bluuebunny/crossref_metadata_2025 huggingface dataset:
Intrinsic functional reorganisation of the attention network in the blind
Authors: Qin Wen , Liu Yong , Jiang Tianzi , Yu Chunshui
Published: January 2018

Attention can bias visual perception by modulating the neuronal activity of visual areas. However, little is known if blindness can reshape the intrinsic functional organisation within the attention networks and between the attention and visual networks. A voxel-wise network-based functional connectivity strengthen mapping analysis was proposed to thirty congenitally, thirty early and thirty late blind subjects, and thirty sighted controls. Both the blind and sighted subjects exhibited similar spatial distributions of the intrinsic dorsal (DAN) and ventral (VAN) attention networks. Moreover, compared to the sighted controls, the blind subjects showed increased functional coupling within the DAN, and between the DAN and VAN, and between the attention sub-networks and visual areas, suggesting an increased information communication by visual deprivation. However, the onset age of blindness had little impact on the functional coupling of the attention network, indicating that non-visual sensory experience is enough for driving the development of intrinsic functional organization of the attention network. Finally, a positive correlation was identified between the duration of blindness and the functional coupling of the posterior inferior frontal gyrus with the visual network, representing an experience-dependent reorganisation after visual deprivation.
Metabolic mechanisms of interaction within a defined gut microbiota
Authors: Medlock Gregory L. , Carey Maureen A. , McDuffie Dennis G. , Mundy Michael B. , Giallourou Natasa , Swann Jonathan R. , Kolling Glynis L. , Papin Jason A.
Published: January 2018

Metabolic interactions among species are ubiquitous in nature, and the fitness costs and benefits they impose often reinforce and stabilize them over time. These interactions are of particular importance in the human gut, where they have functions ranging from enhancing digestion to preventing (or exacerbating) infections. The diversity and sheer number of species present lead to the potential for a multitude of metabolic interactions among species to occur. However, identifying the mechanism and consequences of metabolic interactions between even two species is incredibly challenging. Here, we develop, apply, and experimentally test a framework for identifying potential metabolic mechanisms associated with interspecies interactions. We perform pairwise growth and metabolome profiling of co-cultures of strains from the altered Schaedler flora (ASF), a defined murine microbiota. We then apply our novel framework, which we call the Constant Yield Expectation (ConYE) model, to dissect emergent metabolic behaviors that occur in co-culture. Using the ConYE model, we identify and interrogate an amino acid cross-feeding interaction that is likely to confer a growth benefit to one ASF strain (Clostridium sp. ASF356) in co-culture with another strain (Parabacteroides goldsteinii ASF519). We experimentally validate that the proposed interaction leads to a growth benefit for this strain via media supplementation experiments. Our results reveal the type and extent of emergent metabolic behavior in microbial communities and demonstrate how metabolomic data can be used to identify potential metabolic interactions between organisms such as gut microbes. Ourin vitrocharacterization of the ASF strains and interactions between them also enhances our ability to interpret and design experiments that utilize ASF-colonized animals. We anticipate that this work will improve the tractability of studies utilizing mice colonized with the ASF. Here, we focus on growth-modulating interactions, but the framework we develop can be applied to generate specific hypotheses about mechanisms of interspecies interaction involved in any phenotype of interest within a microbial community.
Atlas of Transcription Factor Binding Sites from ENCODE DNase Hypersensitivity Data Across 27 Tissue Types
Authors: Funk Cory C. , Casella Alex M. , Jung Segun , Richards Matthew A. , Rodriguez Alex , Shannon Paul , Donovan-Maiye Rory , Heavner Ben , Chard Kyle , Xiao Yukai , Glusman Gustavo , Ertekin-Taner Nilufer , Golde Todd E. , Toga Arthur , Hood Leroy , Van Horn John D. , Kesselman Carl , Foster Ian , Madduri Ravi , Price Nathan D. , Ament Seth A.
Published: January 2018

There is intense interest in mapping the tissue-specific binding sites of transcription factors in the human genome to reconstruct gene regulatory networks and predict functions for non-coding genetic variation. DNase-seq footprinting provides a means to predict genome-wide binding sites for hundreds of transcription factors (TFs) simultaneously. However, despite the public availability of DNase-seq data for hundreds of samples, there is neither a unified analytical workflow nor a publicly accessible database providing the locations of footprints across all available samples. Here, we implemented a workflow for uniform processing of footprints using two state-of-the-art footprinting algorithms: Wellington and HINT. Our workflow scans the footprints generated by these algorithms for 1,530 sequence motifs to predict binding sites for 1,515 human transcription factors. We applied our workflow to detect footprints in 192 DNase-seq experiments from ENCODE spanning 27 human tissues. This collection of footprints describes an expansive landscape of potential TF occupancy. At thresholds optimized through machine learning, we report high-quality footprints covering 9.8% of the human genome. These footprints were enriched for true positive TF binding sites as defined by ChIP-seq peaks, as well as for genetic variants associated with changes in gene expression. Integrating our footprint atlas with summary statistics from genome-wide association studies revealed that risk for neuropsychiatric traits was enriched specifically at highly-scoring footprints in human brain, while risk for immune traits was enriched specifically at highly-scoring footprints in human lymphoblasts. Our cloud-based workflow is available at github.com/globusgenomics/genomics-footprint and a database with all footprints and TF binding site predictions are publicly available at http://data.nemoarchive.org/other/grant/sament/sament/footprint_atlas.
An atypical CRISPR-Cas locus in Symbiobacterium thermophilum flanked by a transposase, a reverse transcriptase, the endonuclease MutS2 and a putative Cas9-like protein
Authors: Chakraborty Sandeep
Published: January 2018

Clustered regularly interspaced short palindromic repeats (CRISPR) is a prokaryotic adaptive defense system that assimilates short sequences of invading genomes (spacers) within repeats, and uses nearby effector proteins (Cas), one of which is an endonuclease (Cas9), to cleave homologous nucleic acid during future infections from the same or closely related organisms. Here, a novel CRISPR locus with uncharacterized Cas proteins, is reported in Symbiobacterium thermophilum (Accid:NC 006177.1) around loc.1248561. Credence to this assertion is provided by four arguments. First, the presence of an exact repeat (CACGTGGGGTTCGGGTCGGACTG, 23 nucleotides) occurs eight times encompassing fragments about 83 nucleotides long. Second, comparison to a known CRISPR-Cas locus in the same organism (loc.355482) with an endonuclease Cas3 (WP 011194444.1, 729 aa) ∼10000 nt upstream shows the presence of a known MutS2 endonuclease (WP 011195247.1, 801 aa) in approximately the same distance in loc.1248561. Thirdly, and remarkably, an uncharacterized protein (1357 aa) long is uncannily close in length to known Cas9 proteins (1368 for Streptococcus pyogenes). Lastly, the presence of transposases and reverse transcriptase (RT) downstream of the repeat indicates this is one of an enigmatic RT-CRISPR locus, Also, the MutS2 endonuclease is not characterized as a CRISPR-endonuclease to the best of my knowledge. Interestingly, this locus was not among the four loci (three confirmed, one probable) reported by crisperfinder (http://crispr.i2bc.paris-saclay.fr/Server), indicating that the search algorithm needs to be revisited. This finding begs the question ‐ how many such CRISPR-Cas loci and Cas9-like proteins lie undiscovered within bacterial genomes?
Taxonomic identification from metagenomic and metabarcoding data using any genetic marker
Authors: Bengtsson-Palme Johan , Richardson Rodney T. , Meola Marco , Wurzbacher Christian , Tremblay Émilie D. , Thorell Kaisa , Kanger Kärt , Eriksson K. Martin , Bilodeau Guillaume J. , Johnson Reed M. , Hartmann Martin , Nilsson R. Henrik
Published: January 2018

Correct taxonomic identification of DNA sequences is central to studies of biodiversity using both shotgun metagenomic and metabarcoding approaches. However, there is no genetic marker that gives sufficient performance across all the biological kingdoms, hampering studies of taxonomic diversity in many groups of organisms. We here present a major update to Metaxa2 (http://microbiology.se/software/metaxa2/) that enables the use of any genetic marker for taxonomic classification of metagenome and amplicon sequence data.
On the design of CRISPR-based single cell molecular screens
Authors: Hill Andrew J. , McFaline-Figueroa José L. , Starita Lea M. , Gasperini Molly J. , Matreyek Kenneth A. , Packer Jonathan , Jackson Dana , Shendure Jay , Trapnell Cole
Published: January 2018

Several groups recently reported coupling CRISPR/Cas9 perturbations and single cell RNA-seq as a potentially powerful approach for forward genetics. Here we demonstrate that vector designs for such screens that rely on cis linkage of guides and distally located barcodes suffer from swapping of intended guide-barcode associations at rates approaching 50% due to template switching during lentivirus production, greatly reducing sensitivity. We optimize a published strategy, CROP-seq, that instead uses a Pol II transcribed copy of the sgRNA sequence itself, doubling the rate at which guides are assigned to cells to 94%. We confirm this strategy performs robustly and further explore experimental best practices for CRISPR/Cas9-based single cell molecular screens.
Thermodynamic analysis of mitochondrial DNA breakpoints reveals mechanistic details of deletion mutagenesis
Authors: Lakshmanan Lakshmi Narayanan , Yee Zhuangli , Gruber Jan , Halliwell Barry , Gunawan Rudiyanto
Published: January 2018

Broad evidence support double-strand breaks (DSBs) as initiators of mitochondrial DNA (mtDNA) deletion mutations. But the mechanism of DSB-induced deletions, including the DSB repair pathway(s) involved, remains to be established. Here, we used DNA hybridization thermodynamics to analyze misalignment lengths surrounding deletion breakpoints. Our analysis of 9,655 previously reported mammalian mtDNA deletions and 1,307 novel Caenorhabditis elegans mtDNA deletions, indicates a significant role of 0–25bp misalignments, supporting the role of erroneous non-homologous and micro-homology dependent DSB repair in deletion formation. Based on these insights we propose that DSB-induced mtDNA deletions occur via the misjoining of DSB ends and/or strand invasion of open mtDNA regions by DSB ends.
Microglia inhibition rescues developmental hypofrontality in a mouse model of mental illness
Authors: Chini Mattia , Lindemann Christoph , Pöpplau Jastyn A. , Xu Xiaxia , Ahlbeck Joachim , Bitzenhofer Sebastian H. , Mulert Christoph , Hanganu-Opatz Ileana L.
Published: January 2018

Cognitive deficits, core features of mental illness, largely result from dysfunction of prefrontal-hippocampal networks. This dysfunction emerges already during early development, before a detectable behavioral readout, yet the cellular elements controlling the abnormal maturation are still unknown. Combining in vivo electrophysiology and optogenetics with neuroanatomy and pharmacology in neonatal mice mimicking the dual genetic - environmental etiology of psychiatric disorders, we identified pyramidal neurons in layer II/III of the prefrontal cortex as key elements causing disorganized oscillatory entrainment of local circuits in beta-gamma frequencies. Their abnormal firing rate and timing result from sparser dendritic arborization and lower spine density. Pharmacological modulation of aberrantly hyper-mature microglia rescues morphological, synaptic and functional neuronal deficits and restores the early circuit function. Elucidation of the cellular substrate of developmental miswiring related to later cognitive deficits opens new perspectives for identification of neurobiological targets, amenable to therapies.

Highlights

Mice mimicking the etiology of mental illness have dysregulated prefrontal network

Structural and synaptic deficits cause abnormal rate and timing of pyramidal firing

Weaker activation of prefrontal circuits results from deficits of pyramidal neurons

Rescue of microglial function restores developing prefrontal circuits
Inter- and intra-domain functional redundancy in the rumen microbiome during plant biomass degradation
Authors: Söllinger Andrea , Tveit Alexander Tøsdal , Poulsen Morten , Noel Samantha Joan , Bengtsson Mia , Bernhardt Jörg , Frydendahl Hellwing Anne Louise , Lund Peter , Riedel Katharina , Schleper Christa , Højberg Ole , Urich Tim
Published: January 2018

Background

Ruminant livestock is a major source of the potent greenhouse gas methane (CH4), produced by the complex rumen microbiome. Using an integrated approach, combining quantitative metatranscriptomics with gas- and volatile fatty acid (VFA) profiling, we gained fundamental insights into temporal dynamics of the cow rumen microbiome during feed degradation.

Results

The microbiome composition was highly individual and remarkably stable within each cow, despite similar gas emission and VFA profiles between cows. Gene expression profiles revealed a fast microbial growth response to feeding, reflected by drastic increases in microbial biomass, CH4emissions and VFA concentrations. Microbiome individuality was accompanied by high inter- and intra-domain functional redundancy among pro- and eukaryotic microbiome members in the key steps of anaerobic feed degradation. Methyl-reducing but not CO2-reducing methanogens were correlated with increased CH4emissions during plant biomass degradation.

Conclusions

The major response of the rumen microbiome to feed intake was a general growth of the whole community. The high functional redundancy of the cow-individual microbiomes was possibly linked to the robust performance of the anaerobic degradation process. Furthermore, the strong response of methylotrophic methanogens is suggesting that they might play a more important role in ruminant CH4emissions than previously assumed, making them potential targets for CH4mitigation strategies.
Engineering Plant Architecture via CRISPR/Cas9-mediated Alteration of Strigolactone Biosynthesis
Authors: Butt Haroon , Jamil Muhammad , Wang Jian You , Al-Babili Salim , Mahfouz Magdy
Published: January 2018

Precision plant genome engineering holds much promise for targeted improvement of crop traits via unprecedented single-base level control over the genetic material. Strigolactones (SLs) are a key determinant of plant architecture, known for their role in inhibiting shoot branching (tillering). Here, we used CRISPR/Cas9 in rice (Oryza sativa) for targeted disruption of CAROTENOID CLEAVAGE DIOXYGENASE 7 (CCD7), which controls a key step in SL biosynthesis. The ccd7 mutants exhibited a striking increase in tillering, combined with a dwarf phenotype, which could be rescued by application of the synthetic SL analog GR24. Striga germination assays and liquid chromatography–mass spectrometry analysis showed that root exudates of ccd7 mutants were also SL deficient. Taken together, our results show the power of CRISPR/Cas9 for targeted engineering of plant architecture and for elucidating the molecular underpinnings of architecture-related traits.
An Adaptive Flagellar Photoresponse Determines the Dynamics of Accurate Phototactic Steering inChlamydomonas
Authors: Leptos Kyriacos C , Chioccioli Maurizio , Furlan Silvano , Pesci Adriana I , Goldstein Raymond E
Published: January 2018

Our understanding of phototaxis of biflagellates stems almost exclusively from the model algaChlamydomonas reinhardtii, via studies of its flagella, light-sensor and steering. However, no comprehensive model linking all these aspects of its physiology and behavior has been constructed and tested experimentally. Here, we develop such a mathematical model by coupling an adaptive flagellar photoresponse to rigid-body dynamics tailored to details of flagellar beating, and corroborate it with experimental data – at the flagellar and tactic levels – to explain the accurate phototactic steering of this alga. We experimentally validate the hypothesized adaptive flagellar photoresponse using high spatio-temporal resolution methodology on immobilized cells, and corroborate the predicted reorientation dynamics of phototactic swimmers using 3D-tracking of free-swimming cells. Finally, we reconfirm, both theoretically and experimentally, that the adaptive nature of the response has peak fidelity at a frequency of about 1.6 Hz, corresponding to the rotation frequency of the cell body.
Truncation and Motif Based Pan-Cancer Analysis Highlights Novel Tumor Suppressing Kinases
Authors: Hudson Andrew M. , Stephenson Natalie L. , Li Cynthia , Trotter Eleanor , Fletcher Adam J. , Katona Gitta , Bieniasz-Krzywiec Patrycja , Howell Matthew , Wirth Chris , Furney Simon , Miller Crispin J. , Brognard John
Published: January 2018

A major challenge in cancer genomics is identifying driver mutations from the large number of neutral passenger mutations within a given tumor. Here, we utilize motifs critical for kinase activity to functionally filter genomic data to identify driver mutations that would otherwise be lost within mutational noise. In the first step of our screen, we define a putative tumor suppressing kinome by identifying kinases with truncation mutations occurring within or before the kinase domain. We aligned these kinase sequences and, utilizing data from the Cancer Cell Line Encyclopedia and The Cancer Genome Atlas databases, identified amino acids that represent predicted hotspots for loss-of-function mutations. The functional consequences of new LOF mutations were validated and the top 15 hotspot LOF residues were used in a pan-cancer analysis to define the tumor-suppressing kinome. A ranked list revealed MAP2K7 as a candidate tumor suppressor in gastric cancer, despite the mutational frequency of MAP2K7 falling within the mutational noise for this cancer type. The majority of mutations in MAP2K7 abolished catalytic activity compared to the wild type kinase, consistent with a tumor suppressive role for MAP2K7 in gastric cancer. Furthermore, reactivation of the JNK pathway in gastric cancer cells harboring LOF mutations in MAP2K7 or JNK1 suppresses clonogenicity and growth in soft agar, demonstrating the functional importance of inactivating the JNK pathway in gastric cancer. In summary, our data highlights a broadly applicable strategy to identify functional cancer driver mutations leading us to define the JNK pathway as tumor suppressive in gastric cancer.

A unique computational pan-cancer analysis pinpoints novel tumor suppressing kinases, and highlights the power of functional genomics by defining the JNK pathway as tumor suppressive in gastric cancer.
Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors
Authors: Ayeni Deborah , Miller Braden , Kuhlman Alexandra , Ho Ping-Chih , Robles-Oteiza Camila , Gaefele Mmaserame , Levy Stellar , de Miguel Fernando J. , Perry Curtis , Guan Tianxia , Zelterman Daniel , Homer Robert , Liu Zongzhi , Kaech Susan , Politi Katerina
Published: January 2018

Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) like erlotinib are effective for treating patients with EGFR mutant lung cancer; however, drug resistance inevitably emerges. Approaches to combine immunotherapies and targeted therapies to overcome or delay drug resistance have been hindered by limited knowledge of the effect of erlotinib on tumor-infiltrating immune cells. Using mouse models, we studied the immunological profile of mutantEGFR-driven lung tumors before and after erlotinib treatment. We found that erlotinib triggered the recruitment of inflammatory T cells into the lungs. Interestingly, this phenotype could be recapitulated by tumor regression mediated by deprivation of the EGFR oncogene indicating that tumor regression alone was sufficient for these immunostimulatory effects. Erlotinib treatment also led to increased maturation of myeloid cells and an increase in CD40+ dendritic cells. Our findings lay the foundation for understanding the effects of TKIs on the tumor microenvironment and highlights potential avenues for investigation of targeted and immuno-therapy combination strategies to treat EGFR mutant lung cancer.
Drug Repurposing: The Anthelmintics Niclosamide and Nitazoxanide are Potent TMEM16A Antagonists that Fully Bronchodilate Airways
Authors: Miner Kent , Labitzke Katja , Liu Benxian , Wang Paul , Henckels Kathryn , Gaida Kevin , Elliott Robin , Chen Jian Jeffrey , Liu Longbin , Leith Anh , Trueblood Esther , Hensley Kelly , Xia Xing-Zhong , Homann Oliver , Bennett Brian , Fiorino Mike , Whoriskey John , Yu Gang , Escobar Sabine , Wong Min , Born Teresa L. , Budelsky Alison , Comeau Mike , Smith Dirk , Phillips Jonathan , Johnston James A. , McGivern Joe , Weikl Kerstin , Powers David , Kunzelmann Karl , Mohn Deanna , Hochheimer Andreas , Sullivan John K.
Published: January 2018

There is an unmet need in severe asthma where approximately 40% of patients exhibit poor β-agonist responsiveness, suffer daily symptoms and show frequent exacerbations. Antagonists of the Ca2+-activated-Cl− channel, TMEM16A, offers a new mechanism to bronchodilate airways and block the multiple contractiles operating in severe disease. To identify TMEM16A antagonists we screened a library of ~580,000 compounds. The anthelmintics niclosamide, nitazoxanide and related compounds were identified as potent TMEM16A antagonists that blocked airway smooth muscle depolarization and contraction. To evaluate whether TMEM16A antagonists resist use- and inflammatory-desensitization pathways limiting β-agonist action, we tested their efficacy under harsh conditions using maximally contracted airways or airways pretreated with a cytokine cocktail. Stunningly, TMEM16A antagonists fully bronchodilated airways, while the β-agonist isoproterenol showed only partial effects. Thus, antagonists of TMEM16A and repositioning of niclosamide and nitazoxanide represent an important additional treatment for patients with severe asthma and COPD that is poorly controlled with existing therapies. It is of note that drug repurposing has also attracted wide interest in niclosamide and nitazoxanide as a new treatment for cancer and infectious disease. For the first time we identify TMEM16A as a molecular target for these drugs and thus provide fresh insights into their mechanism for the treatment of these disorders in addition to respiratory disease.
Automatic error control during forward flux sampling of rare events in master equation models
Authors: Klein Max C. , Roberts Elijah
Published: January 2018

Enhanced sampling methods, such as forward flux sampling (FFS), have great capacity for accelerating stochastic simulations of nonequilibrium biochemical systems involving rare events. However, the description of the tradeoffs between simulation efficiency and error in FFS remains incomplete. We present a novel and mathematically rigorous analysis of the errors in FFS that, for the first time, covers the contribution of every phase of the simulation. We derive a closed form expression for the optimally efficient count of samples to take in each FFS phase in terms of a fixed constraint on sampling error. We introduce a new method, forward flux pilot sampling (FFPilot), that is designed to take full advantage of our optimizing equation without prior information or assumptions about the phase weights and costs along the transition path. In simulations of both single- and multi-dimensional gene regulatory networks, FFPilot is able to completely control sampling error. Higher dimensional systems have additional sources of error and we show that this extra error can be traced to correlations between phases due to roughness on the probability landscape. Finally, we show that in sets of simulations with matched error, FFPilot is on the order of tens-to-hundreds of times faster than direct sampling, in a fashion that scales with the rarity of the events.
Global analysis of gene expression dynamics identifies factors required for accelerated mRNA degradation
Authors: Miller Darach , Brandt Nathan , Gresham David
Published: January 2018

Cellular responses to changing environments frequently involve rapid reprogramming of the transcriptome. Regulated changes in mRNA degradation rates can accelerate reprogramming by clearing or stabilizing extant transcripts. Here, we measured mRNA stability using 4-thiouracil labeling in the budding yeastSaccharomyces cerevisiaeduring a nitrogen upshift and found that 78 mRNAs are subject to destabilization. These transcripts include Nitrogen Catabolite Repression (NCR) and carbon metabolism mRNAs, suggesting that mRNA destabilization is a mechanism for targeted reprogramming. To explore the molecular basis of destabilization we implemented a SortSeq approach to screen using the pooled deletion collection library fortransfactors that mediate rapidGAP1mRNA repression. We combined low-input multiplexed Barcode sequencing with branched-DNA single-molecule mRNA FISH and Fluorescence-activated cell sorting (BFF) to identify that the Lsm1-7p/Pat1p complex and general mRNA decay machinery are important forGAP1mRNA clearance. We also find that the decapping modulatorSCD6,translation factor eIF4G2, and the 5’ UTR ofGAP1are important for this repression, suggesting that translational control may impact the post-transcriptional fate of mRNAs in response to environmental changes.
Spindle assembly in egg extracts of the Marsabit clawed frog, Xenopus borealis
Authors: Kitaoka Maiko , Heald Rebecca , Gibeaux Romain
Published: January 2018

Egg extracts of the African clawed frog Xenopus laevis have provided a cell-free system instrumental in elucidating events of the cell cycle, including mechanisms of spindle assembly. Comparison with extracts from the diploid Western clawed frog, Xenopus tropicalis, which is smaller at the organism, cellular and subcellular levels, has enabled the identification of spindle size scaling factors. We set out to characterize the Marsabit clawed frog, Xenopus borealis, which is intermediate in size between the two species, but more recently diverged in evolution from X. laevis than X. tropicalis. X. borealis eggs were slightly smaller than those of X. laevis, and slightly smaller spindles were assembled in egg extracts. Interestingly, microtubule distribution across the length of the X. borealis spindles differed from both X. laevis and X. tropicalis. Extract mixing experiments revealed common scaling phenomena among Xenopus species, while characterization of spindle factors katanin, TPX2, and Ran indicate that X. borealis spindles possess both X. laevis and X. tropicalis features. Thus, X. borealis egg extract provides a third in vitro system to investigate interspecies scaling and spindle morphometric variation.
Rehydration rates and the prevalence of xylem-hydration of flowers
Authors: Roddy Adam B. , Brodersen Craig R.
Published: January 2018

Angiosperm flowers are remarkably diverse anatomically and morphologically, yet they all must satisfy the physiological constraints of supplying sufficient amounts of water and carbon effectively promote pollination. Flowers often occur in the hottest, driest parts of the plant canopy and can face harsh abiotic conditions. Prior evidence suggests that extant species vary dramatically in how water is delivered to flowers, with some evidence that water may be imported into flowers by the phloem. Here we measured midday water potential gradients between flowers, leaves, and stems often phylogenetically diverse species. We further tested the likelihood of xylem-hydration by measuring rates of rehydration after experimentally induced desiccation. There was no significant difference in rehydration rates between leaves and flowers. These results are consistent with xylem-hydration of flowers and suggest that there has been little modification to the mechanisms of water transport despite the diversity of floral form.
Genetically increased serum calcium levels reduce Alzheimer’s disease risk
Authors: Jiang Qinghua , Hu Yang , Jin Shuilin , Liu Guiyou
Published: January 2018

IMPORTANCE Alzheimer’s disease (AD) is the leading cause of disability in the elderly. It has been a long time about the calcium hypothesis of AD on the basis of emerging evidence since 1994. However, most studies focused on the association between calcium homeostasis and AD, and concerned the intracellular calcium concentration. Only few studies reported reduced serum calcium levels in AD. Until now, it remains unclear whether serum calcium levels are genetically associated with AD risk.

OBJECTIVE To evaluate the genetic association between increased serum calcium levels and AD risk

DESIGN, SETTING, AND PARTICIPANTS We performed a Mendelian randomization study to investigate the association of increased serum calcium with AD risk using the genetic variants from the large-scale serum calcium genome-wide association study (GWAS) dataset (N=61,079 individuals of European descent) and the large-scale AD GWAS dataset (N=54,162 individuals including 17,008 AD cases and 37,154 controls of European descent). Inverse-variance weighted meta-analysis (IVW) was used to provide a combined estimate of the genetic association. Meanwhile, we selected the weighted median regression and MR-Egger regression as the complementary analysis methods to examine the robustness of the IVW estimate.

EXPOSURES Genetic predisposition to increased serum calcium levels

MAIN OUTCOMES AND MEASURES The risk of AD.

RESULTS We selected 6 independent genetic variants influencing serum calcium levels as the instrumental variables. IVW analysis showed that a genetically increased serum calcium level (per 1 standard deviation (SD) increase 0.5-mg/dL) was significantly associated with a reduced AD risk (OR=0.56, 95% CI: 0.34-0.94, P=5.00E-03). Meanwhile, both the weighted median estimate (OR=0.60, 95% CI: 0.34-1.06, P=0.08) and MR-Egger estimate (OR=0.66, 95% CI: 0.26-1.67, P=0.381) were consistent with the IVW estimate in terms of direction and magnitude.

CONCLUSIONS AND RELEVANCE We provided evidence that genetically increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be further conducted to assess the effect of serum calcium levels on AD risk, and further clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD.

Key Points

Question Is there a genetic relationship between elevated serum calcium levels and the risk of Alzheimer’s disease?

Findings This Mendelian randomization study showed that the genetically increased serum calcium levels were associated with the reduced risk of Alzheimer’s disease.

Meaning These findings provide evidence that genetically increased serum calcium levels could reduce the risk of Alzheimer’s disease.
Schistosomiasis Induces Persistent DNA Methylation and Tuberculosis-specific Immune Changes
Authors: DiNardo Andrew R. , Nishiguchi Tomoki , Mace Emily M. , Rajapakshe Kimal , Mtetwa Godwin , Kay Alexander , Maphalala Gugu , Secor W. Evan , Mejia Rojelio , Orange Jordan S. , Coarfa Cristian , Bhalla Kapil N. , Graviss Edward A , Mandalakas Anna M. , Makedonas George
Published: January 2018

Epigenetic mechanisms, like DNA methylation, determine immune cell phenotype. To understand the epigenetic alterations induced by helminth co-infections, we evaluated the longitudinal effect of ascariasis and schistosomiasis infection on CD4+ T cell DNA methylation and the downstream tuberculosis (TB)-specific and BCG-induced immune phenotype. All experiments were performed on human primary immune cells from a longitudinal cohort of recently TB-exposed children. Compared to age-matched uninfected controls, children with active Schistosoma haematobium and Ascaris lumbricoides infection had 751 differentially DNA methylated genes with 72% hyper-methylated. Gene ontology pathway analysis identified inhibition of IFN-γ signaling, cellular proliferation, and the Th1 pathway. Targeted RT-PCR after methyl-specific endonuclease digestion confirmed DNA hyper-methylation of the transcription factors BATF3, ID2, STAT5A, IRF5, PPARg, RUNX2, IRF4 and NFATC1 and cytokines or cytokine receptors IFNGR1, TNFS11, RELT (TNF receptor), IL12RB2 and IL12B (p< 0.001; Sidak-Bonferroni). Functional blockage of the IFN-γ signaling pathway was confirmed with helminth-infected individuals having decreased up-regulation of IFN-γ-inducible genes (Mann-Whitney p < 0.05). Hypo-methylation of the IL-4 pathway and DNA hyper-methylation of the Th1 pathway was confirmed by antigen-specific multidimensional flow cytometry demonstrating decreased TB-specific IFN-γ and TNF and increased IL-4 production by CD4+ T cells (Wilcoxon signed rank P <0.05). In S.haematobium infected individuals, these DNA methylation and immune phenotypic changes persisted at least six months after successful deworming. This work demonstrates that helminth infection induces DNA methylation and immune perturbations that inhibit TB-specific immune control and that the duration of these changes are helminth-specific.
Distinct contributions of tensile and shear stress on E-cadherin levels during morphogenesis
Authors: Kale Girish R. , Yang Xingbo , Philippe Jean-Marc , Mani Madhav , Lenne Pierre-François , Lecuit Thomas
Published: January 2018

During epithelial morphogenesis, cell contacts (junctions) are constantly remodeled by mechanical forces that work against adhesive forces. E-cadherin complexes play a pivotal role in this process by providing persistent cell adhesion and by transmitting mechanical tension. In this context, it is unclear how mechanical forces affect E-cadherin adhesion and junction dynamics.

DuringDrosophilaembryo axis elongation, Myosin-II activity in the apico-medial and junctional cortex generates mechanical forces to drive junction remodeling. Here we report that the ratio between Vinculin and E-cadherin intensities acts as a ratiometric readout for these mechanical forces (load) at E-cadherin complexes. Medial Myosin-II loads E-cadherin complexes on all junctions, exerts tensile forces, and increases levels of E-cadherin. Junctional Myosin-II, on the other hand, biases the distribution of load between junctions of the same cell, exerts shear forces, and decreases the levels of E-cadherin. This work suggests distinct effects of tensile versus shear stresses on E-cadherin adhesion.
The Eighty Five Percent Rule for Optimal Learning
Authors: Wilson Robert C. , Shenhav Amitai , Straccia Mark , Cohen Jonathan D.
Published: January 2018

Researchers and educators have long wrestled with the question of how best to teach their clients be they human, animal or machine. Here we focus on the role of a single variable, the difficulty of training, and examine its effect on the rate of learning. In many situations we find that there is a sweet spot in which training is neither too easy nor too hard, and where learning progresses most quickly. We derive conditions for this sweet spot for a broad class of learning algorithms in the context of binary classification tasks, in which ambiguous stimuli must be sorted into one of two classes. For all of these gradient-descent based learning algorithms we find that the optimal error rate for training is around 15.87% or, conversely, that the optimal training accuracy is about 85%. We demonstrate the efficacy of this ‘Eighty Five Percent Rule’ for artificial neural networks used in AI and biologically plausible neural networks thought to describe human and animal learning.
Identifying Antimicrobial Peptides using Word Embedding with Deep Recurrent Neural Networks
Authors: Hamid Md-Nafiz , Friedberg Iddo
Published: January 2018

Antibiotic resistance constitutes a major public health crisis, and finding new sources of antimicrobial drugs is crucial to solving it. Bacteriocins, which are bacterially-produced antimicrobial peptide products, are candidates for broadening the available choices of an-timicrobials. However, the discovery of new bacteriocins by genomic mining is hampered by their sequences’ low complexity and high variance, which frustrates sequence similarity-based searches. Here we use word embeddings of protein sequences to represent bacteriocins, and apply a word embedding method that accounts for amino acid order in protein sequences,to predict novel bacteriocins from protein sequences without using sequence similarity. Our method predicts, with a high probability, six yet unknown putative bacteriocins in Lactobacil-lus. Generalized, the representation of sequences with word embeddings preserving sequence order information can be applied to protein classification problems for which sequence simi-larity cannot be used.
Gut bacterial metabolite Urolithin A (UA) mitigates Ca2+ entry in T cells by regulating miR-10a-5p
Authors: Zhang Shaqiu , Al-Maghout Tamer , Cao Hang , Pelzl Lisann , Salker Madhuri S , Cheng Anchun , Lang Florian , Singh Yogesh
Published: January 2018

The gut microbiota influences several biological functions including immune response. Inflammatory bowel disease is favourably influenced by consumption of several dietary natural plant products such as pomegranate, walnuts and berries containing polyphenolic compounds such as ellagitannins and ellagic acid. The gut microbiota metabolises ellagic acid leading to formation of bioactive urolithins A, B, C and D. Urolithin A (UA) is the most active and effective gut metabolite and acts as a potent anti-inflammatory and anti-oxidant agent. However, how gut metabolite UA affects the function of immune cells remained incompletely understood. T cell proliferation is stimulated by store operated Ca2+ entry (SOCE) resulting from stimulation of Orai1 by STIM1/STIM2. We show here that treatment of murine CD4+ T cells with UA (10 µM, 3 days) significantly blunted SOCE in CD4+ T cells, an effect paralleled by significant downregulation of Orai1 and STIM1/2 transcript levels and protein abundance. UA treatment further increased miR-10a-5p abundance in CD4+ T cells in a dose dependent fashion. Overexpression of miR-10a-5p significantly decreased STIM1/2 and Orai1 mRNA and protein levels as well as SOCE in CD4+ T cells. UA further decreased CD4+ T cell proliferation. Thus, bacterial metabolite UA up-regulates miR-10a-5p thus interfering with Orai1/STIM1/STIM2 expression, store operated Ca2+ entry and proliferation of murine CD4+ T cells.
The chromatin modifiers SET-25 and SET-32 are required for initiation but not long-term maintenance of transgenerational epigenetic inheritance
Authors: Woodhouse Rachel , Buchmann Gabrielle , Hoe Matthew , Harney Dylan , Larance Mark , Boag Peter R. , Ashe Alyson
Published: January 2018

Some epigenetic modifications are inherited from one generation to the next, providing a potential mechanism for the inheritance of environmentally acquired traits. Transgenerational inheritance of RNA interference phenotypes in Caenorhabditis elegans provides an excellent model to study this phenomenon, and whilst studies have implicated both chromatin modifications and small RNA pathways in heritable silencing their relative contributions remain unclear. Here we demonstrate that the histone methyltransferases SET-25 and SET-32 are required for the establishment of a transgenerational silencing signal but not for long-term maintenance of this signal between subsequent generations, suggesting that transgenerational epigenetic inheritance is a multi-step process with distinct genetic requirements for establishment and maintenance of heritable silencing. Furthermore, small RNA sequencing reveals that the abundance of secondary siRNAs (thought to be the effector molecules of heritable silencing) does not correlate with silencing phenotypes. Together, our results suggest that the current mechanistic models of epigenetic inheritance are incomplete.
ClusterMine: a Knowledge-integrated Clustering Approach based on Expression Profiles of Gene Sets
Authors: Li Hong-Dong , Xu Yunpei , Zhu Xiaoshu , Liu Quan , Omenn Gilbert S. , Wang Jianxin
Published: January 2018

Motivation

Clustering analysis is essential for understanding complex biological data. In widely used methods such as hierarchical clustering (HC) and consensus clustering (CC), expression profiles of all genes are often used to assess similarity between samples for clustering. These methods output sample clusters, but are not able to provide information about which gene sets (functions) contribute most to the clustering. So interpretability of their results is limited. We hypothesized that integrating prior knowledge of annotated biological processes would not only achieve satisfying clustering performance but also, more importantly, enable potential biological interpretation of clusters.

Results

Here we report ClusterMine, a novel approach that identifies clusters by assessing functional similarity between samples through integrating known annotated gene sets,e.g.,in Gene Ontology. In addition to outputting cluster membership of each sample as conventional approaches do, it outputs gene sets that are most likely to contribute to the clustering, a feature facilitating biological interpretation. Using three cancer datasets, two single cell RNA-sequencing based cell differentiation datasets, one cell cycle dataset and two datasets of cells of different tissue origins, we found that ClusterMine achieved similar or better clustering performance and that top-scored gene sets prioritized by ClusterMine are biologically relevant.

Implementation and availability

ClusterMine is implemented as an R package and is freely available at:www.genemine.org/clustermine.php

Contact

jxwang@csu.edu.cn

Supplementary Information

Supplementary data are available at Bioinformatics online.
Systematic detection of amino acid substitutions in proteome reveals a mechanistic basis of ribosome errors
Authors: Mordret Ernest , Yehonadav Avia , Barnabas Georgina D , Cox Jürgen , Dahan Orna , Geiger Tamar , Lindner Ariel B , Pilpel Yitzhak
Published: January 2018

Translation errors limit the accuracy of information transmission from DNA to proteins. Selective pressures shape the way cells produce their proteins: the translation machinery and the mRNA sequences it decodes co-evolved to ensure that translation proceeds fast and accurately in a wide range of environmental conditions. Our understanding of the causes of amino acid misincorporations and of their effect on the evolution of protein sequences is largely hindered by the lack of experimental methods to observe errors at the full proteome level. Here, we systematically detect and quantify errors in entire proteomes from mass spectrometry data. Following HPLC MS-MS data acquisition, we identify E. coli and S. cerevisiae peptides whose mass and fragment ion spectrum are consistent with that of a peptide bearing a single amino acid substitution, and verify that such spectrum cannot result from a post-translational modification. Our analyses confirm that most substitutions occur due to codon-to-anticodon mispairing within the ribosome. Patterns of errors due to mispairing were similar in bacteria and yeast, suggesting that the error spectrum is chemically constrained. Treating E. coli cells with a drug known to affect ribosomal proofreading increased the error rates due to mispairing at the wobble codon position. Starving bacteria for serine resulted in specific patterns of substitutions reflecting the amino acid deficiency. Overall, translation errors tend to occur at positions that are less evolutionarily conserved, and that minimally affect protein energetic stability, indicating that they are selected against. Genome wide ribosome density data suggest that errors occur at sites where ribosome velocity is relatively high, supporting the notion of a trade-off between speed and accuracy as predicted by proofreading theories. Together our results reveal a mechanistic basis for ribosome errors in translation.
Sequence-dependent Three Interaction Site (TIS) Model for Single and Double-stranded DNA
Authors: Chakraborty Debayan , Hori Naoto , Thirumalai D.
Published: January 2018

We develop a robust coarse-grained model for single and double stranded DNA by representing each nucleotide by three interaction sites (TIS) located at the centers of mass of sugar, phosphate, and base. The resulting TIS model includes base-stacking, hydrogen bond, and electrostatic interactions as well as bond-stretching and bond angle potentials that account for the polymeric nature of DNA. The choices of force constants for stretching and the bending potentials were guided by a Boltzmann inversion procedure using a large representative set of DNA structures extracted from the Protein Data Bank. Some of the parameters in the stacking interactions were calculated using a learning procedure, which ensured that the experimentally measured melting temperatures of dimers are faithfully reproduced. Without any further adjustments, the calculations based on the TIS model reproduces the experimentally measured salt and sequence dependence of the size of single stranded DNA (ssDNA), as well as the persistence lengths of poly(dA) and poly(dT) chains. Interestingly, upon application of mechanical force the extension of poly(dA) exhibits a plateau, which we trace to the formation of stacked helical domains. In contrast, the force-extension curve (FEC) of poly(dT) is entropic in origin, and could be described by a standard polymer model. We also show that the persistence length of double stranded DNA, formed from two complementary ssDNAs with one hundred and thirty base pairs, is consistent with the prediction based on the worm-like chain. The persistence length, which decreases with increasing salt concentration, is in accord with the Odijk-Skolnick-Fixman theory intended for stiff polyelectrolyte chains near the rod limit. The range of applications, which did not require adjusting any parameter after the initial construction based solely on PDB structures and melting profiles of dimers, attests to the transferability and robustness of the TIS model for ssDNA and dsDNA.
Inclusive estimations of ball screw-based CNC feed drive system over positioning and pre-loading factor
Authors: Verma Kuldeep , Belokar R.M.
Published: January 2018

Purpose

This paper aims to investigate the performance and positioning accuracy of computer numerical controlled (CNC) feed drive system using a ball screw-based pre-loading impact factor.

Design/methodology/approach

Initially, axial displacement of support bearings has been computed in relation to the different preload values. Among the computed values, a basic rule equation has been developed for the calculation of elongation in the bearings. The value of displacements computed from the developed equation has been considered as a pre-loading value, and its behavior on the feed drive system has been analyzed.

Findings

The elongation of bearings impacts the positioning accuracy and repeatability of the feed drive system and of CNC machines. Next, an analytical model for the rigorous assessment of CNC feed drive system has been designed and developed. The positioning accuracy of CNC machine in relation with different pre-loading values has been analyzed.

Practical implications

The results obtained from these investigations enhance the positioning accuracy of CNC machining centers. The optimum pre-loading value has been analyzed among the available ranges, and it has been proposed that optimal results have been achieved at 5 per cent of dynamic load rating.

Originality/value

This paper proposes improved explorations toward the performance of the CNC machines by optimizing the positioning accuracy through pre-loading. Finally, analytical estimations have been carried out to prove the validity of the proposal.