bluuebunny/crossref_metadata_2025_split huggingface dataset:
Geospatial approach to investigate spatial clustering and hotspots of blood lead levels in children within Kabwe, Zambia
Authors: Moonga Given , Chisola Moses N , Berger Ursula , Nowak Dennis , Yabe John , Nakata Hokuto , Nakayama Shouta , Ishizuka Mayumi , Bose-O’Reilly Stephan 
Published: March 2021

AbstractBackgroundCommunities around Kabwe/Zambia are exposed to lead due to deposits from an old lead (Pb) and zinc (Zn) mining site. Children are particularly more vulnerable than adults, presenting with greatest risk of health complications because of their increased oral uptake due to their hand to mouth activities. Spatial analysis of childhood lead exposure is useful in identifying specific areas with highest risk of pollution. The objective of the current study was to use a geospatial approach investigate spatial clustering and hotspots of blood lead levels in children within Kabwe.MethodsWe analysed data on blood lead levels (BLL) for 363 children below the age of 15 from Kabwe town. We used spatial autocorrelation methods involving the global Moran’s I and local Getis-Ord Gi*statistic in ArcMap 10.5.1, to test for spatial dependency among the blood lead levels in children.ResultsBLL in children from Kabwe are spatially autocorrelated with a Moran’s Index of 0.62 (p<0.001). We found distinct hot spots in communities close to the old lead and zinc-mining site, lying on its western side. We observed lower levels of BLL in areas distant to the mine and located at its eastern side. This pattern suggests a possible association between BLL and distance from the abandoned lead and zinc mine, and prevailing winds.ConclusionUsing geocoded data, we found clustering of childhood blood lead and identified distinct hot spot areas with particular high lead levels for Kabwe town. The geospatial approach used is especially valuable in resource-constrained settings like Zambia, where the precise identification of the locations of risk areas allows to initiate targeted remedial and treatment programs.
GlucoCEST MRI for the early evaluation response to chemotherapeutic and metabolic treatments in a murine triple negative breast cancer: a comparison with [18F]F-FDG-PET
Authors: Capozza Martina , Anemone Annasofia , Dhakan Chetan , Peruta Melania Della , Bracesco Martina , Zullino Sara , Villano Daisy , Terreno Enzo , Longo Dario Livio , Aime Silvio 
Published: March 2021

PurposeTriple-negative breast cancer (TNBC) patients have usually poor outcome after chemotherapy and early prediction of therapeutic response would be helpful. [18F]F-FDG-PET/CT acquisitions are often carried out to monitor variation in metabolic activity associated to response to the therapy, despite moderate accuracy and radiation exposure limit its application. The glucoCEST technique relies on the use of unlabelled D-glucose to assess glucose uptake with conventional MRI scanners and is currently under active investigations at clinical level. This work aims at validating the potential of MRI-glucoCEST in monitoring early therapeutic responses in a TNBC tumor murine model.ProceduresBreast tumor (4T1) bearing mice were treated with doxorubicin or dichloroacetate for one week. PET/CT with [18F]F-FDG and MRI-glucoCEST were performed at baseline and after 3 cycles of treatment. Metabolic changes measured with [18F]F-FDG-PET and glucoCEST were compared and evaluated with changes in tumor volumes.ResultsDoxorubicin treated mice showed a significant decrease in tumor growth when compared to the control group. GlucoCEST imaging provided early metabolic response after three cycles of treatment, conversely, no variations were detect by in [18F]F-FDG uptake. Dichloroacetate treated mice did not show any decrease either in tumor volume or in tumor metabolic activity as assessed by both glucoCEST and [18F]F-FDG-PET.ConclusionsEarly metabolic changes during doxorubicin treatment can be predicted by glucoCEST imaging that appears more sensitive than [18F]F-FDG-PET in reporting on early therapeutic response. These findings support the view that glucoCEST may be a sensitive technique for monitoring metabolic response, but future studies are needed to explore the accuracy of this approach in other tumor types and treatments.
Noncanonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α promotes cancer-cell survival
Authors: Le Thomas Adrien , Ferri Elena , Marsters Scot , Harnoss Jonathan M. , Modrusan Zora , Li Weihan , Rudolph Joachim , Wang Weiru , Wu Thomas D. , Walter Peter , Ashkenazi Avi 
Published: March 2021

ABSTRACTEukaryotic IRE1 mitigates endoplasmic-reticulum (ER) stress by orchestrating the unfolded-protein response (UPR). IRE1 spans the ER membrane, and signals through a cytosolic kinase-endoribonuclease module. The endoribonuclease generates the transcription factor XBP1s by intron excision between similar RNA stem-loop endomotifs, and depletes select cellular mRNAs through regulated IRE1-dependent decay (RIDD). Paradoxically, mammalian RIDD seemingly targets only mRNAs with XBP1-like endomotifs, while in flies RIDD exhibits little sequence restriction. By comparing nascent and total IRE1α-controlled mRNAs in human breast cancer cells, we discovered not only canonical endomotif-containing RIDD substrates, but also many targets lacking recognizable motifs—degraded by a process we coin RIDDLE, for RIDD lacking endomotif. IRE1α displayed two basic endoribonuclease modalities: endomotif-specific cleavage, minimally requiring dimers; and endomotif-independent promiscuous processing, requiring phospho-oligomers. An oligomer-deficient mutant that did not support RIDDLE failed to rescue cancer-cell viability. These results link IRE1α oligomers, RIDDLE, and cell survival, advancing mechanistic understanding of the UPR.
Single cell RNA sequencing of theStrongylocentrotus purpuratuslarva reveals the blueprint of major cell types and nervous system of a non-chordate deuterostome
Authors: Paganos Periklis , Voronov Danila , Musser Jacob , Arendt Detlev , Arnone Maria I. 
Published: March 2021

AbstractIdentifying the molecular fingerprint of organismal cell types is key for understanding their function and evolution. Here, we use single cell RNA sequencing (scRNA-seq) to survey the cell types of the sea urchin early pluteus larva, representing an important developmental transition from non-feeding to feeding larva. We identify 21 distinct cell clusters, representing cells of the digestive, skeletal, immune, and nervous systems. Further subclustering of these reveal a highly detailed portrait of cell diversity across the larva, including the identification of neuronal cell types. We then validate important gene regulatory networks driving sea urchin development and reveal new domains of activity within the larval body. Focusing on neurons that co-expressPdx-1andBrn1/2/4, we identify an unprecedented number of genes shared by this population of neurons in sea urchin and vertebrate endocrine pancreatic cells. Using differential expression results from Pdx-1 knockdown experiments, we show that Pdx1 is necessary for the acquisition of the neuronal identity of these cells. We hypothesize that a network similar to the one orchestrated by Pdx1 in the sea urchin neurons was active in an ancestral cell type and then inherited by neuronal and pancreatic developmental lineages in sea urchins and vertebrates.
Establishment of Developmental Gene Silencing by Ordered Polycomb Complex Recruitment in Early Zebrafish Embryos
Authors: Hickey Graham J.M. , Wike Candice , Nie Xichen , Guo Yixuan , Tan Mengyao , Murphy Patrick , Cairns Bradley R. 
Published: March 2021

AbstractVertebrate embryos achieve developmental competency during zygotic genome activation (ZGA) by establishing chromatin states that silence yet poise developmental genes for subsequent lineage-specific activation. Here, we reveal how developmental gene poising is establishedde novoin preZGA zebrafish embryos. Poising is established at promoters and enhancers that initially contain open/permissive chromatin with ‘Placeholder’ nucleosomes (bearing H2A.Z, H3K4me1, and H3K27ac), and DNA hypomethylation. Silencing is initiated by the recruitment of Polycomb Repressive Complex 1 (PRC1), and H2Aub1 deposition by catalytic Rnf2 during preZGA and ZGA stages. During postZGA, H2Aub1 enables Aebp2-containing PRC2 recruitment and H3K27me3 deposition. Notably, preventing H2Aub1 (via Rnf2 inhibition) eliminates recruitment of Aebp2-PRC2 and H3K27me3, and elicits transcriptional upregulation of certain developmental genes during ZGA. However, upregulation is independent of H3K27me3 – establishing H2Aub1 as the critical silencing modification at ZGA. Taken together, we reveal the logic and mechanism for establishing poised/silent developmental genes in early vertebrate embryos.Impact StatementDe novopolycomb domains are formed in zebrafish early embryos by focal histone H2Aub1 deposition by Rnf2-PRC1 – which imposes transcription silencing – followed by subsequent recruitment of Aebp2-PRC2 and H3K27me3 deposition.
BCL-XL blockage in TNBC models confers vulnerability to inhibition of specific cell cycle regulators
Authors: Castellanet Olivier , Ahmad Fahmida , Vinik Yaron , Mills Gordon B. , Habermann Bianca , Borg Jean-Paul , Lev Sima , Lamballe Fabienne , Maina Flavio 
Published: March 2021

AbstractCell cycle regulators are frequently altered in Triple-Negative Breast Cancer (TNBC). Emerging agents targeting these signals offer the possibility to design new combinatorial therapies. However, preclinical models that recapitulate TNBC primary resistance and heterogeneity are essential to evaluate the potency of these combined treatments.MethodsBioinformatic processing of human breast cancer datasets was used to analyse correlations between expression levels of cell cycle regulators and patient survival outcome. TheMMTV-R26Metmouse model of TNBC resistance and heterogeneity was employed to analyse expression and targeting vulnerability of cell cycle regulators in the presence of BCL-XL blockage. Robustness of outcomes and selectivity was further explored using a panel of human breast cancer cells. Alterations of protein expression, phosphorylation, and/or cellular localisation were analysed by western blots, reverse phase protein array, and immunocytochemistry. Bioinformatics was performed to highlight drug’s mechanisms of action.ResultsWe report that high expression levels of BCL-XL and specific cell cycle regulators correlate with poor survival outcomes of TNBC patients. Blockage of BCL-XL confers vulnerability to drugs targeting CDK1/2/4, but not FOXM1, CDK4/6, Aurora A and Aurora B, to allMMTV-R26Metand human TNBC cell lines tested. Mechanistically, we show that, co-targeting of BCL-XL and CDK1/2/4 synergistically inhibited cell growth by combinatorial depletion of survival and RTK/AKT signals, and concomitantly restoring FOXO3a tumour suppression actions. This was accompanied by an accumulation of DNA damage and consequently apoptosis.ConclusionsOur studies illustrate the possibility to exploit the vulnerability of TNBC cells to CDK1/2/4 inhibition by targeting BCL-XL. Moreover, they underline that specificity matters in targeting cell cycle regulators for combinatorial anticancer therapies.
The neural mechanisms of active removal from working memory
Authors: Shan Jiangang , Postle Bradley R. 
Published: March 2021

AbstractThe ability to frequently update the contents working memory (WM) is vital for the flexible control of behavior. Whether there even exists a mechanism for the active removal of information from working memory, however, remains poorly understood. In this Registered Report we will test the predictions of models for two different (and not mutually exclusive) mechanisms of active removal: adaptation-hijacking and mental-context shifting. We will collect functional magnetic resonance imaging (fMRI) data while subjects perform a novel “ABC-retrocuing” task designed to elicit two modes of removal, active or passive (Shan & Postle, Registered Report). The adaptation-hijacking model posits an adaptation-like modification of perceptual circuits combined with a weak activation of the to-be-removed item. Its predictions will be assessed by using multivariate inverted encoding modeling (IEM) and photic “pings” to assay the state of feature-selective encoding channels and of activity-silent representations under active-removal versus passive-removal conditions. A second model – “working memory episodic memory” (WMEM) – posits that interference from no-longer-relevant information is minimized by making the mental context associated with new information dissimilar from that associated with the to-be-“removed” information. This will be tested by using representational similarity analysis (RSA) to compare the rate of contextual drift under active-removal versus passive-removal conditions.
Birdsong Phrase Verification and Classification Using Siamese Neural Networks
Authors: Rentería Santiago , Vallejo Edgar E. , Taylor Charles E. 
Published: March 2021

AbstractThe process of learning good features to discriminate among numerous and different bird phrases is computationally expensive. Moreover, it might be impossible to achieve acceptable performance in cases where training data is scarce and classes are unbalanced. To address this issue, we propose a few-shot learning task in which an algorithm must make predictions given only a few instances of each class. We compared the performance of different Siamese Neural Networks at metric learning over the set of Cassini’s Vireo syllables. Then, the network features were reused for the few-shot classification task. With this approach we overcame the limitations of data scarcity and class imbalance while achieving state-of-the-art performance.
AC2P20 selectively killsM. tuberculosisat acidic pH by depleting free thiols
Authors: Dechow Shelby J. , Coulson Garry B. , Wilson Michael W. , Larsen Scott D. , Abramovitch Robert B. 
Published: March 2021

AbstractMycobacterium tuberculosis(Mtb) senses and adapts to host immune cues as part of its pathogenesis. One environmental cue sensed by Mtb is the acidic pH of its host niche in the macrophage phagosome. Disrupting the ability of Mtb to sense and adapt to acidic pH has the potential to reduce survival of Mtb in macrophages. Previously, a high throughput screen of a ∼220,000 compound small molecule library was conducted to discover chemical probes that inhibit Mtb growth at acidic pH. The screen discovered chemical probes that kill Mtb at pH 5.7 but are inactive at pH 7.0. In this study, AC2P20 was prioritized for continued study to test the hypothesis that it was targeting Mtb pathways associated with pH-driven adaptation. RNAseq transcriptional profiling studies showed AC2P20 modulates expression of genes associated with redox homeostasis. Gene enrichment analysis revealed that the AC2P20 transcriptional profile had significant overlap with a previously characterized pH-selective inhibitor, AC2P36. Like AC2P36, we show that AC2P20 kills Mtb by selectively depleting free thiols at acidic pH. Mass spectrometry studies show the formation of a disulfide bond between AC2P20 and reduced glutathione, supporting a mechanism where AC2P20 is able to deplete intracellular thiols and dysregulate redox homeostasis. The observation of two independent molecules targeting free thiols to kill Mtb at acidic pH further supports that Mtb has restricted redox homeostasis and sensitivity to thiol-oxidative stress at acidic pH.
Cellular pathways during spawning induction in the starlet sea anemoneNematostella vectensis
Authors: Reuven Shelly , Rinsky Mieka , Brekhman Vera , Malik Assaf , Levy Oren , Lotan Tamar 
Published: March 2021

AbstractIn cnidarians, long-term ecological success relies on sexual reproduction. The sea anemoneNematostella vectensis, which has emerged as an important model organism for developmental studies, can be induced for spawning by temperature elevation and light exposure. To uncover molecular mechanisms and pathways underlying spawning, we characterized the transcriptome ofNematostellafemales before and during spawning induction. We identified an array of processes involving numerous receptors, circadian clock components, cytoskeleton, and extracellular transcripts that are upregulated upon spawning induction. Concurrently, processes related to the cell cycle, fatty acid metabolism, and other housekeeping functions are downregulated. Real-time qPCR revealed that light exposure has a minor effect on expression levels of most examined transcripts, implying that temperature change is a stronger inducer for spawning inNematostella. Our findings reveal the mechanisms that may enable the mesenteries to serve as a gonad-like tissue for the developing oocytes and expand our understanding of sexual reproduction in cnidarians.Summary statementAnalysis of transcriptional changes during spawning induction inNematostella vectensis, revealed upregulation of processes related to signal perception and cytoskeleton rearrangement and downregulation of fatty acid metabolism and housekeeping processes.
MDGAs are fast-diffusing molecules that delay excitatory synapse development by altering neuroligin behavior
Authors: Toledo Andrea , Bimbi Giorgia , Letellier Mathieu , Tessier Béatrice , Daburon Sophie , Favereaux Alexandre , Chamma Ingrid , Vennekens Kristel M. , Vanderlinden Jeroen , Sainlos Matthieu , de Wit Joris , Choquet Daniel , Thoumine Olivier 
Published: March 2021

AbstractMDGAs are molecules that can bind neuroliginsin cisand interfere with trans-synaptic neurexin-neuroligin interactions, thereby impairing synapse development. However, the sub-cellular localization and dynamics of MDGAs, as well as their specific mode of action in neurons are still unclear. Here, using both surface immunostaining of endogenous MDGAs and single molecule tracking of recombinant MDGAs in dissociated hippocampal neurons, we show that MDGA1 and MDGA2 molecules are homogeneously distributed and exhibit fast membrane diffusion, with a small reduction in mobility across neuronal maturation in culture Using shRNAs and CRISPR/Cas9 strategies to knock-down/out MDGA1 or MDGA2, we demonstrate an increase in the density of excitatory synapses accompanied by enhanced membrane immobilization and an increase in the phosphotyrosine level of neuroligins associated with excitatory post-synaptic differentiation. Finally, we show that decreasing MDGA expression level reduces the mobility of AMPA receptors and increases the frequency of AMPA receptor mediated mEPSCs. Overall, our results support a mechanism by which interactions between MDGAs and neuroligin-1 delays the assembly of functional excitatory synapses containing AMPA receptors.
FastTomo: A SerialEM Script for Collecting Electron Tomography Data
Authors: Xu Albert , Xu Chen 
Published: March 2021

AbstractFastTomo is a SerialEM script for collecting tilted specimen images in transmission electron microscopes to be further used in tomographic reconstruction. It achieves a speedup over conventional tracking methods by minimizing the usage of off-target tracking shots, and instead applies proportional control to the specimen images. Movement in the Z coordinate is estimated prior to each tilt series in a separate calibration routine. Overall, this method is fast and reliable when the field of view is at least 1 um, and can tolerate minor errors in setting eucentric height. The implemented tilt series schemes include the unidirectional, bidirectional, and dose-symmetric schemes.
Rat ultrasonic vocalizations and novelty-induced social and non-social investigation behavior in a seminatural environment
Authors: Heinla Indrek , Chu Xi , Ågmo Anders , Snoeren Eelke 
Published: March 2021

AbstractAlthough rats are known to emit ultrasonic vocalizations (USVs), it remains unclear whether these calls serve an auditory communication purpose. For USVs to be part of communication, the vocal signals will need to be a transfer of information between two or more conspecifics, and with the possibility to induce changes in the behavior of the recipient. Therefore, the aim of our study was to investigate the role of USVs in adult rats’ social and non-social investigation strategies when introduced into a large novel environment with unfamiliar conspecifics. We quantified a wide range of social and non-social behaviors in the seminatural environment, which could be affected by subtle signals, including USVs. We found that during the first hour in the seminatural environment the ability to vocalize did not affect how quickly adult rats met each other, their overall social investigation behavior, their passive social behavior nor their aggressive behavior. Furthermore, the non-social exploratory behaviors and behaviors reflecting anxiety/stress-like states were also unaffected. These results demonstrated that a disability to vocalize did not result in significant disadvantages (or changes) compared to intact conspecifics regarding social and non-social behaviors. This suggests that other (multi)sensory cues are more relevant in social interactions than USVs.
Towards the NMR solution Structure and the Dynamics of the C-terminal Region of APOL1 and its G1, G2 Variants with a Membrane Mimetic
Authors: Madhavan Sethu M. , Hansen Alexandar L. , Cao Shufen , Sedor John R. , Buck Matthias 
Published: March 2021

ABSTRACTSecreted apolipoprotein L1 (APOL1) is well known as an innate immune factor, protecting against African trypanosomiasis. The intracellular form has multiple functions, including regulating autophagy, intracellular vesicle trafficking, and ion channel activity. The APOL1 protein (G0) has two common variants (denoted G1 and G2) in the C-terminal region and are associated with a high risk of chronic kidney disease (CKD) and progression to end-stage kidney disease. Our previous studies using molecular modeling suggested that APOL1 G1 and G2 stabilize an autoinhibited state of the C-terminus, leading to impaired intracellular interactions with SNARE proteins. To characterize the structural consequence of kidney disease-associated APOL1 variants further, we assigned the C-terminal region proteins using1H,13C,15N multidimensional nuclear magnetic resonance (NMR) spectra in solution in the presence of membrane mimetic dodecylphosphocholine micelles. We then derived models for the three-dimensional structure of APOL1-G0, and -G1 and -G2 variant C-terminal regions using the chemical shifts of the main chain nuclei followed by NMR relaxation measurements. The data suggest that changes in the three-dimensional structure of APOL1 C-terminal region induced by kidney disease-associated variants, not least the alteration of key sidechains and their interactions, could disrupt membrane association and the yet to be characterized protein-protein interactions including its binding partners, such as SNARE proteins. Such interactions could underlie the intracellular mechanisms that mediate the pathogenesis of CKD. In the future, one may try to reverse such structural and dynamics changes in the protein by designing agents that may bind and then mitigate APOL1 variant-associated CKD.