bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fresh extension ofVibrio choleraecompetence type IV pili predisposes them for motor-independent retraction
Authors: Chlebek Jennifer L. , Dalia Triana N. , Biais Nicolas , Dalia Ankur B. 
Published: March 2021

ABSTRACTBacteria utilize dynamic appendages called type IV pili (T4P) to interact with their environment and mediate a wide variety of functions. Pilus extension is mediated by an extension ATPase motor, commonly called PilB, in all T4P. Pilus retraction, however, can either occur with the aid of an ATPase motor, or in the absence of a retraction motor. While much effort has been devoted to studying motor-dependent retraction, the mechanism and regulation of motor-independent retraction remains poorly characterized. We have previously demonstrated thatVibrio choleraecompetence T4P undergo motor-independent retraction in the absence of the dedicated retraction ATPases PilT and PilU. Here, we utilize this model system to characterize the factors that influence motor-independent retraction. We find that freshly extended pili frequently undergo motor-independent retraction, but if these pili fail to retract immediately, they remain statically extended on the cell surface. Importantly, we show that these static pili can still undergo motor-dependent retraction via tightly regulated ectopic expression of PilT, suggesting that these T4P are not broken, but simply cannot undergo motor-independent retraction. Through additional genetic and biophysical characterization of pili, we suggest that pilus filaments undergo conformational changes during dynamic extension and retraction. We propose that only some conformations, like those adopted by freshly extended pili, are capable of undergoing motor-independent retraction. Together, these data highlight the versatile mechanisms that regulate T4P dynamic activity and provide additional support for the long-standing hypothesis that motor-independent retraction occurs via spontaneous depolymerization.SIGNIFICANCEExtracellular pilus fibers are critical to the virulence and persistence of many pathogenic bacteria. A crucial function for most pili is the dynamic ability to extend and retract from the cell surface. Inhibiting this dynamic pilus activity represents an attractive approach for therapeutic interventions, however, a detailed mechanistic understanding of this process is currently lacking. Here, we use the competence pilus ofVibrio choleraeto study how pili retract in the absence of dedicated retraction motors. Our results reveal a novel regulatory mechanism of pilus retraction that is an inherent property of the external pilus filament. Thus, understanding the conformational changes that pili adopt under different conditions may be critical for the development of novel therapeutics that aim to target the dynamic activity of these structures.
Charting oncogenicity of genes and variants across lineages via multiplexed screens in teratomas
Authors: Parekh Udit , McDonald Daniella , Dailamy Amir , Wu Yan , Cordes Thekla , Zhang Kun , Tipps Ann , Metallo Christian , Mali Prashant 
Published: March 2021

SUMMARYDeconstructing tissue-specific effects of genes and variants on proliferative advantage is critical to understanding cellular transformation and to systematic selection of cancer therapeutics. Dissecting these specificities at scale requires integrated methods for multiplexed genetic screens tracking fitness across time, across human cell types, and in a suitable cellular niche since functional differences also depend on physiological cues. Towards this, we present a novel approach, harnessing single-cell cancer driver screens in teratomas coupled with hit enrichment by serial teratoma reinjection, to simultaneously screen drivers across multiple lineages in vivo. Using this system, we analyzed population shifts and lineage-specific enrichment for 51 cancer associated genes and gene variants, profiling over 100,000 cells spanning over 20 lineages, across two rounds of serially injected teratomas. We confirmed that c-MYC alone or combined with myristoylated AKT1 potently drives proliferation in progenitor neural lineages, demonstrating signatures of malignancy. These drivers directed teratoma development to lineages representative of pediatric tumors such as medulloblastoma and rhabdomyosarcoma. Additionally, mutant MEK1S218D/S222D provides a proliferative advantage in mesenchymal lineages like fibroblasts. Our method provides a powerful new platform for multi-lineage longitudinal study of oncogenesis.
No influence of antibiotic on locomotion inDrosophila nigrosparsaafter recovery, but influence on microbiome, possibly mediating wing-morphology change
Authors: Weiland Simon O. , Detcharoen Matsapume , Schlick-Steiner Birgit C. , Steiner Florian M. 
Published: March 2021

ABSTRACTAntibiotics, such as tetracycline, has been frequently used to cure endosymbiontWolbachiain arthropods. After the symbionts had been removed, the hosts must be waited for some generations to recover from side effects of the antibiotics. Knowledge of potential long-term effects of the antibiotic is important. Here, we treatedDrosophila nigrosparsawith and without antibiotic tetracycline for three generations and two generations recovering time to investigate effects of the tetracycline on the flies concerning locomotion of larvae and adults, wing morphology, and gut microbiome of adults. In addition, gut-microbiome restoration was tested as a solution to reducing potential side effects of tetracycline on the flies’ microbiome more quickly. We found significant differences in larval and adult locomotion within groups but no significant differences among the control, antibiotic-treated, and gut-restoration groups. We found a slight differentiation of wing morphology into the three groups and significant differences in bacterial abundance among groups. The influence of tetracycline on the gut microbiome may have contributed to wing-morphology differences among groups, which would be an indirect effect of the antibiotic. Together with the absence of an effect on locomotion, this suggests that checking for both direct and indirect effects of tetracycline after a particular recovery time before using tetracycline curing is important. The microbiome of the gut-restoration group was not like that of the control group. Therefore, gut restoration cannot be used to remove effects of tetracycline inD. nigrosparsa, at least in the setup used here.
A smoothed version of the Lassosum penalty for fitting integrated risk models
Authors: Hahn Georg , Prokopenko Dmitry , Lutz Sharon M. , Mullin Kristina , Tanzi Rudolph E. , Lange Christoph 
Published: March 2021

AbstractPolygenic risk scores are a popular means to predict the disease risk or disease susceptibility of an individual based on its genotype information. When adding other important epidemiological covariates such as age or sex, we speak of an integrated risk model. Methodological advances for fitting more accurate integrated risk models are of immediate importance to improve the precision of risk prediction, thereby potentially identifying patients at high risk early on when they are still able to benefit from preventive steps/interventions targeted at increasing their odds of survival, or at reducing their chance of getting a disease in the first place. This article proposes a smoothed version of the “Lassosum” penalty used to fit polygenic risk scores and integrated risk models. The smoothing allows one to obtain explicit gradients everywhere for efficient minimization of the Lassosum objective function while guaranteeing bounds on the accuracy of the fit. An experimental section on both Alzheimer’s disease and COPD (chronic obstructive pulmonary disease) demonstrates the increased accuracy of the proposed smoothed Lassosum penalty compared to the original Lassosum algorithm, allowing it to draw equal with state-of-the-art methodology such as LDpred2 when evaluated via the AUC (area under the ROC curve) metric.
In situmaturated early-stage human induced pluripotent stem cell-derived cardiomyocytes improve cardiac function by enhancing segmentary contraction in infarcted rats
Authors: Biagi Diogo , Fantozzi Evelyn Thais , Campos-Oliveira Julliana C , Naghetini Marcus Vinicius , Ribeiro Antonio F. , Rodrigues Sirlene , Ogusuku Isabella , Vanderlinde Rubia , Christie Michelle Lopes Araújo , Mello Debora B. , de Carvalho Antonio C. Campos , Valadares Marcos , Cruvinel Estela , Dariolli Rafael 
Published: March 2021

AbstractThe scant ability of cardiomyocytes to proliferate makes heart regeneration one of the biggest challenges of science. Current therapies do not contemplate heart re-muscularization. In this scenario, stem cell-based approaches have been proposed to overcome the lack of regeneration. We hypothesize PluriCell hiPSC-derived cardiomyocytes (hiPSC-CMs) could enhance rat’s cardiac function after myocardial infarction (MI). Animals were subjected to permanent occlusion of the Left-Ventricle (LV) anterior descending coronary artery (LAD). Seven days after MI, Early-stage hiPSC-CMs were injected intramyocardially. Rats were subjected to Echocardiography pre- and post-treatment. Thirty days after injections, treated rats displayed 6.2% human cardiac grafts, which were characterized molecularly. Left ventricle ejection fraction (LVEF) was improved by 7.8% in cell-injected rats, while placebo controls showed an 18.2% deterioration. Also, cell-treated rats displayed a 92% and 56% increase in radial and circumferential strains, respectively. Human cardiac grafts maturate in situ, preserving proliferation with 10% Ki67 and 3% PHH3 positive nuclei. Grafts were perfused by host vasculature with no evidence for immune rejection nor ectopic tissue formations. Our findings supportPluriCell hiPSC-CMsas an alternative therapy to treat MI. The next steps of preclinical development include efficacy studies in large animals on the path to clinical-grade regenerative therapy targeting human patients.
FKBP5expression is related to HPA flexibility and the capacity to cope with stressors in the house sparrow
Authors: Zimmer Cedric , Hanson Haley E. , Martin Lynn B. 
Published: March 2021

AbstractThe hypothalamic-pituitary-adrenal (HPA) axis and its end products, the glucocorticoids, are critical to responding appropriately to stressors. Subsequently, many studies have sought relationships between glucocorticoids and measures of health or fitness, but such relationships are at best highly context dependent. Recently, some endocrinologists have started to suggest that a focus on HPA flexibility, the ability of an individual to mount appropriate responses to different stressors, could be useful. Here, we tested the hypothesis that expression ofFKBP5, a cochaperone in the glucocorticoid receptor complex, is a simple and reliable proxy of HPA flexibility in a wild songbird, the house sparrow (Passer domesticus). We quantified HPA flexibility in a novel way, using guidance from research on heart rhythm regulation. As predicted, we found that adult sparrows with low stress-inducedFKBP5expression in the hypothalamus exhibited high HPA flexibility. Moreover, lowFKBP5expression was associated with better stress coping capacities in terms of exploratory disposition and body mass maintenance. Altogether, these results suggest thatFKBP5may be important in the regulation HPA flexibility, potentially affecting how individuals cope with natural and anthropogenic adversity.
Distinct Neural Profiles of Frontoparietal Networks in Boys with ADHD and Boys with Persistent Depressive Disorder
Authors: Vilgis Veronika , Yee Debbie , Silk Tim J. , Vance Alasdair 
Published: March 2021

AbstractWorking memory deficits are common in attention-deficit/hyperactivity disorder (ADHD) and depression, two common neurodevelopmental disorders with overlapping cognitive profiles but distinct clinical presentation. Multivariate techniques have previously been utilized to understand working memory processes in functional brain networks in healthy adults, but have not yet been applied to investigate how working memory processes within the same networks differ within typical and atypical developing populations. We used multivariate pattern analysis (MVPA) to identify whether brain networks discriminated between spatial vs. verbal working memory processes in ADHD and Persistent Depressive Disorder (PDD). 36 male clinical participants and 19 typically developing (TD) boys participated in a fMRI scan while completing a verbal and a spatial working memory task. Withina priorifunctional brain networks (frontoparietal, default mode, salience) the TD group demonstrated differential response patterns to verbal and spatial working memory. The PDD group showed weaker differentiation than TD, with lower classification accuracies observed in primarily the left frontoparietal network. The neural profiles of the ADHD and PDD differed specifically in the SN where the ADHD group’s neural profile suggests significantly less specificity in neural representations of spatial and verbal working memory. We highlight within-group classification as an innovative tool for understanding the neural mechanisms of how cognitive processes may deviate in clinical disorders, an important intermediary step towards improving translational psychiatry.
Tumor protein D52 (TPD52) affects cancer cell metabolism by negatively regulating AMPK
Authors: Chen Yali , Peng Changmin , Tan Wei , Yu Jia , Zayas Jacqueline , Peng Yihan , Lou Zhenkun , Pei Huadong , Wang Liewei 
Published: March 2021

AbstractThe AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, with deregulation leading to cancer and other diseases. When intracellular ATP levels decrease during energy stress, AMPK is phosphorylated and activated through AMP binding. However, how this pathway is dysregulated in cancer remains unclear. Here, we find that tumor protein D52 (TPD52), initially identified to be overexpressed in many human cancers, forms a stable complex with AMPK in cancer cells. TPD52 directly interacts with AMPKα and inhibits AMPKα kinase activityin vitroandin vivo. We generated TPD52 transgenic mice, and found that overexpression of TPD52 leads to AMPK inhibition and multiple metabolic defects in mice. Together, our results shed new light on AMPK regulation and on our understanding of the etiology of cancers with TPD52 overexpression.
Trophic transfer of microplastics enhances plastic additive accumulation in fish
Authors: Hasegawa Takaaki , Mizukawa Kaoruko , Yeo Bee Geok , Sekioka Tomonori , Takada Hideshige , Nakaoka Masahiro 
Published: March 2021

AbstractOrganisms ingest microplastics directly from environments and indirectly from food sources. Ingesting microplastics can lead to an organism accumulating plastic-derived chemicals. However, the relative contributions of the two exposure routes (direct ingestion vs. indirect ingestion) to plastic-derived chemical accumulation in an organism are unknown. Using microplastics containing different types of plastic additives, we performed exposure experiments to compare chemical accumulation patterns in fish (Myoxocephalus brandti) between the exposure from the water and prey (Neomysisspp.). We found significantly higher brominated flame retardant concentrations in fish fed microplastic-contaminated prey than fish exposed to microplastics suspended in the water. The results indicate that prey-mediated ingestion of microplastics can be a more significant route for organisms accumulating plastic-derived chemicals, suggesting that organisms at higher trophic levels are more exposed to microplastics and associated chemicals than organisms at lower trophic levels.
Molecular mechanism underlying substrate recognition of the peptide macrocyclase PsnB
Authors: Song Inseok , Kim Younghyeon , Yu Jaeseung , Go Su Yong , Lee Hong Geun , Song Woon Ju , Kim Seokhee 
Published: March 2021

AbstractGraspetides, also known as omega-ester-containing peptides (OEPs), are a family of ribosomally synthesized and post-translationally modified peptides (RiPPs) bearing side-to-side macrolactone or macrolactam linkages. Here we present molecular details of the precursor recognition of the macrocyclase enzyme PsnB in the biosynthesis of plesiocin, a Group 2 graspetide. Biochemical analysis revealed that, in contrast to other RiPPs, the core region of the plesiocin precursor peptide noticeably enhanced the enzyme-precursor interaction via the conserved glutamates. We obtained four crystal structures of symmetric or asymmetric PsnB dimers including those with a bound core peptide and a nucleotide, and suggest that the highly conserved Arg213 at the enzyme active site specifically recognizes a ring-forming acidic residue and escorts it to ATP for phosphorylation. Collectively, this study provides insights into the mechanism underlying substrate recognition in the graspetide biosynthesis, and lays a foundation for engineering new variants.
Psychomotor Impairments and Therapeutic Implications Revealed by a Mutation Associated with Infantile Parkinsonism-Dystonia
Authors: Aguilar Jenny I. , Cheng Mary Hongying , Font Josep , Schwartz Alexandra C. , Ledwitch Kaitlyn , Duran Amanda , Mabry Samuel J. , Belovich Andrea N. , Zhu Yanqi , Carter Angela M. , Shi Lei , Kurian Manju A. , Fenollar-Ferrer Cristina , Meiler Jens , Ryan Renae M. , Mchaourab Hassane S. , Bahar Ivet , Matthies Heinrich J. G. , Galli Aurelio 
Published: March 2021

ABSTRACTParkinson disease (PD) is a progressive, neurodegenerative disorder affecting over 6.1 million people worldwide. Although the cause of PD remains unclear, studies of highly-penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the molecular mechanisms underlying disease pathology. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a distinct type of infantile parkinsonism-dystonia that shares key clinical features with PD, including motor deficits (progressive bradykinesia, tremor, hypomimia) and altered DA neurotransmission. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. We found that this R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. This is demonstrated by both Rosetta molecular modeling and fine-grained simulations using hDAT R445C, as well as EPR analysis and X-ray crystallography of the bacterial homolog leucine transporter. Notably, the disruption of this IC network of interactions supported a channel-like intermediate of hDAT and compromised hDAT function. We demonstrate thatDrosophila melanogasterexpressing hDAT R445C show impaired hDAT activity, which is associated with DA dysfunction in isolated brains and with abnormal behaviors monitored at high-speed time resolution.We show that hDAT R445CDrosophilaexhibit motor deficits, lack of motor coordination (i.e. flight coordination) and phenotypic heterogeneity in these behaviors that is typically associated with DTDS and PD. These behaviors are linked with altered dopaminergic signaling stemming from loss of DA neurons and decreased DA availability. We rescued flight coordination through enhanced DAT surface expressionviathe lysosomal inhibitor chloroquine. Together, these studies shed light on how a DTDS-linked DAT mutation underlies DA dysfunction and, more broadly, the clinical phenotypes shared by DTDS and PD.
Structure and dynamics of the SARS-CoV-2 envelope protein monomer
Authors: Kuzmin Alexander , Orekhov Philipp , Astashkin Roman , Gordeliy Valentin , Gushchin Ivan 
Published: March 2021

AbstractCoronaviruses, especially SARS-CoV-2, present an ongoing threat for human wellbeing. Consequently, elucidation of molecular determinants of their function and interaction with host is an important task. Whereas some of the coronaviral proteins are extensively characterized, others remain understudied. Here, we use molecular dynamics simulations to analyze the structure and dynamics of the SARS-CoV-2 envelope (E) protein (a viroporin) in the monomeric form. The protein consists of the hydrophobic α-helical transmembrane domain (TMD) and amphiphilic α-helices H2 and H3, connected by flexible linkers. We show that TMD has a preferable orientation in the membrane, while H2 and H3 reside at the membrane surface. Orientation of H2 is strongly influenced by palmitoylation of cysteines Cys40, Cys43 and Cys44. Glycosylation of Asn66 affects the orientation of H3. We also observe that the E protein both generates and senses the membrane curvature, preferably localizing with the C-terminus at the convex regions of the membrane. This may be favorable for assembly of the E protein oligomers, whereas induction of curvature may facilitate budding of the viral particles. The presented results may be helpful for better understanding of the function of coronaviral E protein and viroporins in general, and for overcoming the ongoing SARS-CoV-2 pandemic.
A role for glial fibrillary acidic protein (GFAP)-expressing cells in the regulation of gonadotropin-releasing hormone (GnRH) but not arcuate kisspeptin neuron output
Authors: Vanacker Charlotte , DeFazio R. Anthony , Sykes Charlene M. , Moenter Suzanne M. 
Published: March 2021

AbstractGnRH neurons are the final central neural output regulating fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (KNDy neurons) are considered the main regulator of GnRH output. GnRH and KNDy neurons are surrounded by astrocytes, which can modulate neuronal activity and communicate over distances. Prostaglandin E2 (PGE2), synthesized primarily by astrocytes, increases GnRH neuron activity and downstream pituitary release of luteinizing hormone (LH). We hypothesized GFAP-expressing astrocytes play a role regulating GnRH and/or KNDy neuron activity and LH release. We used adenoassociated viruses to target designer receptor exclusively activated by designer drugs (DREADDs) to GFAP-expressing cells to activate Gq or Gi-mediated signaling. Activating Gq signaling in the preoptic area, near GnRH neurons, but not in the arcuate, increases LH releasein vivoand GnRH firingin vitrovia a mechanism in part dependent upon PGE2. These data suggest astrocytes can activate GnRH/LH release in a manner independent of KNDy neurons.