bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and gut dysbiosis of gentamicin-intercalated smectite as a new therapeutic agent againstHelicobacter pyloriin a mouse model
Authors: Jeong Su Jin , Lee Kyoung Hwa , Kim Jie-Hyun , Park Soon Young , Song Young Goo 
Published: July 2020

AbstractBackgroundHelicobacter pylorieradication rate with conventional standard therapy is decreasing owing to antibiotic resistance, necessitating novel antibacterial strategies againstH. pylori. We evaluated the efficacy of a gentamicin-intercalated smectite hybrid (S-GM)-based treatment, and analyzed fecal microbiome composition inH. pylori-infected mice.MethodologyTo evaluate anti-H. pyloriefficacy, mice were divided into eight groups, andH. pylorieradication was assessed byCampylobacter-like organism (CLO) test and PCR assay ofH. pyloriin gastric mucosa. One week afterH. pylorieradication, proinflammatory cytokine levels and atrophic changes in gastric mucosa were examined. Stool specimens were collected and analyzed for microbiome changes. The S-GM-based triple regimen decreased bacterial burdenin vivo, compared with that in untreated mice or mice treated with other regimens. The therapeutic reactions in the CLO test from gastric mucosa were both 90% in standard triple therapy and S-GM therapy group, respectively. Those ofH. pyloriPCR in mouse gastric mucosa were significantly lower in standard triple therapy and S-GM therapy groups than in non-treatment group. Toxicity test results showed that S-GM therapy reduced IL-8 level and atrophic changes in gastric mucosa. Stool microbiome analysis revealed that compared with mice treated with the standard triple therapy, mice treated with the S-GM therapy showed microbiome diversity and abundant microorganisms at the phylum level.ConclusionOur results suggested that S-GM is a promising and effective therapeutic agent againstH. pyloriinfection.Author summaryThe eradication rate onHelicobacter pylori(H. pylori) showed decreasing trend due to antibiotic resistance, especially clarithromycin. Therefore, we made a smectite hybrid as a drug delivery system using aminoglycosides antibiotic-gentamicin, and applied it to the mouse stomach wall to confirm the localized therapeutic effect, and set the different treatment duration to verify the effect. As a result, it was confirmed that the therapeutic efficacy of gentamicin (GM)-intercalated smectite hybrid (S-GM) was not inferior to the existing standard triple therapy, based on amoxicillin and clarithromycin, and preserved the diversity of gut microbiome composition. Therefore, a S-GM treatment is expected to be a new alternative regimen toH. pyloriinfection.
The glycosyltransferase UGT76B1 is critical for plant immunity as it governs the homeostasis ofN-hydroxy-pipecolic acid
Authors: Mohnike Lennart , Rekhter Dmitrij , Huang Weijie , Feussner Kirstin , Tian Hainan , Herrfurth Cornelia , Zhang Yuelin , Feussner Ivo 
Published: July 2020

AbstractThe trade-off between growth and defense is a critical aspect of plant immunity. Therefore, plant immune response needs to be tightly regulated. The hormone regulating plant defense against biotrophic pathogens is salicylic acid (SA). Recently,N-hydroxy-pipecolic acid (NHP) was identified as second regulator for plant innate immunity and systemic acquired resistance. Although the biosynthetic pathway leading to NHP formation has already been identified, the route how NHP is further metabolized was unclear. Here, we present UGT76B1 as a UDP-dependent glycosyltransferase that modifies NHP by catalyzing the formation of 1-O-glucosyl-pipecolic acid (NHP-OGlc). Analysis of T-DNA and CRISPR knock-out mutant lines ofUGT76B1by targeted and non-targeted UHPLC-HRMS underlined NHP and SA as endogenous substrates of this enzyme in response toPseudomonasinfection and UV treatment. UGT76B1 shows similar KMfor NHP and SA.ugt76b1mutant plants have a dwarf phenotype and a constitutive defense response which can be suppressed by loss of function of the NHP biosynthetic enzyme FMO1. This suggests that elevated accumulation of NHP contributes to the enhanced disease resistance inugt76b1. Externally applied NHP can move to distal tissue inugt76b1mutant plants. Although glycosylation is not required for the long distance movement of NHP during systemic acquired resistance, it is crucial to balance growth and defense.
Phosphosite T674A mutation in kinesin family member 3A fails to reproduce tissue and ciliary defects characteristic of CILK1 loss of function
Authors: Gailey Casey D. , Wang Eric J. , Jin Li , Ahmadi Sean , Brautigan David L. , Li Xudong , Xu Wenhao , Fu Zheng 
Published: July 2020

AbstractBackgroundKinesin family member 3A (KIF3A) is a molecular motor protein in the heterotrimeric kinesin-2 complex that drives anterograde intraflagellar transport. This process plays a pivotal role in both biogenesis and maintenance of the primary cilium that supports tissue development. Ciliogenesis associated kinase 1 (CILK1) phosphorylates human KIF3A at Thr672. CILK1 loss of function causes ciliopathies that manifest profound and multiplex developmental defects, including polydactyly, shortened and hypoplastic bones and alveoli airspace deficiency, leading to perinatal lethality. Prior studies have raised the hypothesis that CILK1 phosphorylation of KIF3A is critical for its regulation of organ development.ResultsWe produced a mouse model with phosphorylation site Thr674 in mouseKif3amutated to Ala.Kif3aT674A homozygotes are viable and exhibit no skeletal abnormalities, and only mildly reduced airspace in alveoli. Mouse embryonic fibroblasts carryingKif3aT674A mutation show a normal rate of ciliation and a moderate increase in cilia length.ConclusionThese results indicate that eliminating Kif3a Thr674 phosphorylation by CILK1 is insufficient to reproduce the severe developmental defects in ciliopathies caused by Cilk1 loss of function. This suggests KIF3A phosphorylation by CILK1 is not essential for tissue development and other substrates are involved in Cilk1 ciliopathies.
Mapping cellular nanoscale viscoelasticity and relaxation times relevant to growth of living Arabidopsis thaliana plants using multifrequency AFM
Authors: Seifert Jacob , Kirchhelle Charlotte , Moore Ian , Contera Sonia 
Published: July 2020

AbstractThe shapes of living organisms are formed and maintained by precise control in time and space of growth, which is achieved by dynamically fine-tuning the mechanical (viscous and elastic) properties of their hierarchically built structures from the nanometer up. Most organisms on Earth including plants grow by yield (under pressure) of cell walls (bio-polymeric matrices equivalent to extracellular matrix in animal tissues) whose underlying nanoscale viscoelastic properties remain unknown. Multifrequency atomic force microscopy (AFM) techniques exist that are able to map properties to a small subgroup of linear viscoelastic materials (those obeying the Kelvin-Voigt model), but are not applicable to growing materials, and hence are of limited interest to most biological situations. Here, we extend existing dynamic AFM methods to image linear viscoelastic behavior in general, and relaxation times of cells of multicellular organisms in vivo with nanoscale resolution, featuring a simple method to test the validity of the mechanical model used to interpret the data. We use this technique to image cells at the surface of livingArabidopsis thalianahypocotyls to obtain topographical maps of storage E’ = 120 − 200 MPa and loss E’’= 46 − 111 MPa moduli as well as relaxation times τ = 2.2 − 2.7 µs of their cell walls. Our results demonstrate that cell walls, despite their complex molecular composition, display a striking continuity of simple, linear, viscoelastic behavior across scales–following almost perfectly the standard linear solid model–with characteristic nanometer scale patterns of relaxation times, elasticity and viscosity, whose values correlate linearly with the speed of macroscopic growth. We show that the time-scales probed by dynamic AFM experiments (milliseconds) are key to understand macroscopic scale dynamics (e.g. growth) as predicted by physics of polymer dynamics.
USP11 deubiquitinates monoubiquitinated SPRTN to repair DNA-protein crosslinks
Authors: Perry Megan , Kollala Sai Sundeep , Biegert Meghan , Su Grace , Kodavati Manohar , Mallard Halle , Kreiling Natasha , Holbrook Alexander , Ghosal Gargi 
Published: July 2020

SUMMARYDNA-protein crosslinks (DPCs) are toxic DNA lesions that interfere with DNA metabolic processes such as replication, transcription and recombination. SPRTN is a replication-coupled DNA-dependent metalloprotease that cleaves proteins crosslinked to DNA to promote DPC repair. SPRTN function is tightly regulated by a monoubiquitin switch that controls SPRTN chromatin accessibility during DPC repair. The deubiquitinase regulating SPRTN function in DPC repair is unknown. Here, we identify USP11 as a SPRTN deubiquitinase. USP11 interacts with SPRTN and cleaves monoubiquitinated SPRTN in cells andin vitro.USP11 depletion impairs SPRTN deubiquitination in response to formaldehyde-induced DPCs. Loss of USP11 causes an accumulation of unrepaired DPCs and cellular hypersensitivity to treatment with DPC-inducing agents. Our findings elucidate the function of USP11 in the regulation of SPRTN monoubiquitination and SPRTN-mediated DPC repair.
Leptin suppresses development of GLP-1 Inputs to the Paraventricular Nucleus of the Hypothalamus
Authors: Biddinger Jessica E. , Lazarenko Roman M. , Scott Michael M. , Simerly Richard B. 
Published: July 2020

AbstractThe nucleus of the solitary tract is critical for the central integration of signals from visceral organs and contains preproglucagon (PPG) neurons, which express leptin receptors and send direct projections to the paraventricular nucleus of the hypothalamus (PVH). Here, we visualized neuronal projections of PPG neurons in leptin-deficient Lepob/obmice and found that projections from PPG neurons are elevated compared with controls, and PPG projections were normalized by targeted rescue of leptin receptors in LepRbTB/TBmice, which lack functional neuronal leptin receptors. Moreover, Lepob/oband LepRbTB/TBmice displayed increased levels of neuronal activation in the PVH following vagal stimulation, and whole-cell patch recordings of GLP-1 receptor-expressing PVH neurons revealed enhanced excitatory neurotransmission, suggesting that leptin acts cell autonomously to suppress representation of excitatory afferents from PPG neurons, thereby diminishing the impact of visceral sensory information on GLP-1 receptor neurons in the PVH.
Structural basis of TRPC4 regulation by calmodulin and pharmacological agents
Authors: Vinayagam Deivanayagabarathy , Quentin Dennis , Sitsel Oleg , Merino Felipe , Stabrin Markus , Hofnagel Oliver , Yu Maolin , Ledeboer Mark W. , Malojcic Goran , Raunser Stefan 
Published: July 2020

ABSTRACTCanonical transient receptor potential channels (TRPC) are involved in receptor-operated and/or store-operated Ca2+signaling. Inhibition of TRPCs by small molecules was shown to be promising in treating renal diseases. In cells, the channels are regulated by calmodulin. Molecular details of both calmodulin and drug binding have remained elusive so far. Here we report structures of TRPC4 in complex with a pyridazinone-based inhibitor and a pyridazinone-based activator and calmodulin. The structures reveal that both activator and inhibitor bind to the same cavity of the voltage-sensing-like domain and allow us to describe how structural changes from the ligand binding site can be transmitted to the central ion-conducting pore of TRPC4. Calmodulin binds to the rib helix of TRPC4, which results in the ordering of a previously disordered region, fixing the channel in its closed conformation. This represents a novel calmodulin-induced regulatory mechanism of canonical TRP channels.
Galectin-8 senses phagosomal damage and recruits selective autophagy adapter TAX1BP1 to controlMycobacterium tuberculosisinfection in macrophages
Authors: Bell Samantha L. , Lopez Kayla L. , Cox Jeffery S. , Patrick Kristin L. , Watson Robert O. 
Published: July 2020

ABSTRACTMycobacterium tuberculosis(Mtb) infects a quarter of the world and causes the deadliest infectious disease worldwide. Upon infection, Mtb is phagocytosed by macrophages and uses its virulence-associated ESX-1 secretion system to modulate the host cell and establish a replicative niche. We have previously shown the ESX-1 secretion system permeabilizes the Mtb-containing phagosome and that a population (~30%) of intracellular Mtb are recognized within the cytosol, tagged with ubiquitin, and targeted to the selective autophagy pathway. Despite the importance of selective autophagy in controlling infection, the mechanisms through which macrophages sense and respond to damaged Mtb-containing phagosomes remains unclear. Here, we demonstrate that several cytosolic glycan-binding proteins, known as galectins, recognize Mtb-containing phagosomes. We found that galectins-3, -8, and -9 are all recruited to the same Mtb population that colocalizes with selective autophagy markers like ubiquitin, p62, and LC3, which indicates Mtb damages its phagosomal membrane such that cytosolic host sensors can recognize danger signals in the lumen. To determine which galectins are required for controlling Mtb replication in macrophages, we generated CRISPR/Cas9 knockout macrophages lacking individual or multiple galectins and found that galectin-8-/-and galectin-3/8/9-/-knockout macrophages were similarly defective in targeting Mtb to selective autophagy and controlling replication, suggesting galectin-8 plays a privileged role in anti-Mtb autophagy. In investigating this specificity, we identified a novel and specific interaction between galectin-8 and TAX1BP1, one of several autophagy adaptors that bridges cargo and LC3 during the course of autophagosome formation, and this galectin-8/TAX1BP1 interaction was necessary to efficiently target Mtb to selective autophagy. Remarkably, overexpressing individual galectins increased targeting of Mtb to antibacterial autophagy and limited Mtb replication. Taken together, these data imply that galectins recognize damaged Mtb-containing phagosomes, recruit downstream autophagy machinery, and may represent promising targets for host-directed therapeutics to treat Mtb.
SWR1-independent association of H2A.Z to the LINC complex promotes meiotic chromosome motion
Authors: González-Arranz Sara , Gardner Jennifer M. , Yu Zulin , Patel Neem J. , Heldrich Jonna , Santos Beatriz , Carballo Jesús A. , Jaspersen Sue L. , Hochwagen Andreas , San-Segundo Pedro A. 
Published: July 2020

ABSTRACTThe H2A.Z histone variant is deposited into chromatin by the SWR1 complex affecting multiple aspects of meiosis. Here we describe a SWR1-independent localization of H2A.Z at meiotic telomeres and the centrosome. We demonstrate that H2A.Z colocalizes and interacts with Mps3, the SUN component of the LINC complex that spans the nuclear envelope and links meiotic telomeres to the cytoskeleton promoting meiotic chromosome movement. H2A.Z also interacts with the meiosis-specific Ndj1 protein that anchors telomeres to the nuclear periphery via Mps3. Telomeric localization of H2A.Z depends on Ndj1 and the N-terminal domain of Mps3. Although telomeric attachment to the nuclear envelope is maintained in the absence of H2A.Z, the distribution of Mps3 is altered. The velocity of chromosome movement during meiotic prophase I is reduced in thehtz1Δmutant lacking H2A.Z, but it is unaffected inswr1Δcells. We reveal that H2A.Z is an additional LINC-associated factor that contributes to promote telomere-driven chromosome motion critical for error-free gametogenesis.
Cryo-EM structure of enteric adenovirus HAdV-F41 highlights structural divergence among human adenoviruses
Authors: Pérez-Illana Marta , Martínez Marta , Condezo Gabriela N. , Hernando-Pérez Mercedes , Mangroo Casandra , Brown Martha , Marabini Roberto , Martín Carmen San 
Published: July 2020

AbstractEnteric adenoviruses are one of the main causes of viral gastroenteritis in the world. To carry out a successful infection, the virions must withstand the harsh conditions found in the gut. This requirement suggests that capsid stability must be different from that of other adenoviruses. We have determined the structure of a human enteric adenovirus, HAdV-F41, at 4.0 Å resolution by single particle averaging cryo-electron microscopy, and compared it with that of other adenoviruses with respiratory (HAdV-C5) and ocular (HAdV-D26) tropisms. While the overall structures of hexon, penton base and internal minor coat proteins IIIa and VIII are conserved, we observe partially ordered elements reinforcing the vertex region, which suggests their role in enhancing the physicochemical capsid stability of HAdV-F41. Unexpectedly, we find an organization of the external minor coat protein IX different from all previously characterized human and non-human mastadenoviruses. Knowledge of the structure of enteric adenoviruses can provide a starting point for the design of vectors suitable for oral delivery or intestinal targeting.
H-Mem: Harnessing synaptic plasticity with Hebbian Memory Networks
Authors: Limbacher Thomas , Legenstein Robert 
Published: July 2020

AbstractThe ability to base current computations on memories from the past is critical for many cognitive tasks such as story understanding. Hebbian-type synaptic plasticity is believed to underlie the retention of memories over medium and long time scales in the brain. However, it is unclear how such plasticity processes are integrated with computations in cortical networks. Here, we propose Hebbian Memory Networks (H-Mems), a simple neural network model that is built around a core hetero-associative network subject to Hebbian plasticity. We show that the network can be optimized to utilize the Hebbian plasticity processes for its computations. H-Mems can one-shot memorize associations between stimulus pairs and use these associations for decisions later on. Furthermore, they can solve demanding question-answering tasks on synthetic stories. Our study shows that neural network models are able to enrich their computations with memories through simple Hebbian plasticity processes.
BDNF Overexpression in the Prelimbic Cortex Does Not Reduce Anxiety- and Depression-like Behavior in Serotonin Knockout Rats
Authors: Diniz Danielle M. , Bosch Kari , Calabrese Francesca , Brivio Paola , Riva Marco A. , Grandjean Joanes , Homberg Judith R. 
Published: July 2020

AbstractDepressive disorders are one of the leading causes of non-fatal health loss in the last decade. Adding to the burden, the available treatments not always properly work for some individuals. There is, therefore, a constant effort from clinical and preclinical studies to bring forward a better understanding of the disease and look for novel alternative therapies. Two target systems very well explored are the serotonin and the brain-derived neurotrophic factor (BDNF) systems. Selective serotonin reuptake inhibitors (SSRIs), a commonly used class of antidepressants, target the serotonin transporter (SERT) and increase serotonin levels, which in turn also leads to an increase in BDNF. A rat model lacking SERT (SERT knockout) has been a useful tool to study the interplay between serotonin and BDNF. SERT−/−rats present increased extracellular levels of serotonin, yet BDNF levels are decreased, especially in the prefrontal cortex (PFC) and hippocampus. The animals further display anxiety- and depression-like behavior. Therefore, BDNF might mediate the phenotype expressed by the SERT−/−rats. In this study, we sought to investigate whether overexpression of BDNF in the brain of SERT−/−rats would rescue its anxious and depressive-like behavior. Through stereotaxic surgery, SERT−/−and wild-type (WT) rats received BDNF or GFP lentivirus microinfusions into the prelimbic cortex subregion of the mPFC and were submitted to the sucrose consumption, open field test, and forced swim tests. Additionally, we measured hypothalamus-pituitary-adrenal (HPA)-axis reactivity. The results revealed that SERT−/−rats presented decreased sucrose intake, decreased locomotor activity, and increased escape-oriented behavior in the forced swim test compared to WT rats. BDNF upregulation in WT rats caused alterations in the HPA-axis function, resulting in elevated basal plasma corticosterone levels and decreased plasma corticosterone upon stress. In conclusion, BDNF overexpression in the PrL, in general, did not rescue SERT−/−rats from its depression- and anxiety-like behavior, and in WT animals, it caused a malfunction in the HPA-axis.
Functional specialization within the inferior parietal lobes across cognitive domains
Authors: Numssen Ole , Bzdok Danilo , Hartwigsen Gesa 
Published: July 2020

AbstractThe inferior parietal lobe (IPL) is a key neural substrate underlying diverse mental processes, from basic attention to language and social cognition, that define human interactions. Its putative domain-global role appears to tie into poorly understood differences between cognitive domains in both hemispheres. Across attentional, semantic, and social cognitive tasks, our study explored functional specialization within the IPL. The task specificity of IPL subregion activity was substantiated by distinct predictive signatures identified by multivariate pattern-learning algorithms. Moreover, the left and right IPL exerted domain-specific modulation of effective connectivity among their subregions. Task-evoked functional interactions of the anterior and posterior IPL subregions involved recruitment of distributed cortical partners. While anterior IPL subregions were engaged in strongly lateralized coupling links, both posterior subregions showed more symmetric coupling patterns across hemispheres. Our collective results shed light on how under-appreciated functional specialization in the IPL supports some of the most distinctive human mental capacities.
Identification of a long non-coding RNA regulator of liver carcinoma cell survival
Authors: Rybakova Yulia , Gonzalez John T. , Bogorad Roman , Chauhan Vikash P. , Dong Yize L. , Whittaker Charles A. , Koteliansky Victor , Anderson Daniel G. 
Published: July 2020

ABSTRACTGenomic studies have significantly improved our understanding of hepatocellular carcinoma (HCC) biology and have led to the discovery of multiple protein-coding genes driving hepatocarcinogenesis. In addition, these studies have identified thousands of new non-coding transcripts deregulated in HCC. We hypothesize that some of these transcripts may be involved in disease progression. Long non-coding RNAs are a large class of non-coding transcripts which participate in the regulation of virtually all cellular functions. However, a majority of lncRNAs remain dramatically understudied. Here, we applied a pooled shRNA-based screen to identify lncRNAs essential for HCC cell survival. We validated our screening results using RNAi, CRISPRi, and antisense oligonucleotides. We found a lncRNA, termed ASTILCS, that is critical for HCC cell growth and is overexpressed in tumors from HCC patients. We demonstrated that HCC cell death upon ASTILCS knockdown is associated with apoptosis induction and downregulation of a neighboring gene, Protein Tyrosine Kinase 2 (PTK2), a crucial protein for HCC cell survival. Taken together, our study describes a new, non-coding RNA regulator of HCC.