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Landry Blanc, Isaac B Daudelin, Brendan K Podell, Pei-Yu Chen, Matthew Zimmerman, Amanda J Martinot, Rada M Savic, Brendan Prideaux, Veronique Anne Dartois
Understanding the distribution patterns of antibiotics at the site of infection is paramount to selecting adequate drug regimens and developing new antibiotics. Tuberculosis (TB) lung lesions are made of various immune cell types, some of which harbor persistent forms of the pathogen, Mycobacterium tuberculosis . By combining high resolution MALDI MSI with histology staining and quantitative image analysis in rabbits with active TB, we have mapped the distribution of a fluoroquinolone at high resolution, and identified the immune-pathological factors driving its heterogeneous penetration within TB lesions, in relation to where bacteria reside...
November 14, 2018: ELife
Judy Lisette Martin, Erin Nicole Sanders, Paola Moreno-Roman, Leslie Ann Jaramillo Koyama, Shruthi Balachandra, XinXin Du, Lucy Erin O'Brien
Organ renewal is governed by the dynamics of cell division, differentiation, and loss. To study these dynamics in real time, we present a platform for extended live imaging of the adult Drosophila midgut, a premier genetic model for stem cell-based organs. A window cut into a living animal allows the midgut to be imaged while intact and physiologically functioning. This approach prolongs imaging sessions to 12-16 hours and yields movies that document cell and tissue dynamics at vivid spatiotemporal resolution...
November 14, 2018: ELife
Margarita V Meer, Dmitriy I Podolskiy, Alexander Tyshkovskiy, Vadim N Gladyshev
Age predictors based on DNA methylation levels at a small set of CpG sites, DNAm clocks, have been developed for humans and extended to several other species. Three currently available versions of mouse DNAm clocks were either created for individual tissues or tuned towards young ages. Here, we constructed a robust multi-tissue age predictor based on 435 CpG sites, which covers the entire mouse lifespan and remains unbiased with respect to any particular age group. It can successfully detect the effects of certain lifespan-modulating interventions on DNAm age as well as the rejuvenation effect related to the transition from fibroblasts to iPSCs...
November 14, 2018: ELife
Atsushi Kikumoto, Ulrich Mayr
Despite strong theoretical reasons for assuming that abstract representations organize complex action sequences in terms of subplans (chunks) and sequential positions, we lack methods to directly track such content-independent, hierarchical representations in humans. We applied time-resolved, multivariate decoding analysis to the pattern of rhythmic EEG activity that was registered while participants planned and executed individual elements from pre-learned, structured sequences. Across three experiments, the theta and alpha-band activity coded basic elements and abstract control representations, in particular the ordinal position of basic elements, but also the identity and position of chunks...
November 14, 2018: ELife
Mei Zeng, Nicholas P Kwiatkowski, Tinghu Zhang, Behnam Nabet, Mousheng Xu, Yanke Liang, Chunshan Quan, Jinhua Wang, Mingfeng Hao, Sangeetha Palakurthi, Shan Zhou, Qing Zeng, Paul T Kirschmeier, Khyati Meghani, Alan L Leggett, Jun Qi, Geoffrey I Shapiro, Joyce F Liu, Ursula A Matulonis, Charles Y Lin, Panagiotis A Konstantinopoulos, Nathanael S Gray
High-grade serous ovarian cancer is characterized by extensive copy number alterations, among which the amplification of MYC oncogene occurs in nearly half of tumors. We demonstrate that ovarian cancer cells highly depend on MYC for maintaining their oncogenic growth, indicating MYC as a therapeutic target for this difficult-to-treat malignancy. However, targeting MYC directly has proven difficult. We screen small molecules targeting transcriptional and epigenetic regulation, and find that THZ1 - a chemical inhibiting CDK7, CDK12, and CDK13 - markedly downregulates MYC...
November 13, 2018: ELife
Peter Tonzi, Yandong Yin, Chelsea Wei Ting Lee, Eli Rothenberg, Tony T Huang
DNA replication stress is often defined by the slowing or stalling of replication fork progression leading to local or global DNA synthesis inhibition. Failure to resolve replication stress in a timely manner contribute towards cell cycle defects, genome instability and human disease; however, the mechanism for fork recovery remains poorly defined. Here we show that the translesion DNA polymerase (Pol) kappa, a DinB orthologue, has a unique role in both protecting and restarting stalled replication forks under conditions of nucleotide deprivation...
November 13, 2018: ELife
Jennifer M Ortega, Özgür Genç, Graeme W Davis
Presynaptic homeostatic plasticity (PHP) compensates for impaired postsynaptic neurotransmitter receptor function through a rapid, persistent adjustment of neurotransmitter release, an effect that can exceed 200%. An unexplained property of PHP is the preservation of short-term plasticity (STP), thereby stabilizing activity-dependent synaptic information transfer. We demonstrate that the dramatic potentiation of presynaptic release during PHP is achieved while simultaneously maintaining a constant ratio of primed to super-primed synaptic vesicles, thereby preserving STP...
November 13, 2018: ELife
Kevin C Courtney, Karen Yy Fung, Frederick R Maxfield, Gregory D Fairn, Xiaohui Zha
The plasma membrane in mammalian cells is rich in cholesterol. How cholesterol partitions between the two leaflets of the plasma membrane remains a matter of debate. Recently, Liu et al used domain 4 (D4) of perfringolysin O as a cholesterol sensor to argue that cholesterol is mostly in the exofacial leaflet ( Liu et al. , 2017). This conclusion was made by interpreting D4 binding in live cells using in vitro calibrations with liposomes. However, liposomes may be unfaithful in mimicking the plasma membrane, as we demonstrate here...
November 13, 2018: ELife
Jamshid Faraji, Mitra Karimi, Nabiollah Soltanpour, Alireza Moharrerie, Zahra Rouhzadeh, Hamid Lotfi, S Abedin Hosseini, S Yaghoob Jafari, Shabnam Roudaki, Reza Moeeini, Gerlinde As Metz
The quality of social relationships is a powerful determinant of lifetime health. Here, we explored the impact of social experiences on circulating oxytocin (OT) concentration, telomere length (TL) and novelty-seeking behaviour in male and female rats. Prolonged social housing raised circulating OT levels in both sexes while elongating TL only in females. Novelty-seeking behaviour in females was more responsive to social housing and increased OT levels than males. The OT antagonist (OT ANT) L-366,509 blocked the benefits of social housing in all conditions along with female-specific TL erosion and novelty-seeking deficit...
November 13, 2018: ELife
Stanley Nithianantham, Brian D Cook, Madielene Beans, Fei Guo, Fred Chang, Jawdat Al-Bassam
XMAP215/Stu2/Alp14 proteins accelerate microtubule plus-end polymerization by recruiting tubulins via arrays of Tumor Overexpressed Gene (TOG) domains, yet their mechanism remains unknown. Here, we describe the biochemical and structural basis for TOG arrays in recruiting and polymerizing tubulins. Alp14 binds four tubulins via dimeric TOG1-TOG2 subunits, in which each domain exhibits a distinct exchange rate for tubulin. X-ray structures revealed square-shaped assemblies composed of pseudo-dimeric TOG1-TOG2 subunits assembled head-to-tail, positioning four unpolymerized tubulins in a polarized wheel-like configuration...
November 13, 2018: ELife
Ximena I Salinas-Hernández, Pascal Vogel, Sebastian Betz, Raffael Kalisch, Torfi Sigurdsson, Sevil Duvarci
Extinction of fear responses is critical for adaptive behavior and deficits in this form of safety learning are hallmark of anxiety disorders. However, the neuronal mechanisms that initiate extinction learning are largely unknown. Here we show, using single-unit electrophysiology and cell-type specific fiber photometry, that dopamine neurons in the ventral tegmental area (VTA) are activated by the omission of the aversive unconditioned stimulus (US) during fear extinction. This dopamine signal occurred specifically during the beginning of extinction when the US omission is unexpected, and correlated strongly with extinction learning...
November 13, 2018: ELife
Dilawar Singh, Upinder Singh Bhalla
Molecular bistables are strong candidates for long-term information storage, for example, in synaptic plasticity. Calcium/calmodulin dependent protein Kinase II (CaMKII) is a highly expressed synaptic protein which has been proposed to form a molecular bistable switch capable of maintaining its state for years despite protein turnover and stochastic noise. It has recently been shown that CaMKII holoenzymes exchange subunits among themselves. Here we used computational methods to analyze the effect of subunit exchange on the CaMKII pathway in the presence of diffusion in two different micro-environments, the post synaptic density (PSD) and spine cytosol...
November 12, 2018: ELife
Hugo Balleza-Tapia, Sophie Crux, Yuniesky Andrade-Talavera, Pablo Dolz-Gaiton, Daniela Papadia, Gefei Chen, Jan Johansson, André Fisahn
Amyloid-β peptide (Aβ) forms plaques in Alzheimer's Disease (AD) and is responsible for early cognitive deficits in AD patients. Advancing cognitive decline is accompanied by progressive impairment of cognition-relevant EEG patterns such as gamma oscillations. The endocannabinoid anandamide, a TrpV1-receptor agonist, reverses hippocampal damage and memory impairment in rodents and protects neurons from Aβ-induced cytotoxic effects. Here we investigate a restorative role of TrpV1-receptor activation against Aβ-induced degradation of hippocampal neuron function and gamma oscillations...
November 12, 2018: ELife
Haichuan Zhu, Liuzhen Zhang, Yilin Wu, Bingjie Dong, Weilong Guo, Mei Wang, Lu Yang, Xiaoying Fan, Yuliang Tang, Ningshu Liu, Xiaoguang Lei, Hong Wu
Leukemia stem cells (LSCs) are regarded as the origins and key therapeutic targets of leukemia, but limited knowledge is available on the key determinants of LSC 'stemness'. Using single-cell RNA-seq analysis, we identify a master regulator, SPI1, the LSC-specific expression of which determines the molecular signature and activity of LSCs in the murine Pten -null T-ALL model. Although initiated by PTEN-controlled b-catenin activation, Spi1 expression and LSC 'stemness' are maintained by a b-catenin-SPI1-HAVCR2 regulatory circuit independent of the leukemogenic driver mutation...
November 9, 2018: ELife
Diego Balboa, Jonna Saarimäki-Vire, Daniel Borshagovski, Mantas Survila, Päivi Lindholm, Emilia Galli, Solja Eurola, Jarkko Ustinov, Heli Grym, Hanna Huopio, Juha Partanen, Kirmo Wartiovaara, Timo Otonkoski
Insulin gene mutations are a leading cause of neonatal diabetes. They can lead to proinsulin misfolding and its retention in endoplasmic reticulum (ER). This results in increased ER-stress suggested to trigger beta-cell apoptosis. In humans, the mechanisms underlying beta-cell failure remain unclear. Here we show that misfolded proinsulin impairs developing beta-cell proliferation without increasing apoptosis. We generated induced pluripotent stem cells (iPSCs) from people carrying insulin ( INS ) mutations, engineered isogenic CRISPR-Cas9 mutation-corrected lines and differentiated them to beta-like cells...
November 9, 2018: ELife
Jasenko Zivanov, Takanori Nakane, Björn O Forsberg, Dari Kimanius, Wim Jh Hagen, Erik Lindahl, Sjors Hw Scheres
Here, we describe the third major release of RELION. CPU-based vector acceleration has been added in addition to GPU support, which provides flexibility in use of resources and avoids memory limitations. Reference-free autopicking with Laplacian-of-Gaussian filtering and execution of jobs from python allows non-interactive processing during acquisition, including 2D-classification, de novo model generation and 3D-classification. Per-particle refinement of CTF parameters and correction of estimated beam tilt provides higher-resolution reconstructions when particles are at different heights in the ice, and/or coma-free alignment has not been optimal...
November 9, 2018: ELife
Yael Riahi, Tal Israeli, Roni Yeroslaviz, Shoshana Chimenez, Dana Avrahami, Miri Stolovich-Rain, Ido Alter, Marina Sebag, Nava Polin, Ernesto Bernal-Mizrachi, Yuval Dor, Erol Cerasi, Gil Leibowitz
Unresolved ER stress followed by cell death is recognized as the main cause of a multitude of pathologies including neonatal diabetes. A systematic analysis of the mechanisms of β-cell loss and dysfunction in Akita mice, in which a mutation in the proinsulin gene causes a severe form of permanent neonatal diabetes, showed no increase in β-cell apoptosis throughout life. Surprisingly, we found that the main mechanism leading to β-cell dysfunction is marked impairment of β-cell growth during the early postnatal life due to transient inhibition of mTORC1, which governs postnatal β-cell growth and differentiation...
November 9, 2018: ELife
Manuela D'Alessandro, Magali Richard, Christian Stigloher, Vincent Gache, Thomas Boulin, Janet E Richmond, JeanLouis Bessereau
The assembly of neurotransmitter receptors in the endoplasmic reticulum limits the number of receptors delivered to the plasma membrane, ultimately controlling neurotransmitter sensitivity and synaptic transfer function. In a forward genetic screen conducted in the nematode C. elegans , we identified c rld-1 as a gene required for the synaptic expression of ionotropic acetylcholine receptors (AChR). We demonstrated that the CRLD-1A isoform is a membrane-associated ER-resident protein disulfide isomerase (PDI)...
November 8, 2018: ELife
Lorna Moll, Noa Roitenberg, Michal Bejerano-Sagie, Hana Boocholez, Filipa Carvalhal Marques, Yuli Volovik, Tayir Elami, Atif Ahmed Siddiqui, Danielle Grushko, Adi Biram, Bar Lampert, Hana Achache, Tommer Ravid, Yonatan B Tzur, Ehud Cohen
Although aging-regulating pathways were discovered a few decades ago, it is not entirely clear how their activities are orchestrated, to govern lifespan and proteostasis at the organismal level. Here we utilized the nematode Caenorhabditis elegans to examine whether the alteration of aging, by reducing the activity of the Insulin/IGF signaling (IIS) cascade, affects protein SUMOylation. We found that IIS activity promotes the SUMOylation of the germline protein, CAR-1, thereby shortening lifespan and impairing proteostasis...
November 7, 2018: ELife
Andrew J Borst, Connor E Weidle, Matthew D Gray, Brandon Frenz, Joost Snijder, M Gordon Joyce, Ivelin S Georgiev, Guillaume Be Stewart-Jones, Peter D Kwong, Andrew T McGuire, Frank DiMaio, Leonidas Stamatatos, Marie Pancera, David Veesler
VRC01 broadly neutralizing antibodies (bnAbs) target the CD4-binding site (CD4BS ) of the human immunodeficiency virus-1 (HIV-1) envelope glycoprotein (Env). Unlike mature antibodies, corresponding VRC01 germline precursors poorly bind to Env. Immunogen design has mostly relied on glycan removal from trimeric Env constructs and has had limited success in eliciting mature VRC01 bnAbs. To better understand elicitation of such bnAbs, we characterized the inferred germline precursor of VRC01 in complex with a modified trimeric 426c Env by cryo-electron microscopy and a 426c gp120 core by X-ray crystallography, biolayer interferometry, immunoprecipitation, and glycoproteomics...
November 7, 2018: ELife
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