bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neurexins Regulate GABA Co-release by Dopamine Neurons
Authors: Ducrot Charles , de Carvalho Gregory , Delignat-Lavaud Benoît , Delmas Constantin V.L. , Giguère Nicolas , Mukherjee Sriparna , Burke-Nanni Samuel , Bourque Marie-Josée , Parent Martin , Chen Lulu Y. , Trudeau Louis-Éric 
Published: October 2021

SummaryMidbrain dopamine (DA) neurons are key regulators of basal ganglia functions. The axonal domain of these neurons is highly complex, with a large subset of non-synaptic release sites and a smaller subset of synaptic terminals from which glutamate or GABA are released. The molecular mechanisms regulating the connectivity of DA neurons and their neurochemical identity are unknown. Here we tested the hypothesis that the trans-synaptic cell adhesion molecules neurexins (Nrxns) regulate DA neuron neurotransmission. Conditional deletion of all Nrxns in DA neurons (DAT::Nrxns KO) showed that loss of Nrxns does not impair the basic development and ultrastructural characteristics of DA neuron terminals. However, loss of Nrxns caused an impairment of DA transmission revealed as a reduced rate of DA reuptake following activity-dependent DA release, decreased DA transporter levels, increased vesicular monoamine transporter expression, and impaired amphetamine-induced locomotor activity. Strikingly, electrophysiological recording revealed an increase of GABA co-release from DA neuron axons in the striatum of the KO mice. These findings suggest that Nrxns act as key regulators of DA neuron connectivity and DA-mediated functions.HighlightsThe study provides the first direct evidence of the role of neurexins in dopaminergic neurons.The synaptic adhesion molecules, neurexins, are not required for maintaining the structure of dopamine neuron terminals.Neurexins regulate dopaminergic neurotransmission through regulation of dopamine reuptake, impacting amphetamine-induced locomotion.Deletion of Nrxns in DA neurons causes a region-specific increase of GABA release by DA neurons.
Transcriptional Regulation of Synthetic Polymer Networks
Authors: Graham Austin J. , Dundas Christopher M. , Partipilo Gina , Miniel Mahfoud Ismar E. , FitzSimons Thomas , Rinehart Rebecca , Chiu Darian , Tyndall Avery E. , Rosales Adrianne M. , Keitz Benjamin K. 
Published: October 2021

AbstractIndividual cells direct non-equilibrium processes through coordinated signal transduction and gene expression, allowing for dynamic control over multicellular, system-wide behavior. This behavior extends to remodeling the extracellular polymer matrix that encases biofilms and tissues, where constituent cells dictate spatiotemporal network properties including stiffness, pattern formation, and transport properties. The majority of synthetic polymer networks cannot recreate these phenomena due to their lack of autonomous centralized actuators (i.e., cells). In addition, non-living polymer networks that perform computation are generally restricted to a few inputs (e.g., light, pH, enzymes), limiting the logical complexity available to a single network chemistry. Toward synergizing the advantages of living and synthetic systems, engineered living materials leverage genetic and metabolic programming to establish control over material-wide properties. Here we demonstrate that a bacterial metal respiration mechanism, extracellular electron transfer (EET), can control metal-catalyzed radical cross-linking of polymer networks. Linking metabolic electron flux to a synthetic redox catalyst allows dynamic, tunable, and predictable control over material formation and bulk polymer network mechanics using genetic circuits. By programming key EET genes with transcriptional Boolean logic, we rationally design computational networks that sense-and-respond to multiple inputs in biological contexts. Finally, we capitalize on the wide reactivity of EET and redox catalyses to predictably control another class of living synthetic materials using copper(I) alkyne-azide cycloaddition click chemistry. Our results demonstrate the utility of EET as a bridge for controlling abiotic materials and how the design rules of synthetic biology can be applied to emulate physiological behavior in polymer networks.
In situ architecture of the ciliary base reveals the stepwise assembly of IFT trains
Authors: van den Hoek Hugo , Klena Nikolai , Jordan Mareike A. , Viar Gonzalo Alvarez , Schaffer Miroslava , Erdmann Philipp S. , Wan William , Plitzko Jürgen M. , Baumeister Wolfgang , Pigino Gaia , Hamel Virginie , Guichard Paul , Engel Benjamin D. 
Published: October 2021

AbstractThe cilium is an antenna-like organelle that performs numerous cellular functions, including motility, sensing, and signaling. The base of the cilium contains a selective barrier that regulates the entry of large intraflagellar transport (IFT) trains, which carry cargo proteins required for ciliary assembly and maintenance. However, the native architecture of the ciliary base and the process of IFT train assembly remain unresolved. Here, we use in situ cryo-electron tomography to reveal native structures of the transition zone region and assembling IFT trains at the ciliary base. We combine this direct cellular visualization with ultrastructure expansion microscopy to describe the front-to-back stepwise assembly of IFT trains: IFT-B forms the backbone, onto which IFT-A, then dynein-1b, and finally kinesin-2 sequentially bind before entry into the cilium.One Sentence SummaryNative molecular structure of the ciliary transition zone and hierarchical order of IFT assembly visualized within Chlamydomonas cells.
An optimized live bacterial delivery platform for the production and delivery of therapeutic nucleic acids and proteins
Authors: Mora Darcy S.O. , Cox Madeline , Magunda Forgivemore , Williams Ashley B. , Linke Lyndsey 
Published: October 2021

AbstractThere is an unmet need for delivery platforms that realize the full potential of next-generation therapeutic and vaccine technologies, especially those that require intracellular delivery of nucleic acids. The in vivo usefulness of the current state-of-the-art delivery systems is limited by numerous intrinsic weaknesses, including lack of targeting specificity, inefficient entry and endosomal escape into target cells, undesirable immune activation, off-target effects, a small therapeutic window, limited genetic encoding and cargo capacity, and manufacturing challenges. Here we present our characterization of a delivery platform based on the use of engineered live, tissue-targeting, non-pathogenic bacteria (Escherichia coli strain SVC1) for intracellular cargo delivery. The SVC1 bacteria are engineered to specifically bind to epithelial cells via a surface-expressed targeting ligand, to escape the endosome upon intracellularization, and to have minimal immunogenicity. Here we report findings on key features of this system. First, we demonstrated that bacterial delivery of a short hairpin RNA (shRNA) can target and silence a gene in an in vitro mammalian respiratory cell model. Next, we used an in vivo mouse model to demonstrate that SVC1 bacteria are invasive to epithelial cells of various tissues and organs (eye, nose, mouth, stomach, vagina, skeletal muscle, and lungs) via local administration. We also showed that repeat dosing of SVC1 bacteria to the lungs is minimally immunogenic and that it does not have adverse effects on tissue homeostasis. Finally, to validate the potential of SVC1 bacteria in therapeutic applications, we demonstrated that bacterial delivery of influenza-targeting shRNAs to the respiratory tissues can mitigate viral replication in a mouse model of influenza infection. Our ongoing work is focused on further refining this platform for efficient delivery of nucleic acids, gene editing machinery, and therapeutic proteins, and we expect that this platform technology will enable a wide range of advanced therapeutic approaches.
Structure of the human ATM kinase and mechanism of Nbs1 binding
Authors: Warren C. , Pavletich N.P. 
Published: October 2021

AbstractDNA double-strand breaks (DSBs) can lead to mutations, chromosomal rearrangements, genome instability, and ultimately cancer. Central to the sensing of DSBs are ATM (Ataxia-telangiectasia mutated) kinase, which belongs to the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family, and the MRN (Mre11-Rad50-Nbs1) protein complex that activates ATM. How the MRN complex recruits and activates ATM kinase is poorly understood. Previous studies indicate that the FxF/Y motif of Nbs1 directly binds to ATM kinase and is required to retain active ATM at sites of DNA damage. Here, we report the 2.5 Å resolution cryo-EM structures of human ATM and its complex with the Nbs1 FxF/Y motif. In keeping with previous structures of ATM and its yeast homolog Tel1, the dimeric human ATM kinase adopts a symmetric, butterfly-shaped autoinhibited structure. The conformation of the ATM kinase domain is most similar to the inactive states of other PIKKs, suggesting that activation may involve an analogous realigning the N and C lobes along with relieving the blockage of the substrate-binding site. We show that the Nbs1 FxF/Y motif binds to a conserved hydrophobic cleft within the Spiral domain of ATM, suggesting an allosteric mechanism of activation. We evaluate the importance of these interactions with mutagenesis and biochemical assays.
Synaptotagmin-7 enhances phasic dopamine release
Authors: Kissiwaa Sarah A. , Lebowitz Joseph J. , Engeln Kim A. , Bowman Anna M. , Williams John T. , Jackman Skyler L. 
Published: October 2021

AbstractDopamine released from substantia nigra pars compacta (SNc) neurons modulates movement, motivation, and reward. In addition to their tonic firing pattern, dopamine neurons also fire high-frequency bursts that cause superlinear increases in dopamine release. To study this poorly understood form of short-term plasticity, we used the fluorescent dopamine sensor dLight1.3b to examine the role of the calcium-binding protein synaptotagmin-7 (SYT7). We report that SYT7 mediates a hidden component of facilitation, which was unmasked by lowering initial release probability, or by low-frequency stimulation of nerve terminals. InSyt7KO neurons, there was profound synaptic depression that significantly reduced release during stimulations that mimicin vivofiring patterns of SNc neurons. D2-mediated inhibitory postsynaptic currents in the SNc revealed a similar role for SYT7 in somatodendritic release. Our results indicate that SYT7 drives short-term facilitation of release from dopamine neurons, which likely underlies frequency-dependence of dopamine signalingin vivo.
Cell type matching in single-cell RNA-sequencing data using FR-Match
Authors: Zhang Yun , Aevermann Brian , Gala Rohan , Scheuermann Richard H. 
Published: October 2021

AbstractReference cell type atlases powered by single cell transcriptomic profiling technologies have become available to study cellular diversity at a granular level. We present FR-Match for matching query datasets to reference atlases with robust and accurate performance for identifying common and novel cell types and suboptimally clustered cell types in the query data. FR-Match shows excellent performance for cross-platform, cross-sample type, and cross-tissue region cell type matching.
Repression of MAPK/Erk signaling by Efnb2-Ephb4-Rasa1 is required for lymphatic valve formation
Authors: Meng Yaping , Lv Tong , Zhang Junfeng , Meng Anming , Jia Shunji 
Published: October 2021

AbstractThe lymphatic vascular system plays important roles in various physiological and pathological processes, and lack of lymphatic or lymphovenous valves always causes lymph or blood reflux, and can lead to lymphedema. However, the molecular mechanism underlying the valve formation is poorly understood. Here we report that the MAPK/Erk signaling needs to be repressed during the valve-forming lymphatic endothelial cells (LECs) fate determination, which differs from its positive role in the LECs specification. Up-regulation of MAPK/Erk signaling in ephb4b, efnb2a;efnb2b and rasa1a;rasa1b mutants leads to lymphatic valve defects, whereas simultaneous loss of Erk1 and Erk2 causes valve hyperplasia. Moreover, valve defects in ephb4b or rasa1a;rasa1b mutants are mitigated in the presence of MEK inhibitors, indicating a new function of Efnb2-Ephb4-Rasa1 cassette in lymphatic valve progenitor cells specification by repressing MAPK/Erk activity. Therefore, our findings provide a mechanistic understanding of the lymphatic valve formation and potential drug targets for related lymphatic diseases.
T7Max transcription system
Authors: Deich Christopher , Cash Brock , Sato Wakana , Sharon Judee , Aufdembrink Lauren , Gaut Nathaniel J. , Heili Joseph , Stokes Kaitlin , Engelhart Aaron E , Adamala Katarzyna P 
Published: October 2021

AbstractEfficient cell-free protein expression from linear DNA templates has remained a challenge primarily due to template degradation. Here we present a modified T7 RNA polymerase promoter that acts to significantly increase the yields of both transcription and translation withinin vitrosystems. The modified promoter, termed T7Max, recruits standard T7 RNA polymerase, so no protein engineering is needed to take advantage of this method. This technique could be used with any T7 RNA polymerase-basedin vitroprotein expression system. Unlike other methods of limiting linear template degradation, the T7Max promoter increases transcript concentration in a T7 transcription reaction, providing more mRNA for translation.
Causes and consequences of unauthorized use of books: readers, authors, and publishers' perspective
Authors: Gudinavičius Arūnas , Grigas Vincas 
Published: October 2021

PurposeThe current study aims to identify and explore causes and consequences of unauthorized use of books from readers', publishers', and authors' points of view. The case of Lithuania also assessed, especially historical background (banned alphabet, book smuggling, theft as the social norm in Soviet times) of the country.Design/methodology/approachAiming for more understanding why readers, authors and publishers are using or not using technology for unauthorized access of books, technology acceptance model approach was used, a total of 30 respondents (publishers, authors and readers) were interviewed in semi-structured face-to-face interviews and thematic analysis of collected qualitative data was conducted. Interviews were coded in English with coding software for further analysis.FindingsFindings indicate that the main cause for the unauthorized use of books is a lack of legal e-book titles and acquisition options. This mainly points at publishers, however, instead of using unauthorized sources as opportunities for author promotion or marketing, they rather concentrate on the causes of unauthorized use of books which they are not in control of, including access to unauthorized sources, habits and economic causes. Some publishers believe that the lack of legal e-book titles is the consequence of unauthorized use of book rather than its cause.Originality/valueThis research contributed to the body of knowledge by investigating unauthorized use of books from readers', publishers' and authors' points of view which renders to have a better understanding of the causes and consequences of such behavior, as well as differences between these roles. The authors suggest that these causes lead to the intention to use and actual use of technology which is easier to use and which gives more perceived advantages – technology for unauthorized downloading and reading of books vs legal e-book acquisition options.Peer reviewThe peer review history for this article is available at:https://publons.com/publon/10.1108/OIR-03-2021-0133.
Biome Awareness Disparity is BAD for tropical ecosystem conservation and restoration
Authors: Silveira Fernando A. O. , Ordóñez‐Parra Carlos A. , Moura Livia C. , Schmidt Isabel B. , Andersen Alan N. , Bond William , Buisson Elise , Durigan Giselda , Fidelis Alessandra , Oliveira Rafael S. , Parr Catherine , Rowland Lucy , Veldman Joseph W. , Pennington R. Toby 
Published: October 2021

Abstract

We introduce the concept of Biome Awareness Disparity (BAD)—defined as a failure to appreciate the significance of all biomes in conservation and restoration policy—and quantify disparities in (a) attention and interest, (b) action and (c) knowledge among biomes in tropical restoration science, practice and policy.

By analysing 50,000 tweets from all Partner Institutions of the UN Decade of Ecosystem Restoration, and 45,000 tweets from the main science and environmental news media world‐wide, we found strong disparities in attention and interest relative to biome extent and diversity. Tweets largely focused on forests, whereas open biomes (such as grasslands, savannas and shrublands) received less attention in relation to their area. In contrast to these differences in attention, there were equivalent likes and retweets between forest versus open biomes, suggesting the disparities may not reflect the views of the general public.

Through a literature review, we found that restoration experiments are disproportionately concentrated in rainforests, dry forests and mangroves. More than half of the studies conducted in open biomes reported tree planting as the main restoration action, suggesting inappropriate application of forest‐oriented techniques.

Policy implications. We urge scientists, policymakers and land managers to recognise the value of open biomes for protecting biodiversity, securing ecosystem services, mitigating climate change and enhancing human livelihoods. Fixing Biome Awareness Disparity will increase the likelihood of the United Nations Decade on Ecosystem Restoration successfully delivering its promises.
Receptor binding domain‐IgG levels correlate with protection in residents facing SARS‐CoV‐2 B.1.1.7 outbreaks
Authors: Blain Hubert , Tuaillon Edouard , Gamon Lucie , Pisoni Amandine , Miot Stéphanie , Delpui Valentin , Si‐Mohamed Nejm , Niel Clémence , Rolland Yves , Montes Brigitte , Groc Soraya , Rafasse Sophia , Dupuy Anne‐Marie , Gros Nathalie , Muriaux Delphine , Picot Marie‐Christine , Bousquet Jean 
Published: October 2021

AbstractBackgroundLimited information exists on nursing home (NH) residents regarding BNT162b2 vaccine efficacy in preventing SARS‐CoV‐2 and severe COVID‐19, and its association with post‐vaccine humoral response.Methods396 residents from seven NHs suffering a SARS‐CoV‐2 B.1.1.7 (VOC‐α) outbreak at least 14 days after a vaccine campaign were repeatedly tested using SARS‐CoV‐2 real‐time reverse‐transcriptase polymerase chain reaction on nasopharyngeal swab test (RT‐qPCR). SARS‐CoV‐2 receptor‐binding domain (RBD) of the S1 subunit (RBD‐IgG) was measured in all residents. Nucleocapsid antigenemia (N‐Ag) was measured in RT‐qPCR‐positive residents and serum neutralizing antibodies in vaccinated residents from one NH.ResultsThe incidence of positive RT‐qPCR was lower in residents vaccinated by two doses (72/317; 22.7%) vs one dose (10/31; 32.3%) or non‐vaccinated residents (21/48; 43.7%; p < .01). COVID‐19–induced deaths were observed in 5 of the 48 non‐vaccinated residents (10.4%), in 2 of the 31 who had received one dose (6.4%), and in 3 of the 317 (0.9%) who had received two doses (p = .0007). Severe symptoms were more common in infected non‐vaccinated residents (10/21; 47.6%) than in infected vaccinated residents (15/72; 21.0%; p = .002). Higher levels of RBD‐IgG (n = 325) were associated with a lower SARS‐CoV‐2 incidence. No in vitro serum neutralization activity was found for RBD‐IgG levels below 1050 AU/ml. RBD‐IgG levels were inversely associated with N‐Ag levels, found as a risk factor of severe COVID‐19.ConclusionsTwo BNT162b2 doses are associated with a 48% reduction of SARS‐CoV‐2 incidence and a 91.3% reduction of death risk in residents from NHs facing a VOC‐α outbreak. Post‐vaccine RBD‐IgG levels correlate with BNT162b2 protection against SARS‐CoV‐2 B.1.1.7.
Autoimmune diseases in microscopic colitis: A Danish nationwide case–control study
Authors: Wildt Signe , Munck Lars Kristian , Winther‐Jensen Matilde , Jess Tine , Nyboe Andersen Nynne 
Published: October 2021

SummaryBackgroundThe association between autoimmune diseases and microscopic colitis remains uncertain.AimsTo describe the association between autoimmune diseases and microscopic colitis by using a matched case–control design based on nationwide registry data.MethodsAll adult Danish patients with a diagnosis of microscopic colitis from 2001 to 2018 were identified from nationwide registries. Odds of autoimmune diseases were compared between cases with microscopic colitis and sex‐ and age‐matched controls from the background population in a 1:10 ratio and evaluated by logistic regression calculating odds ratios (OR) with 95% confidence intervals (CI) adjusted for comorbidity. Analyses were stratified according to sex, age and the subtypes of lymphocytic and collagenous colitis.ResultsWe identified 15 597 cases with microscopic colitis and matched to 155 910 controls. In total, 3491 (22%) of patients with microscopic colitis had concomitant autoimmune disease compared to 16 521 (11%) of controls (OR, 2.46; 95% CI, 2.36‐2.56). Adjusting for comorbidities reduced the OR to 2.09 (95% CI, 2.01‐2.19). Analyses showed increased ORs with 16 different autoimmune diseases, particularly of gastrointestinal and endocrine origin, and connective tissue disorders. The highest ORs were for coeliac disease (OR = 10.15; 95% CI, 8.20‐12.6), Crohn’s disease (OR = 2.47; 95% CI, 2.10‐2.91) and ulcerative colitis (OR = 6.73; 95% CI, 6.20‐7.30). In stratified analyses younger age at diagnosis and collagenous colitis were associated with higher odds.ConclusionUsing nationwide registry data, microscopic colitis was associated with a wide range of autoimmune diseases, especially of gastrointestinal origin. The results suggest an autoimmune predisposition to microscopic colitis.
Trends in statin utilisation in US adults with non‐alcoholic fatty liver disease
Authors: Henson Jacqueline B. , Patel Yuval A. , Muir Andrew J. 
Published: October 2021

SummaryBackgroundNon‐alcoholic fatty liver disease (NAFLD) has high morbidity and mortality related to cardiovascular disease (CVD), but statins have been historically underutilised in these patients due to concern for hepatotoxicity.AimsTo characterise trends in statin use among individuals with NAFLD and to determine predictors of statin utilisation in this population.MethodsIndividuals with NAFLD were identified from 2005 to 2018 continuous National Health and Nutrition Examination Survey. Trends in statin use over time were assessed, and predictors of statin under‐utilisation for primary prevention were identified. The roles of a known diagnosis of liver disease and disease severity were examined.ResultsWe included 14 113 individuals; 34.6% had NAFLD, of whom 5.4% reported a liver disease diagnosis. There was a significant increase in statin use for primary prevention between 2005 and 2018 (18.1%‐25.0%; P = 0.03), but guideline‐indicated use for this purpose was low (54.5% between 2005 and 2012; 48.6% between 2013 and 2018). A known NAFLD diagnosis was a negative predictor of statin use during the earlier time period but not more recently. Utilisation did not decrease with increasing liver disease severity.ConclusionsIn a nationally representative population with NAFLD, statin use for primary prevention has increased over time, but guideline‐concordant use remains low. A known liver disease diagnosis was associated with lack of statin use in the earlier time period but not more recently, suggesting a changing perspective of underlying liver disease impacting statin utilisation. Further work to improve guideline‐indicated statin use in this high‐risk population is needed.