bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kin17 drives dissociation of Mira from the centrosome in neuroblasts by regulating splicing of Flfl
Authors: Connell Marisa , Xie Yonggong , Chen Rui , Zhu Sijun 
Published: November 2021

AbstractDuring asymmetric division of Drosophila neuroblasts, the fate determinant Prospero and its adaptor Miranda are segregated to the basal cortex through aPKC phosphorylation of Miranda and displacement from the apical cortex. Here we identify Kin17 as a novel regulator of Miranda localization during asymmetric cell division and loss of Kin17 or Protein Phosphatase 4 leads to aberrant localization of Miranda to the centrosome and cytoplasm and Prospero to the centrosome and nucleus. We report that dephosphorylation of Mira by Protein Phosphatase 4 at Serine-96 at the centrosome is required for the proper basal localization of Mira after being phosphorylated at the apical cortex. We further demonstrate that Kin17 regulates Miranda localization by promoting splicing of the transcript of a PP4 component Falafel. Taken together, our work reveals a novel mechanism that ensures proper basal localization of Miranda by preventing its aberrant localization to the centrosome during the asymmetric division.SummaryConnell et al. show that proper segregation of cell fate determinant Miranda requires PP4-mediated dissociation of Miranda from the centrosome/spindle in Drosophila neuroblasts, a critical step that has been overlooked previously. Further, they identify a novel regulator of Miranda localization, Kin17, which promotes splicing of the transcript of the PP4 component Falafel.
Prediction of Kv11.1 potassium channel PAS-domain variants trafficking via machine learning
Authors: Immadisetty Kalyan , Fang Xuan , Hartle Cassandra M. , McCoy Thomas P. ,   Regeneron Genetics Center, Mirshahi Tooraj , Delisle Brian P. , Kekenes-Huskey Peter M. 
Published: November 2021

1AbstractCongenital long QT syndrome (LQTS) is characterized by a prolonged QT-interval on an electrocardiogram (ECG). An abnormal prolongation in the QT-interval increases the risk for fatal arrhythmias despite otherwise normal metrics of cardiac function. Genetic variants in several different cardiac ion channel genes, includingKCNH2, are known to cause LQTS. The population frequency of rare non-synonymous (missense) variants in LQTS-linked genes far outpaces the true incidence of the disease. Therefore, only a small percentage of missense variants identified in LQTS-linked genes are expected to associate with LQTS. Because of a lack of clear association between variants identified in LQTS-linked alleles and diseases, most variants are classified as variants of uncertain physiological significance (VUS). Here, we evaluated whether structure-based molecular dynamics (MD) simulations and machine learning (ML) can improve the identification of missense variants in LQTS-linked genes that associate with LQTS. To do this, we focused on investigatingKCNH2missense variants in the Kv11.1 channel protein shown to have wild type (WT) like or loss-of-function (LOF) phenotypesin vitro. We focused onKCNH2missense variants that disrupt normal Kv11.1 channel protein trafficking, as it is the most common LOF phenotype for LQTS-associated variants. Specifically, we used these computational techniques to correlate structural and dynamic changes in the Kv11.1 channel protein PAS domain (PASD) with Kv11.1 channel protein trafficking phenotypes. These simulations unveiled several molecular features, including the numbers of hydrating waters and H-Bonds, as well as FoldX scores, that are predictive of trafficking. We then used statistical and ML (Decision tree (DT), Random forest (RF), and Support vector machine (SVM)) techniques to classify variants using these simulation-derived features. Together with bioinformatics data, such as sequence conservation and folding energies, we were able to predict with reasonable accuracy (≈75%) whichKCNH2variants do not traffic normally. We conclude, structure-based simulations ofKCNH2variants localized to the Kv11.1 channel PASD led to a significant improvement (≈10%) in classification accuracy and this approach should therefore be considered to complement the classification of VUS in the Kv11.1 channel PASD.
SYMBIOSIS: Synthetic Manipulable Biobricks via Orthogonal Serine Integrase Systems
Authors: Ba Fang , Liu Yushi , Liu Wan-Qiu , Tian Xintong , Li Jian 
Published: November 2021

AbstractSerine integrases are emerging as one of the most powerful biological tools for synthetic biology. They have been widely used across genome engineering and genetic circuit design. However, developing serine integrase-based tools for directly/precisely manipulating synthetic biobricks is still missing. Here, we report SYMBIOSIS, a versatile method that can robustly manipulate DNA parts in vivo and in vitro. First, we proposed a “Keys match Locks” model to demonstrate that three orthogonal serine integrases are able to irreversibly and stably switch on seven synthetic biobricks with high accuracy in vivo. Then, we demonstrated that purified integrases can facilitate the assembly of “Donor” and “Acceptor” plasmids in vitro to construct composite plasmids. Finally, we used SYMBIOSIS to assemble different chromoprotein genes and create novel colored Escherichia coli. We anticipate that our SYMBIOSIS strategy will accelerate synthetic biobricks manipulation, genetic circuit design, and multiple plasmids assembly for synthetic biology with broad potential applications.
Amelioration of DSS-induced Acute Colitis in Mice by Recombinant Monomeric Human Interleukin-22
Authors: Kim Suhyun , Hong Eun-Hye , Lee Cheol-Ki , Ryu Yiseul , Jeong Hyunjin , Heo Seungnyeong , Lee Joong-jae , Ko Hyun-Jeong 
Published: November 2021

AbstractInterleukin-22 (IL-22), a pleiotropic cytokine, is known to have a profound effect on the regeneration of damaged intestinal barriers. The tissue-protective properties of IL-22 are expected to be potentially exploited in the attenuation and treatment of colitis. However, because of the disease-promoting role of IL-22 in chronic inflammation, a comprehensive evaluation is required to translate IL-22 into the clinical domain. Here, we present the effective production of soluble human IL-22 in bacteria to prove whether recombinant IL-22 has the ability to ameliorate colitis and inflammation. IL-22 was expressed in the form of a biologically active monomer and a non-functional dimer. Monomeric IL-22 (mIL-22) was highly purified through a series of three separate chromatographic methods and an enzymatic reaction. We reveal that the resulting mIL-22 is correctly folded and is able to phosphorylate signal transducer and activator of transcription 3 in HT-29 cells. Subsequently, we demonstrate that mIL-22 enables the attenuation of dextran sodium sulfate-induced acute colitis in mice, as well as the suppression of pro-inflammatory cytokine production. Collectively, our results suggest that the recombinant mIL-22 is suitable to study the biological roles of endogenous IL-22 in immune responses and can be developed as a biological agent associated with inflammatory disorders.
Disease-linked mutations trigger exposure of a protein quality control degron in the DHFR protein
Authors: Kampmeyer Caroline , Larsen-Ledet Sven , Wagnkilde Morten Rose , Michelsen Mathias , Iversen Henriette K. M. , Nielsen Sofie V. , Lindemose Søren , Caregnato Alberto , Ravid Tommer , Stein Amelie , Teilum Kaare , Lindorff-Larsen Kresten , Hartmann-Petersen Rasmus 
Published: November 2021

AbstractDegrons are short stretches of amino acids or structural motifs that are embedded in proteins. They mediate recognition by E3 ubiquitin-protein ligases and thus confer protein degradation via the ubiquitin-proteasome system. Well-described degrons include the N-degrons, destruction boxes, and the PIP degrons, which mediate the controlled degradation of various proteins including signaling components and cell cycle regulators. In comparison, the so-called protein quality control (PQC) degrons that mediate the degradation of structurally destabilized or misfolded proteins are not well described. Here, we show that disease-linked DHFR missense variants are structurally destabilized and chaperone-dependent proteasome targets. We systematically mapped regions within DHFR to assess those that act as cytosolic PQC degrons in yeast cells. Two regions, DHFR-Deg13-36 (here Deg1) and DHFR-Deg61-84 (here Deg2), act as degrons and conferred degradation to unrelated fusion partners. The proteasomal turnover of Deg2 was dependent on the molecular chaperone Hsp70. Structural analyses by NMR and hydrogen/deuterium exchange revealed that Deg2 is buried in wild-type DHFR, but becomes transiently exposed in the disease-linked missense variants.
Regulation of invasion-associated actin dynamics by the Chlamydia trachomatis effectors TarP and TmeA
Authors: Romero Matthew D. , Carabeo Rey A. 
Published: November 2021

AbstractThe obligate intracellular pathogen Chlamydia trachomatis manipulates the host actin cytoskeleton to assemble actin-rich structures that drive pathogen entry. The recent discovery of TmeA, which like TarP is an invasion-associated type III effector implicated in actin remodeling, raised questions regarding the nature of their functional interaction. Quantitative live-cell imaging of actin remodeling at invasion sites revealed differences in recruitment and turnover kinetics associated with TarP and TmeA pathways, with the former accounting for most of the robust actin dynamics at invasion sites. TarP-mediated recruitment of the actin nucleators formin and the Arp2/3 complex were crucial for rapid actin kinetics, generating a collaborative positive feedback loop that enhanced their respective actin-nucleating activities within invasion sites. In contrast, Fmn1 is neither recruited to invasion sites nor collaborates with Arp2/3 within the context of TmeA-associated actin recruitment. While the TarP-Fmn1-Arp2/3 signaling axis is responsible for the majority of actin dynamics, its inhibition had similar effects as deletion of TmeA on invasion efficiency, consistent with the proposed model that TarP and TmeA acting on different stages of the same invasion pathway.Summary StatementKinetic analysis of actin recruitment during C. trachomatis invasion reveals TarP as the major contributor relative to TmeA, via its ability to facilitate collaboration between actin nucleators Formin 1 and Arp2/3.
The Conformational Plasticity of the Selectivity Filter Methionines Controls the In-Cell Cu(I) Uptake through the CTR1 transporter
Authors: Janoš Pavel , Aupič Jana , Ruthstein Sharon , Magistrato Alessandra 
Published: November 2021

AbstractCopper is a trace element vital to many cellular functions. Yet its abnormal levels are toxic to cells, provoking a variety of severe diseases. The high affinity Copper Transporter 1 (CTR1), being the main in-cell copper (Cu(I)) entry route, tightly regulates its cellular uptake via a still elusive mechanism. Here, all-atoms simulations unlock the molecular terms of Cu(I) transport in eukaryotes disclosing that the two Methionine triads, forming the selectivity filter, play an unprecedented dual role both enabling selective Cu(I) transport and regulating its uptake-rate thanks to an intimate coupling between the conformational plasticity of their bulky side chains and the number of bound Cu(I) ions. Namely, the Met residues act as a gate reducing the Cu(I) import-rate when two ions simultaneously bind to CTR1. This may represent an elegant autoregulatory mechanism through which CTR1 protects the cells from excessively high, and hence toxic, in-cell Cu(I) levels. Overall, these outcomes resolve fundamental questions in CTR1 biology and open new windows of opportunity to tackle diseases associated with an imbalanced copper uptake.Abstract Figure
On the importance of accounting for alternative foraging tactics when assessing cognitive performance in wild animals
Authors: Vernouillet Alizée 
Published: November 2021

AbstractResearch Highlight: Reichert, S., Morand‐Ferron, J., Kulahci, I. G., Firth, J. A., Davidson, G. L., Crofts, S. J., & Quinn, J. L. (2021) Cognition and covariance in the producer–scrounger game. Journal of Animal Ecology, https://doi.org/10.1111/1365‐2656.13551. When foraging in groups, individuals can either acquire their own resources, as producers, or profit from the work of other individuals, as scroungers. Individuals vary in how much they rely on one foraging tactic over the other. Yet, each of these foraging tactics presents unique cognitive challenges. Using a field experiment with a mixed‐species flock of birds, Reichert et al. (2021) investigated how production learning (i.e. successfully feeding from their assigned rewarded feeder) and scrounging propensity (i.e. collecting food from a non‐assigned feeders by following another individual) are related at an individual level, as well as the repeatability of both production learning and scrounging propensity. The authors show that overall, (a) individuals learned to scrounge, (b) individuals who rely more on scrounging took longer to learn their assigned feeder and (c) variation in each cognitive trait was mostly explained by individual behavioural flexibility rather than by consistent differences between individuals. Since learning was negatively correlated with the use of an alternative foraging tactic (i.e. scrounging), results of this study also suggest that individual choice of foraging tactics should be considered when evaluating cognitive abilities in wild animals.
The impact of blowflies on pig cadaver decomposition on Yeongdo Island, Busan, South Korea
Authors: Park Sang‐Hyun , Baek Seung‐Ho , Moon Tae‐Young 
Published: November 2021

AbstractThe decomposition process is an important factor in forensics, and flies play a crucial role in the decomposition of animals and humans. However, there remains limited information on the effect of flies that attend death scenes. This study assesses the effect of the presence or absence of blowflies on the rate and process of cadaver decomposition in the spring, summer, and autumn from 2016 to 2020 on Yeongdo Island, Busan, South Korea. Nine blowfly species belonging to four genera in two subfamilies were sampled. The blowflies that approached the cadavers differed between seasons, but Chrysomya pinguis (Walker) was the dominant species regardless of the season. Blowfly presence on cadavers significantly affected the duration of the decomposition stage and the pattern of weight loss in nearly all scenarios. With the presence of blowflies, the decomposition rate was four times faster in spring, three times faster in summer, and nine times faster in autumn. These results show that the presence or absence of blowflies is an essential factor in the decomposition process of cadavers. Therefore, it should be taken into account when estimating postmortem intervals in medicolegal forensic entomology.
Functional connectivity during feedback learning in smokers
Authors: Duehlmeyer Leonie , Parsons Nicholas , Malpas Charles B. , Hester Robert 
Published: November 2021

AbstractBackgroundAlthough it has been traditionally assumed that dysregulation of psychological processes in smokers results from activity within specific brain regions, an emerging view regards such dysregulation as attributable to aberrant communication between distinct brain regions. These processes can be measured during appropriate task paradigms such as the learning from errors task. This study aims to elucidate interactions between brain regions underlying the process of learning from errors, punishment and sensitivity to reward in dependent smokers.MethodsFunctional MRI data from 23 age‐matched dependent smokers (8 females, mean age = 25.48, SD = 4.46) and 23 controls (13 females, mean age = 24.83, SD = 5.99) were analysed during a feedback‐based associative learning task. Functional connectivity between the dorsal anterior cingulate cortex, nucleus accumbens and reward/sensorimotor areas was investigated during a feedback learning task.ResultsBehaviourally, smokers exhibited lower error correction rates and were less sensitive to punishment magnitude. Smokers showed increased functional connectivity between dorsal anterior cingulate cortex/nucleus accumbens seed regions and numerous reward‐related target regions including the putamen, anterior cingulate and orbitofrontal cortex.ConclusionsReduced learning from errors and widespread aberrant functional connectivity contribute to the emerging functional characterisation of dependent smokers and may bear significant implications when considering the efficacy of smoking interventions.
Polymorphisms contribute to differences in the effect of rocuronium in Chinese patients
Authors: Zhu Hongyu , Wang Yafeng , Wang Qi , Zhao Shuai , Xu Feng , Hu Zhiqiang , Zhou Ruihui , Huang Shiqian , Han Linlin , Chen Xiangdong 
Published: November 2021

AbstractRocuronium is widely utilized in clinical general anaesthesia, and individual differences in pharmacology and clearance have been observed. Two hundred thirty‐six Chinese patients undergoing selective thyroid/breast mass resection were studied. Total intravenous anaesthesia was induced with a single dose of propofol (2 mg·kg−1), sufentanil (0.5 μg·kg−1), and rocuronium (0.6 mg·kg−1) and maintained with propofol (3–5 mg·kg−1·h−1) and remifentanil (0.2–0.4 μg·kg−1·min−1). Intubation conditions and a train‐of‐four index of patients were utilized to assess the effects and duration of rocuronium. The data from 228 patients were analysed and reported. Genotypes NR1I2 rs2472677 C > T, NR1I2 rs6785049 G > A, SLCO1B1 rs4363657 T > C, SLCO1A2 rs4762699 T > C, and UGT1A1 rs4148323 G > A contributed to individual variation in rocuronium. Of the clinical variables tested, age, BMI, total dose of propofol, NR1I2 rs2472677, and SLCO1A2 rs4762699 correlated significantly (P < 0.05 for all) with the clinical duration or total clinical action time of rocuronium in a multiple linear regression model. No significant interactions were observed in intubation conditions. Genetic variations in NR1I2 rs2472677, NR1I2 rs6785049, SLCO1B1 rs4363657, SLCO1A2 rs4762699, and UGT1A1 rs4148323 were related to extensive interindividual variability in the clinical duration and total clinical action time of rocuronium.
Randomized controlled trial of a mindfulness‐based intervention in adolescents from the general population: The Mindfulteen neuroimaging study protocol
Authors: Piguet Camille , Klauser Paul , Celen Zeynep , James Murray Ryan , Magnus Smith Mariana , Merglen Arnaud 
Published: November 2021

AbstractAimAdolescence is a period of vulnerability to stress. Increased anxiety during this period has been associated with the later development of mental disorders, hence the growing interest for interventions that could decrease stress reactivity and improve cognitive control in adolescents. Mindfulness‐based interventions have demonstrated their efficacy on stress reactivity and anxiety in adults, but evidence is lacking in youth.MethodsThe Mindfulteen Study is a 3‐year longitudinal cohort with a nested randomized controlled trial examining the effectiveness of mindfulness‐based interventions for adolescents. Young adolescents from the general population, aged between 13 and 15 years old, with no history of current mental health disorder (apart from past mood disorders or current anxiety disorders) are included and stratified into low or high anxiety based on trait anxiety scores before being randomized to early or late 8‐week intervention groups. Primary outcomes are based on neuroimaging data (i.e., structural and functional measures in the cortico‐limbic network) while secondary outcomes are psychological (i.e., anxiety and stress‐associated dimensions) and biological (i.e., cortisol, inflammatory and redox markers). Assessments are performed at baseline, immediately after intervention or waiting time and after 18 months of intervention.ConclusionTo the best of our knowledge, this is the first randomized controlled trail examining the effect of a mindfulness‐based intervention in young adolescents from the general population based on the measurement and analyses of psychological, neuroimaging and biological data.
Perceptions of adolescents' racial discrimination experiences, racial identity, and depressive symptoms among Black American fathers
Authors: Jelsma Elizabeth , Varner Fatima , Engineer Nabeeha 
Published: November 2021

AbstractObjectiveThis study examined whether Black American fathers' perceptions of their adolescents' experiences of racial discrimination were related to fathers' depressive symptoms and if this association was moderated by fathers' racial identity beliefs and adolescent gender.BackgroundRacial discrimination is not only an individual‐level but also a family‐level stressor for Black families. Racial discrimination experienced by parents can spillover to influence their children; however, fewer studies have examined how adolescents' discrimination experiences relate to parents' psychological outcomes, especially among Black fathers.MethodData were collected via online survey from 240 Black fathers (Mage = 45.93 years,SD = 8.72) of adolescents (Mage = 14.44 years,SD = 2.11) residing in the United States. Participants completed questions about their racial identity beliefs and depressive symptoms, as well as their adolescents' experiences with racial discrimination.ResultsRegression analyses revealed that adolescent‐experienced racial discrimination was directly associated with fathers' depressive symptoms. Fathers whose race was more central to them (racial centrality) had higher depressive symptoms when their adolescents had high racial discrimination experiences. Also, fathers' beliefs about how Black people are viewed by society (public regard) moderated the relation between adolescent‐experienced racial discrimination and fathers' depressive symptoms differently based on adolescent gender. Adolescent gender also moderated the relation between fathers' personal feelings about being Black (private regard) and their depressive symptoms.ConclusionsOverall, fathers' beliefs about their race, as well as the gender of their adolescents, play a role in their psychological health when their adolescents experience discrimination.
Deformation and fracture behavior of granite by the short core in compression method with 3D digital image correlation
Authors: Li Diyuan , Zhang Chenxi , Zhu Quanqi , Ma Jinyin , Gao Feihong 
Published: November 2021

AbstractBased on three‐dimensional digital image correlation (3D‐DIC) technique, the deformation behavior, damage and fracture characteristics of the granite specimens have been tested and observed by the short core in compression (SCC) method. The test results show that (1) the damage degree of rock in the region of interest (ROI) increases with axial stress. Before peak stress, damage factor based on apparent principal strain increases slowly, then rises rapidly; (2) relative displacements in both horizontal and vertical directions are observed, indicating that the fracture mode for SCC specimens subjected to uniaxial compression is the tensile‐shear mixed mode fracture; (3) new fracture initiates from the middle part of the expected shear fracture band (ESFB) then propagates along the loading direction. A dominant macro‐fracture, linking up the tips of two notches, eventually forms. Meanwhile, a calculation method based on the energy conservation law for the fracture energy of SCC specimens is proposed. The fracture energy of granite is estimated as 1760.4 J/m2.