slope of each component. This approach is termed as ‘Xi rhythms’, with Xi and rhythms standing for the background activity and multiple peaks. We apply it to: 1) multinational EEG database consisting of 535 subjects to create the quantitative spectrum norms (QSN); 2) large sample intracranial EEG (iEEG) dataset to infer the oscillations from recorded region to unrecorded areas within one subject and over inter-individuals and create the full brain high resolution statistical spectra parametric mapping. The statistical spectrum parameter mapping of iEEG promisingly provides an atlas and creates a norm for neural oscillations and quantitative electrophysiology study which can gain us more insightful understanding to brain dynamics, cognitive process and mental disorders.
Dose–response relationship between physical activity and mortality in adults with noncommunicable diseases: A systematic review and meta-analysis of cohort studies
Authors: Geidl Wolfgang , Schlesinger Sabrina , Mino Eriselda , Miranda Lorena , Pfeifer Klaus
Published: December 2019

Objective

To investigate the relationship between post-diagnosis physical activity and mortality in patients with selected noncommunicable diseases, including breast cancer, lung cancer, type 2 diabetes (T2D), ischemic heart disease (IHD), chronic obstructive pulmonary disease (COPD), stroke, osteoarthritis, low back pain and major depressive disorders.

Design

Systematic review and dose–response meta-analysis.

Data sources

PubMed, Scopus and the Web of Science were searched systematically for English publications from the inception of the platforms until August 2018. Additionally, the search was updated in August 2019.

Eligibility criteria

Prospective observational studies examining the relationship between at least three physical activity categories and all-cause mortality or disease-specific mortality as the primary outcome.

Results

In total, 28 studies were included: 12 for breast cancer, 6 for T2D, 8 for IHD and 2 for COPD. The linear meta-analysis revealed that each 10 metabolic equivalent tasks (MET) h increase of physical activity per week was associated with a 22% lower mortality rate in breast cancer patients (Hazard Ratio [HR], 0.78; 95% CI: 0.71, 0.86), 12% in IHD patients (HR, 0.88; 95% CI: 0.83, 0.93), 30% in COPD patients (HR, 0.70; 95% CI: 0.45, 1.09) and 4% in T2D patients (HR, 0.96; 95% CI: 0.93, 0.99). The non-linear meta-analysis showed a regressive association with no threshold for the beneficial effect of physical activity on mortality.

Conclusion

Higher levels of post-diagnosis physical activity are associated with lower mortality rates in breast cancer, T2D, IHD and COPD patients, with evidence of a no-threshold and non-linear dose–response pattern.

SUMMARY BOX

Existing findings

- Higher levels of physical activity are associated with a clear reduction in all-cause mortality in the general population.

- In the general population, the shape of the dose–response curve between levels of physical activity and reduced mortality rates is characterized by a regressive, non-linear effect.

New findings

- Higher levels of post-diagnosis physical activity are associated with a clear reduction in all-cause mortality in adults with breast cancer, T2D, IHD and COPD.

- The shape of the indication-specific dose–response curves between post-diagnosis physical activity and mortality are characterized by a regressive, non-linear association with (1) no threshold for the beneficial effect, (2) pronounced reductions of mortality for lower levels of physical activity compared to those who are physically inactive and (3) no harmful effects at higher levels of physical activity.
Dopamine manipulations modulate paranoid social inferences in healthy people
Authors: Barnby J.M. , Bell V. , Deeley Q. , Mehta M.A.
Published: December 2019

Altered dopamine transmission is thought to influence the formation of persecutory delusions. However, despite extensive evidence from clinical studies there is little experimental evidence on how modulating the dopamine system changes social attributions related to paranoia, and the salience of beliefs more generally. 27 healthy male participants received 150mg L-DOPA, 3mg haloperidol, or placebo in a double blind, randomised, placebo-controlled study, over three within-subject sessions. Participants completed a multi-round Dictator Game modified to measure social attributions, and a measure of belief salience spanning themes of politics, religion, science, morality, and the paranormal. We preregistered predictions that altering dopamine function would affect i) attributions of harmful intent and ii) salience of paranormal beliefs. As predicted, haloperidol reduced attributions of harmful intent across all conditions compared to placebo. L-DOPA reduced attributions of harmful intent in fair conditions compared to placebo. Unexpectedly, haloperidol increased attributions of self-interest for opponents’ decisions. There was no change in belief salience within any theme. These results could not be explained by scepticism or subjective mood. Our findings demonstrate the selective involvement of dopamine in social inferences related to paranoia in healthy individuals.
Exploring prokaryotic transcription, operon structures, rRNA maturation and modifications using Nanopore-based native RNA sequencing
Authors: Grünberger Felix , Knüppel Robert , Jüttner Michael , Fenk Martin , Borst Andreas , Reichelt Robert , Hausner Winfried , Soppa Jörg , Ferreira-Cerca Sébastien , Grohmann Dina
Published: December 2019

The prokaryotic transcriptome is shaped by transcriptional and posttranscriptional events that define the characteristics of an RNA, including transcript boundaries, the base modification status, and processing pathways to yield mature RNAs. Currently, a combination of several specialised short-read sequencing approaches and additional biochemical experiments are required to describe all transcriptomic features. In this study, we present native RNA sequencing of bacterial (E. coli) and archaeal (H. volcanii, P. furiosus) transcriptomes employing the Oxford Nanopore sequencing technology. Based on this approach, we could address multiple transcriptomic characteristics simultaneously with single-molecule resolution. Taking advantage of long RNA reads provided by the Nanopore platform, we could (re-)annotate large transcriptional units and boundaries. Our analysis of transcription termination sites suggests that diverse termination mechanisms are in place in archaea. Moreover, we shed additional light on the poorly understood rRNA processing pathway in Archaea. One of the key features of native RNA sequencing is that RNA modifications are retained. We could confirm this ability by analysing the well-known KsgA-dependent methylation sites and mapping of N4-acetylcytosines modifications in rRNAs. Notably, we were able to follow the relative timely order of the installation of these modifications in the rRNA processing pathway.
ADAMDEC1 maintains a novel growth factor signaling loop in cancer stem cells
Authors: Hale James S. , Jimenez-Pascual Ana , Kordowski Anja , Pugh Jamie , Rao Shilpa , Silver Daniel J. , Alban Tyler , Watson Defne Bayik , Chen Rui , McIntyre Thomas M. , Colombo Giorgio , Taraboletti Giulia , Holmberg Karl O. , Forsberg-Nilsson Karin , Lathia Justin D. , Siebzehnrubl Florian A.
Published: December 2019

Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSCs), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs. This loop consists of an atypical metalloproteinase, a disintegrin and metalloproteinase domain-like protein decysin 1 (ADAMDEC1), secreted by GSCs. ADAMDEC1 rapidly solubilizes fibroblast growth factor-2 (FGF2) to stimulate FGF receptor 1 (FGFR1) expressed on GSCs. This signaling axis induces upregulation of Zinc finger E-box-binding homeobox 1 (ZEB1) that regulates ADAMDEC1 expression, creating a positive feedback loop. Genetic or pharmacological targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signaling axis for GSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GBM.

Statement of Significance

Cancer stem cells (CSC) drive tumor growth in many cancers including glioblastoma. We identified a novel sheddase, a disintegrin and metalloproteinase domain-like protein decysin 1, that initiates a fibroblast growth factor autocrine loop to promote stemness in CSCs. This loop can be targeted to reduce glioblastoma growth.
CDK7 regulates organ size and tumor growth by safeguarding the Hippo pathway effector Yki/Yap/Taz in the nucleus
Authors: Cho Yong Suk , Li Shuang , Wang Xiaohui , Zhu Jian , Zhuo Shu , Han Yuhong , Yue Tao , Yang Yingzi , Jiang Jin
Published: December 2019

Hippo signaling controls organ size and tumor progression through a conserved pathway leading to nuclear translocation of the transcriptional effector Yki/Yap/Taz. Most of our understanding of Hippo signaling pertains to its cytoplasmic regulation, but how the pathway is controlled in the nucleus remains poorly understood. Here we uncover an evolutionarily conserved mechanism by which CDK7 promotes Yki/Yap/Taz stabilization in the nucleus to sustain Hippo pathway outputs. We found that a modular E3 ubiquitin ligase complex CRL4DCAF12binds and targets Yki/Yap/Taz for ubiquitination and degradation, whereas CDK7 phosphorylates Yki/Yap/Taz at S169/S128/S90 to inhibit CRL4DCAF12recruitment, leading to Yki/Yap/Taz stabilization. As a consequence, inactivation of CDK7 reduced organ size and inhibited tumor growth, which could be reversed by restoring Yki/Yap activity. Our study identifies an unanticipated layer of Hippo pathway regulation, defines a novel mechanism by which CDK7 regulates tissue growth, and implies CDK7 as a drug target for Yap/Taz-driven cancer.
Heterodimerization of TFAP2 pioneer factors drives epigenomic remodeling during neural crest specification
Authors: Rothstein Megan , Simoes-Costa Marcos
Published: December 2019

Cell fate commitment involves the progressive restriction of developmental potential. Recent studies have shown that this process requires not only shifts in gene expression but also an extensive remodeling of the epigenomic landscape. To examine how chromatin states are reorganized during cellular specification in an in vivo system, we examined the function of pioneer factor TFAP2A at discrete stages of neural crest development. Our results show that TFAP2A activates distinct sets of genomic regions during induction of the neural plate border and specification of neural crest cells. Genomic occupancy analysis revealed that the repertoire of TFAP2A targets depends upon its dimerization with paralogous proteins TFAP2C and TFAP2B. During gastrula stages, TFAP2A/C heterodimers activate components of the neural plate border induction program. As neurulation begins, TFAP2A trades partners, and TFAP2A/B heterodimers reorganize the epigenomic landscape of progenitor cells to promote neural crest specification. We propose that this molecular switch acts to drive progressive cell commitment, remodeling the epigenomic landscape to define the presumptive neural crest. Our findings show how pioneer factors regulate distinct genomic targets in a stage-specific manner and highlight how paralogy can serve as an evolutionary strategy to diversify the function of the regulators that control embryonic development.
IPCAS: a direct-method-based pipeline from phasing to model building and refinement for macromolecular structure determination
Authors: Ding Wei , Zhang Tao , He Yao , Wang Jiawei , Wu Lijie , Han Pu , Zheng Chaode , Gu Yuanxin , Zeng Lingxiao , Hao Quan , Fan Haifu
Published: December 2019

A new version (2.0) of the pipeline IPCAS (Iterative Protein Crystal structure Automatic Solution) has been released, in which the program OASIS performs direct-method single-wavelength anomalous diffraction/single isomorphous replacement phasing and direct-method-aided partial-structure extension. IPCAS incorporates the widely used packages CCP4 and PHENIX for locating heavy atoms, density modification, molecular replacement, model building and refinement. Important extensions to the previous version of IPCAS include a resolution screening method for non-crystallographic symmetry searching, an alternate model-building protocol for avoiding premature convergence and direct-method image processing for electron microscopy maps, including single-particle cryo-EM maps. Moreover, a new graphical user interface is provided for controlling and real-time monitoring of the whole dual-space iterative process, which works as a plugin to CCP4i. Applications of the new IPCAS to difficult cases have yielded promising results, including `direct-method phasing and fragment extension' from weak anomalous diffraction signal data and `direct-method-aided partial-structure extension' from low-homology models.
Edge controller – a small UAVs distributed avionics paradigm
Authors: Zabunov Svetoslav , Nedkov Roumen
Published: December 2019

Purpose

This paper aims to reveal the authors’ conceptual and experimental work on an innovative avionics paradigm for small unmanned aerial vehicles (UAVs).

Design/methodology/approach

This novel approach stipulates that, rather than being centralized at the autopilot, control of avionics devices is instead distributed among controllers – spread over the airframe span, in response to avionics devices’ natural location requirements. The latter controllers are herein referred to as edge controllers by the first author.

Findings

The edge controller manifests increased efficiency in a number of functions, some of which are unburdened from the autopilot. The edge controller establishes a new paradigm of structure and design of small UAVs avionics such that any functionality related to the periphery of the airframe is implemented in the controller.

Research limitations/implications

The research encompasses a workbench prototype testing on a breadboard, as the presented idea is a novel concept. Further, another test has been conducted with four controllers mounted on a quadcopter; results from the vertical attitude sustenance are disclosed herein.

Practical implications

The motivation behind developing this paradigm was the need to position certain avionics devices at different locations on the airframe. Due to their inherent functional requirements, most of these devices have hitherto been placed at the periphery of the aircraft construction.

Originality/value

The current paper describes the novel avionics paradigm, compares it to the standard approach and further reveals two experimental setups with testing results.