bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deficiency of complement component C1Q prevents cerebrovascular damage and white matter loss in a mouse model of chronic obesity
Authors: Graham Leah C. , Kocalis Heidi E. , Soto Ileana , Howell Gareth R. 
Published: February 2020

ABSTRACTAge-related cognitive decline and many dementias involve complex interactions of both genetic and environmental risk factors. Recent evidence has demonstrated a strong association of obesity with the development of dementia. Furthermore, white matter damage is found in obese subjects and mouse models of obesity. Here, we found that components of the complement cascade, including C1QA and C3 are increased in the brain of western diet (WD)-fed obese mice, particularly in white matter regions. To functionally test the role of the complement cascade in obesity induced brain pathology, female and male mice deficient in complement component 1qa (C1QA), an essential molecule in the activation of the classical pathway of the complement cascade, were fed a WD and compared to WD-fed WT mice, and toC1qaknockout (KO) and WT mice fed a control diet (CD).C1qaKO mice fed a WD became obese but did not show pericyte loss or a decrease in laminin density in the cortex and hippocampus that was observed in obese WT controls. Furthermore, obesity-induced microglia phagocytosis and breakdown of myelin in the corpus callosum were also prevented by deficiency of C1QA. Collectively, these data show that C1QA is necessary for damage to the cerebrovasculature and white matter damage in diet-induced obesity.SIGNIFICANCE STATEMENTEconomic growth, an increasingly sedentary lifestyle and a nutritional transition to processed foods and high calorie diets have led to a significant increase in obesity prevalence. Several chronic diseases have been associated with obesity, including dementia. Obesity-induced, peripheral inflammation has been proposed as a possible trigger of pathological changes in the brain that lead to cognitive dysfunction and predisposition to dementia. Here we show that genetic deletion of the complement component C1QA prevents cerebrovascular damage, neuroinflammation and white matter degradation in a mouse model of western diet-induced obesity, demonstrating that inflammatory responses play a significant role in obesity-induced brain pathology. The complement pathway is an attractive therapeutic target to prevent cognitive decline and reduction of dementia risk caused by obesity.
Anin vivoProbabilistic Atlas of the Human Locus Coeruleus at Ultra-high Field
Authors: Ye Rong , Rua Catarina , O’Callaghan Claire , Jones P Simon , Hezemans Frank , Kaalund Sanne S. , Tsvetanov Kamen A. , Rodgers Christopher T. , Williams Guy , Passamonti Luca , Rowe James B. 
Published: February 2020

AbstractEarly and profound pathological changes are evident in the locus coeruleus (LC) in dementia and Parkinson’s disease, with effects on arousal, attention, cognitive and motor control. The LC can be identifiedin vivousing non-invasive magnetic resonance imaging techniques which have potential as biomarkers for detecting and monitoring disease progression. Technical limitations of existing imaging protocols have impaired the sensitivity to regional contrast variance or the spatial variability on the rostrocaudal extent of the LC, with spatial mapping consistent withpost mortemfindings. The current study employs a sensitive magnetisation transfer sequence using ultrahigh field 7T MRI to investigate the LC structurein vivoat high-resolution (resolution 0.4×0.4×0.5 mm, duration seven minutes). Magnetisation transfer images from 53 healthy older volunteers (52-84 years) revealed the spatial features of the LC and were used to create a probabilistic LC atlas for older adults, appropriate for clinical research. Consistent rostrocaudal gradients of slice-wise volume, contrast and variance differences of the LC were observed, mirroring distinctiveex vivospatial distributions of LC cells in its subregions. The contrast-to-noise ratios were calculated for the peak voxels, and for the averaged signals within the atlas, to accommodate the volumetric differences in estimated contrast. The probabilistic atlas is freely available, and the MRI dataset is available for researchers, for replication or to facilitate accurate LC localisation and unbiased contrast extraction in future studies.
A deep learning approach to identify new gene targets of a novel therapeutic for human splicing disorders
Authors: Gao Dadi , Morini Elisabetta , Salani Monica , Krauson Aram J. , Ragavendran Ashok , Erdin Serkan , Logan Emily M. , Chekuri Anil , Li Wencheng , Dakka Amal , Naryshkin Nikolai , Trotta Chris , Effenberger Kerstin A. , Woll Matt , Gabbeta Vijayalakshmi , Karp Gary , Yu Yong , Johnson Graham , Paquette William D. , Talkowski Michael E. , Slaugenhaupt Susan A. 
Published: February 2020

AbstractPre-mRNA splicing is a key control point in human gene expression. Disturbances in splicing due to mutation or aberrant splicing regulatory networks lead to dysregulated protein expression and contribute to a substantial fraction of human disease. Several classes of active and selective splicing modulator compounds have been recently identified, thus proving that pre-mRNA splicing is a viable target for therapy. We describe herein the identification of BPN-15477, a novel splicing modulator compound, that restores correct splicing of exon 20 in the Elongator complex protein 1(ELP1)gene carrying the major IVS20+6T>C mutation responsible for familial dysautonomia. We then developed a machine learning approach to evaluate the therapeutic potential of BPN-15477 to correct splicing in other human genetic diseases. Using transcriptome sequencing from compound-treated fibroblast cells, we identified treatment responsive sequence signatures, the majority of which center at the 5’ splice site of exons whose inclusion or exclusion is modulated by SMC treatment. We then leveraged this model to identify 155 human disease genes that harbor ClinVar mutations predicted to alter pre-mRNA splicing as potential targets for BPN-15477 treatment. Usingin vitrosplicing assays, we validated representative predictions by demonstrating successful correction of splicing defects caused by mutations in genes responsible for cystic fibrosis (CFTR), cholesterol ester storage disease (LIPA), Lynch syndrome (MLH1) and familial frontotemporal dementia (MAPT). Our study shows that deep learning techniques can identify a complex set of sequence signatures and predict response to pharmacological modulation, strongly supporting the use ofin silicoapproaches to expand the therapeutic potential of drugs that modulate splicing.
Leukotriene B4licenses inflammasome activation to enhance skin host defense
Authors: Salina Ana Carolina G , Brandt Stephanie , Klopfenstein Nathan , Blackman Amondrea , Byers-Glosson Nicole , Brodskyn Claudia , Tavares Natalia Machado , Silva Icaro Bonyek Santos Da , de Medeiros Alexandra I , Serezani C. Henrique 
Published: February 2020

AbstractThe initial production of inflammatory mediators dictates host defense as well as tissue injury. Inflammasome activation is a constituent of the inflammatory response by recognizing pathogen and host-derived products and eliciting the production of IL-1β, IL-18 as well as inducing a type of inflammatory cell death termed “pyroptosis”. Leukotriene B4(LTB4) is a lipid mediator produced quickly (seconds to minutes) by phagocytes and induces chemotaxis, enhances cytokine/chemokine production, and enhances antimicrobial effector functions. Whether LTB4directly activates the inflammasome is not well understood. Our data show that endogenously produced LTB4is required for the expression of pro-IL-1βin vivoandin vitroand enhances inflammasome assembly. Furthermore, LTB4-mediated Bruton’s tyrosine kinase (BTK) activation is required for inflammasome assemblyin vivoas well for IL-1β-enhanced skin host defense. Together, these data unveil a new role for LTB4in enhancing the expression and assembly of inflammasome components and suggest that while blocking LTB4actions could be a promising therapeutic strategy to prevent inflammasome-mediated diseases, exogenous LTB4can be used as an adjuvant to boost inflammasome-dependent host defense.
Persistent telomere cohesion protects aged cells from premature senescence
Authors: Azarm Kameron , Bhardwaj Amit , Kim Eugenie , Smith Susan 
Published: February 2020

AbstractHuman telomeres are bound by the telomere repeat binding proteins TRF1 and TRF2. Telomere shortening in human cells leads to a DNA damage response that signals replicative senescence. While insufficient loading of TRF2 at shortened telomeres contributes to the DNA damage response in senescence, the contribution of TRF1 to senescence induction has not been determined. Here we show that counter to TRF2 deficiency-mediated induction of DNA damage, TRF1 deficiency serves a protective role to limit induction of DNA damage induced by subtelomere recombination. Shortened telomeres recruit insufficient TRF1 and as a consequence inadequate tankyrase 1 to resolve sister telomere cohesion. The persistent cohesion protects short telomeres from inappropriate recombination. Ultimately, in the final division, telomeres are no longer able to maintain cohesion and subtelomere copying ensues. Thus, the gradual loss of TRF1 and concomitant persistent cohesion that occurs with telomere shortening ensures a measured approach to replicative senescence.
Targeting STAT3 signalling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer
Authors: Simões Bruno M. , Santiago-Gómez Angélica , Chiodo Chiara , Moreira Tiago , Conole Daniel , Lovell Scott , Alferez Denis , Eyre Rachel , Spence Katherine , Sarmiento-Castro Aida , Kohler Bertram , Lanzino Marilena , Andò Sebastiano , Marangoni Elisabetta , Sims Andrew H. , Tate Edward , Howell Sacha J. , Clarke Robert B. 
Published: February 2020

ABSTRACTPURPOSEEstrogen receptor (ER) positive breast cancer is frequently sensitive to endocrine therapy. Multiple mechanisms of endocrine therapy resistance have been identified, including cancer stem-like cell (CSC) activity. Sulforaphane (SFN) has previously been shown to target CSCs but its mechanism of action is unclear. Here we investigate SFX-01, a stabilised formulation of SFN, for its effects on breast CSC activity in ER+ preclinical models and to study its mechanism.EXPERIMENTAL DESIGNCSC activity was measured by mammosphere formation efficiency (MFE), aldehyde dehydrogenase (ALDH) activity, and tumor formation using patient samples and patient-derived xenograft (PDX) tumors treated with SFX-01 alone or in combination with tamoxifen or fulvestrant. Gene expression and SFN target proteins in treated samples were assessed.RESULTSSFX-01 reduced MFE of both ER+ primary and metastatic patient samples. Both tamoxifen and fulvestrant increased MFE and ALDH activity of PDX tumors, which was reversed by combination with SFX-01. SFX-01 significantly reduced tumor initiating cell frequency in secondary transplants at limiting dilution and reduced the formation of spontaneous lung micrometastases by PDX tumors in mice. Mechanistically, we establish that both tamoxifen and fulvestrant induce STAT3 phosphorylation. SFX-01 suppressed phospho-STAT3 and SFN directly bound STAT3 in patient and PDX samples. Analysis of ALDH+ cells from endocrine-resistant patient samples revealed activation of STAT3 target genesMUC1andOSMR, which were inhibited by SFX-01 in patient samples. Increased expression of these genes after 3 months’ endocrine treatment of ER+ patients (n=68) predicted poor prognosis.CONCLUSIONSOur data establish the importance of STAT3 signaling in CSC-mediated resistance to endocrine therapy and the potential of SFX-01 for improving clinical outcomes in ER+ breast cancer.
LIVE-PAINT: Super-Resolution Microscopy Inside Live Cells Using Reversible Peptide-Protein Interactions
Authors: Oi Curran , Gidden Zoe , Holyoake Louise , Kantelberg Owen , Mochrie Simon , Horrocks Mathew H. , Regan Lynne 
Published: February 2020

AbstractWe present LIVE-PAINT, a new approach to super-resolution fluorescent imaging inside live cells. In LIVE-PAINT only a short peptide sequence is fused to the protein being studied, unlike conventional super-resolution methods, which rely on directly fusing the biomolecule of interest to a large fluorescent protein, organic fluorophore, or oligonucleotide. LIVE-PAINT works by observing the blinking of localized fluorescence as this peptide is reversibly bound by a protein that is fused to a fluorescent protein. We have demonstrated the effectiveness of LIVE-PAINT by imaging a number of different proteins inside liveS. cerevisiae. Not only is LIVE-PAINT widely applicable, easily implemented, and the modifications minimally perturbing, but we also anticipate it will extend data acquisition times compared to those previously possible with methods that involve direct fusion to a fluorescent protein.
Energy supply per neuron is constrained by capillary density in the mouse brain
Authors: Ventura-Antunes Lissa , Herculano-Houzel Suzana 
Published: February 2020

AbstractNeuronal densities vary enormously across sites within a brain. Does the density of the capillary bed accompany the presumably larger energy requirement of sites with more neurons, or with larger neurons, or is energy supply constrained by a mostly homogeneous capillary bed? Here we find evidence for the latter across various sites in the mouse brain and show that as a result, the ratio of capillary cells per neuron, and thus presumably blood and energy supply per neuron, decreases uniformly with increasing neuronal density and therefore smaller average neuronal size across sites. Additionally, we find that local capillary density is also not correlated with local synapse densities, although there is a small but significant correlation between lower neuronal density (and therefore larger neuronal size) and more synapses per neuron within the restricted range of 6,500-9,500 across cortical sites. Further, local variations in the glial/neuron ratio are also not correlated with local variations in number of synapses per neuron or local synaptic densities. These findings suggest that it is not that larger neurons, neurons with more synapses, or even sites with more synapsesdemandmore energy, but simply that larger (and thus fewer) neurons have more energy available per cell, and to its synapses as a whole, than smaller (and thus more numerous) neurons due to competition for limited resources supplied by a capillary bed of fairly homogeneous density throughout the brain.Significance StatementThe brain is an expensive organ and at rest already uses nearly as much energy as during sensory activation. To ultimately determine whether the high energy cost of the brain is driven by an unusually high energy demand by neurons or constrained by capillary density in the organ, we examine whether sites in the mouse brain with more neurons, larger neurons, or more synapses have more capillary supply, and find instead that capillary density is mostly homogeneous across brain structures. We propose that neurons are constrained to using what energy is available, with little evidence for adjustments according to local demand, which explains its high risk of ischemia and vulnerability to states of compromised metabolism, including normal aging.
Consistent Effects of Pesticides on Community Structure and Ecosystem Function in Freshwater Systems
Authors: Rumschlag Samantha L. , Mahon Michael B. , Hoverman Jason T. , Raffel Thomas R. , Carrick Hunter J. , Hudson Peter J. , Rohr Jason R. 
Published: February 2020

AbstractPredicting ecological effects of contaminants remains challenging because of the sheer number of chemicals and their ambiguous role in biodiversity-ecosystem function relationships. We evaluated responses of pond ecosystems to standardized concentrations of 12 pesticides, nested in four pesticide classes and two pesticide types. We show consistent effects of herbicides and insecticides on ecosystem function, but slightly less consistent effects on community composition. Effects of pesticides on ecosystem functions were often mediated by changes to biodiversity, and our analyses show that consistency in effects of pesticide types on functions was driven by functional redundancy among species. These results suggest that risk assessment of the thousands of registered chemicals on ecosystem responses could be simplified to a smaller number of chemical groups and to groups of functionally redundant taxa.
Plastid EF-Tu Regulates Root Development through Both the ATM Pathway and GUN1
Authors: Li Pengcheng , Ma Junjie , Sun Xueping , Zhao Chuanzhi , Ma Changle , Wang Xingjun 
Published: February 2020

ABSTRACTImpaired plastid translation affects various aspects of plant development, but the molecular mechanism remains elusive. Here, we described that the reduced function of plastid translation elongation factor EF-Tu encoded byRAB GTPASE HOMOLOG 8D(Rab8d) elicits defects in root development, including the reduced meristem size, programmed cell death (PCD) in the stem cell niche (SCN), and quiescent center (QC) division. We found that the ATAXIA-TELANGIECTASIA-MUTATED (ATM)-SUPPRESSOR OF GAMMA RESPONSE 1 module mediated overexpression ofSIAMSE-RELATED 5in the root meristem region is responsible for the reduced meristem size in therab8dmutant through arresting the cell cycle. The QC activation inrab8dis dependent onETHYLENE RESPONSE FACTOR 115, which expression is tightly associated with the PCD in SCN. We further found that Rab8d physically interacts with GENOME UNCOUPLED 1 (GUN1), and GUN1 is required for inducing PCD in therab8dSCN. However, the loss of GUN1 function inrab8dseverely impairs the root architecture, suggesting that the GUN1-mediated renewal of stem cells is essential for maintaining root growth. Our observations extend our knowledge on the roles of ATM and GUN1 in regulating root development through mediating plastid translation dependent signals.One-sentence summaryTherab8d-dependent plastid signal mediated by ATM and GUN1 regulates the root meristem size and renewal of root stem cells, respectively.
Behavioural cue reactivity to alcohol and non-alcohol-related stimuli among individuals with severe alcohol use disorder: an fMRI study with a visual task
Authors: Fukushima Shou , Kuga Hironori , Oribe Naoya , Mutou Takeo , Yuzuriha Takefumi , Ozawa Hiroki , Ueno Takefumi 
Published: February 2020

AbstractPatients with alcohol use disorder (AUD) have difficulties controlling alcohol cravings and thus exhibit increased use and earlier relapse. Although patients tend to respond more strongly to alcohol-related images compared with non-alcohol-related images, few researchers examined the factors that modulate cravings. Here, we examined whole-brain blood oxygen level-dependent (BOLD) responses to behavioural cues in individuals with AUD and healthy controls (HCs). The participants included 24 patients with severe AUD and 15 HCs. We presented four beverage images (juice, drinking juice, sake, and drinking sake) and compared participant BOLD responses between the two groups. Multiple comparisons revealed that the AUD group had lower BOLD responses compared with the HC group to images of drinking juice in the left precuneus (p = 0.036) and the left posterior cingulate cortex (PCC) (p = 0.044) and higher BOLD responses to images of drinking sake in the left PCC (p = 0.044). Furthermore, compared to the HCs, the AUD patients had decreased BOLD responses associated with cue reactivity to drinking juice in the left precuneus during the period from 15 to 18 s (p = 0.004, df = 37) and 18 to 21 s (p = 0.002, df = 37). Using the Spearman correlation, we found a significant negative correlation between BOLD responses in the left PCC of the AUD patients and Mini–Mental State Examination (MMSE) scores (r = −0.619, p = 0.001). Our findings suggest that HCs and severe AUD patients differ in their responses not to images of alcoholic beverages but those related to alcohol drinking behavior. Thus, these patients appear to have different patterns of brain activity. This information may aid clinicians in developing treatments for patients with AUD.
An isothermal method for sensitive detection ofMycobacterium tuberculosis complexesusing CRISPR/Cas12acis-andtrans-cleavage
Authors: Xu Haipo , Zhang Xiaolong , Cai Zhixiong , Dong Xiuqing , Chen Geng , Li Zhenli , Qiu Liman , He Lei , Liu Xiaolong , Liu Jingfeng 
Published: February 2020

AbstractTuberculosis is still one of the most serious infectious diseases resulting in lethal death worldwide. The traditional method is still not enough to meet the clinical requirements of rapid diagnosis, high specificity and sensitivity. Fast, sensitive and accurate detection ofmycobacterium tuberculosis(MTB) is an urgent need for the treatment and control of tuberculosis disease. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated proteins (Cas12a) exhibits strongly nonspecific degradation ability of exogenous single-strand nucleic acid (trans-cleavage) after specific recognition of target sequence. We purified Cas12a protein and selected a proper guide RNA (gRNA) based on conserved sequences of MTB from gRNA library we designed. Then, we proposed a novel method based on recombinase polymerase amplification (RPA) and CRISPR/Cas12a nuclease system for specific and sensitive detection of MTB DNA. The assay based on fluorescence detection pattern showed 4.48 fM of limit of detection (LOD) and good linear correlation of concentration and fluorescence value (R2=0.9775). Also, it showed good performance in distinguishing other bacteria. Furthermore, its clinical performance was evaluated by 193 samples and showed sensitivity of 99.29% (139/140) and specificity of 100% (53/53) at 99% confidence interval, respectively, compared with culture method. The CRISPR/Cas12a system showed good specificity, excellent sensitivity and accuracy for MTB detection, and it meets requirements of MTB detection in clinical samples and has great potential for clinical translation.
EM-net: Deep learning for electron microscopy image segmentation
Authors: Khadangi Afshin , Boudier Thomas , Rajagopal Vijay 
Published: February 2020

AbstractRecent high-throughput electron microscopy techniques such as focused ion-beam scanning electron microscopy (FIB-SEM) provide thousands of serial sections which assist the biologists in studying sub-cellular structures at high resolution and large volume. Low contrast of such images hinder image segmentation and 3D visualisation of these datasets. With recent advances in computer vision and deep learning, such datasets can be segmented and reconstructed in 3D with greater ease and speed than with previous approaches. However, these methods still rely on thousands of ground-truth samples for training and electron microscopy datasets require significant amounts of time for carefully curated manual annotations. We address these bottlenecks with EM-net, a scalable deep convolutional neural network for EM image segmentation. We have evaluated EM-net using two datasets, one of which belongs to an ongoing competition on EM stack segmentation since 2012. We show that EM-net variants achieve better performances than current deep learning methods using small- and medium-sized ground-truth datasets. We also show that the ensemble of top EM-net base classifiers outperforms other methods across a wide variety of evaluation metrics.