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Membrane contact sites regulate vacuolar fission via sphingolipid metabolism eLife (IF 7.7) Pub Date : 2024-03-27 Kazuki Hanaoka, Kensuke Nishikawa, Atsuko Ikeda, Philipp Schlarmann, Saku Sasaki, Sotaro Fujii, Sayumi Yamashita, Aya Nakaji, Kouichi Funato
Membrane contact sites (MCSs) are junctures that perform important roles including coordinating lipid metabolism. Previous studies have indicated that vacuolar fission/fusion processes are coupled with modifications in the membrane lipid composition. However, it has been still unclear whether MCS-mediated lipid metabolism controls the vacuolar morphology. Here, we report that deletion of tricalbins
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Exploration of drug resistance mechanisms in triple negative breast cancer cells using a microfluidic device and patient tissues eLife (IF 7.7) Pub Date : 2024-03-27 Wanyoung Lim, Inwoo Hwang, Jiande Zhang, Zhenzhong Chen, Jeonghun Han, Jaehyung Jeon, Bon-Kyoung Koo, Sangmin Kim, Jeong Eon Lee, Youngkwan Kim, Kenneth J Pienta, Sarah R Amend, Robert H Austin, Jee-Yin Ahn, Sungsu Park
Chemoresistance is a major cause of treatment failure in many cancers. However, the life cycle of cancer cells as they respond to and survive environmental and therapeutic stress is understudied. In this study, we utilized a microfluidic device to induce the development of doxorubicin-resistant (DOXR) cells from triple negative breast cancer (TNBC) cells within 11 days by generating gradients of DOX
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Intermittent fasting promotes type 3 innate lymphoid cells secreting IL-22 contributing to the beigeing of white adipose tissue eLife (IF 7.7) Pub Date : 2024-03-27 Hong Chen, Lijun Sun, Lu Feng, Xue Han, Yunhua Zhang, Wenbo Zhai, Zehe Zhang, Michael Mulholland, Weizhen Zhang, Yue Yin
Mechanism underlying the metabolic benefit of intermittent fasting remains largely unknown. Here, we reported that intermittent fasting promoted interleukin-22 (IL-22) production by type 3 innate lymphoid cells (ILC3s) and subsequent beigeing of subcutaneous white adipose tissue. Adoptive transfer of intestinal ILC3s increased beigeing of white adipose tissue in diet-induced-obese mice. Exogenous IL-22
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Comprehensive mutagenesis maps the effect of all single-codon mutations in the AAV2 rep gene on AAV production eLife (IF 7.7) Pub Date : 2024-03-27 Nina K Jain, Pierce J Ogden, George M Church
Recombinant adeno-associated viruses (rAAVs) are the predominant gene therapy vector. Several rAAV vectored therapies have achieved regulatory approval, but production of sufficient rAAV quantities remains difficult. The AAV Rep proteins, which are essential for genome replication and packaging, represent a promising engineering target for improvement of rAAV production but remain underexplored. To
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Synaptotagmin 7 docks synaptic vesicles to support facilitation and Doc2α-triggered asynchronous release eLife (IF 7.7) Pub Date : 2024-03-27 Zhenyong Wu, Grant F Kusick, Manon MM Berns, Sumana Raychaudhuri, Kie Itoh, Alexander M Walter, Edwin R Chapman, Shigeki Watanabe
Despite decades of intense study, the molecular basis of asynchronous neurotransmitter release remains enigmatic. Synaptotagmin (syt) 7 and Doc2 have both been proposed as Ca2+ sensors that trigger this mode of exocytosis, but conflicting findings have led to controversy. Here, we demonstrate that at excitatory mouse hippocampal synapses, Doc2α is the major Ca2+ sensor for asynchronous release, while
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Kit Ligand and Kit receptor tyrosine kinase sustain synaptic inhibition of Purkinje cells eLife (IF 7.7) Pub Date : 2024-03-27 Tariq Zaman, Daniel Vogt, Jeremy Prokop, Qusai Abdulkhaliq Alsabia, Gabriel Simms, April Stafford, Bryan W Luikart, Michael R Williams
The cell-type-specific expression of ligand/receptor and cell-adhesion molecules is a fundamental mechanism through which neurons regulate connectivity. Here, we determine a functional relevance of the long-established mutually exclusive expression of the receptor tyrosine kinase Kit and the trans-membrane protein Kit Ligand by discrete populations of neurons in the mammalian brain. Kit is enriched
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Affinity-tagged SMAD1 and SMAD5 mouse lines reveal transcriptional reprogramming mechanisms during early pregnancy eLife (IF 7.7) Pub Date : 2024-03-27
Endometrial decidualization, a prerequisite for successful pregnancies, relies on transcriptional reprogramming driven by progesterone receptor (PR) and bone morphogenetic protein (BMP)-SMAD1/SMAD5 signaling pathways. Despite their critical roles in early pregnancy, how these pathways intersect in reprogramming the endometrium into a receptive state remains unclear. To define how SMAD1 and/or SMAD5
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Conformation selection by ATP-competitive inhibitors and allosteric communication in ERK2 eLife (IF 7.7) Pub Date : 2024-03-27 Jake W Anderson, David Vaisar, David N Jones, Laurel M Pegram, Guy P Vigers, Huifen Chen, John G Moffat, Natalie G Ahn
Activation of the extracellular signal-regulated kinase-2 (ERK2) by phosphorylation has been shown to involve changes in protein dynamics, as determined by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and NMR relaxation dispersion measurements. These can be described by a global exchange between two conformational states of the active kinase, named ‘L’ and ‘R,’ where R is associated with
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Meta-Research: Understudied genes are lost in a leaky pipeline between genome-wide assays and reporting of results eLife (IF 7.7) Pub Date : 2024-03-28 Reese Richardson, Heliodoro Tejedor Navarro, Luis A Nunes Amaral, Thomas Stoeger
Present-day publications on human genes primarily feature genes that already appeared in many publications prior to completion of the Human Genome Project in 2003. These patterns persist despite the subsequent adoption of high-throughput technologies, which routinely identify novel genes associated with biological processes and disease. Although several hypotheses for bias in the selection of genes
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voyAGEr, a free web interface for the analysis of age-related gene expression alterations in human tissues eLife (IF 7.7) Pub Date : 2024-03-28 Arthur L Schneider, Rita Martins-Silva, Alexandre Kaizeler, Nuno Saraiva-Agostinho, Nuno L Barbosa-Morais
We herein introduce voyAGEr, an online graphical interface to explore age-related gene expression alterations in 49 human tissues. voyAGEr offers a visualisation and statistical toolkit for the finding and functional exploration of sex- and tissue-specific transcriptomic changes with age. In its conception, we developed a novel bioinformatics pipeline leveraging RNA sequencing data, from the GTEx project
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Neurophysiological trajectories in Alzheimer’s disease progression eLife (IF 7.7) Pub Date : 2024-03-28 Kiwamu Kudo, Kamalini G Ranasinghe, Hirofumi Morise, Faatimah Syed, Kensuke Sekihara, Katherine P Rankin, Bruce L Miller, Joel H Kramer, Gil D Rabinovici, Keith Vossel, Heidi E Kirsch, Srikantan S Nagarajan
Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline
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Task-anchored grid cell firing is selectively associated with successful path integration-dependent behaviour eLife (IF 7.7) Pub Date : 2024-03-28 Harry Clark, Matthew F Nolan
Grid firing fields have been proposed as a neural substrate for spatial localisation in general or for path integration in particular. To distinguish these possibilities, we investigate firing of grid and non-grid cells in the mouse medial entorhinal cortex during a location memory task. We find that grid firing can either be anchored to the task environment, or can encode distance travelled independently
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Imaging analysis of six human histone H1 variants reveals universal enrichment of H1.2, H1.3, and H1.5 at the nuclear periphery and nucleolar H1X presence eLife (IF 7.7) Pub Date : 2024-03-26
Histone H1 participates in chromatin condensation and regulates nuclear processes. Human somatic cells may contain up to seven histone H1 variants, although their functional heterogeneity is not fully understood. Here, we have profiled the differential nuclear distribution of the somatic H1 repertoire in human cells through imaging techniques including super-resolution microscopy. H1 variants exhibit
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Genetic associations between circulating immune cells and periodontitis highlight the prospect of systemic immunoregulation in periodontal care eLife (IF 7.7) Pub Date : 2024-03-27 Xinjian Ye, Yijing Bai, Mengjun Li, Yuhang Ye, Yitong Chen, Bin Liu, Yuwei Dai, Shan Wang, Weiyi Pan, Zhiyong Wang, Yingying Mao, Qianming Chen
Periodontitis drives irreversible destruction of periodontal tissue and is prone to exacerbating inflammatory disorders. Systemic immunomodulatory management continues to be an attractive approach in periodontal care, particularly within the context of ‘predictive, preventive, and personalized’ periodontics. The present study incorporated genetic proxies identified through genome-wide association studies
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More than just a simple barrier eLife (IF 7.7) Pub Date : 2024-03-27
Endothelial cell subpopulations are characterized by unique gene expression profiles, epigenetic landscapes and functional properties.
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The cryo-EM structure of ASK1 reveals an asymmetric architecture allosterically modulated by TRX1 eLife (IF 7.7) Pub Date : 2024-03-27 Karolina Honzejkova, Dalibor Kosek, Veronika Obsilova, Tomas Obsil
Apoptosis signal-regulating kinase 1 (ASK1) is a crucial stress sensor, directing cells toward apoptosis, differentiation, and senescence via the p38 and JNK signaling pathways. ASK1 dysregulation has been associated with cancer and inflammatory, cardiovascular, and neurodegenerative diseases, among others. However, our limited knowledge of the underlying structural mechanism of ASK1 regulation hampers
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Phosphorylation, disorder, and phase separation govern the behavior of Frequency in the fungal circadian clock eLife (IF 7.7) Pub Date : 2024-03-25 Daniyal Tariq, Nicole Maurici, Bradley M Bartholomai, Siddarth Chandrasekaran, Jay C Dunlap, Alaji Bah, Brian R Crane
Circadian clocks are composed of transcription-translation negative feedback loops that pace rhythms of gene expression to the diurnal cycle. In the filamentous fungus Neurospora crassa, the proteins Frequency (FRQ), the FRQ-interacting RNA helicase (FRH), and Casein-Kinase I (CK1) form the FFC complex that represses expression of genes activated by the white-collar complex (WCC). FRQ orchestrates
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Blinding reduces institutional prestige bias during initial review of applications for a young investigator award eLife (IF 7.7) Pub Date : 2024-03-25 Anne E Hultgren, Nicole MF Patras, Jenna Hicks
Organizations that fund research are keen to ensure that their grant selection processes are fair and equitable for all applicants. In 2020, the Arnold and Mabel Beckman Foundation introduced blinding to the first stage of the process used to review applications for Beckman Young Investigator (BYI) awards: applicants were instructed to blind the technical proposal in their initial Letter of Intent
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Dopamine lesions alter the striatal encoding of single-limb gait eLife (IF 7.7) Pub Date : 2024-03-25
The striatum serves an important role in motor control, and neurons in this area encode the body’s initiation, cessation, and speed of locomotion. However, it remains unclear whether the same neurons also encode the step-by-step rhythmic motor patterns of individual limbs that characterize gait. By combining high-speed video tracking, electrophysiology, and optogenetic tagging, we found that a sizable
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A novel MARV glycoprotein-specific antibody with potentials of broad-spectrum neutralization to filovirus eLife (IF 7.7) Pub Date : 2024-03-25
Marburg virus (MARV) is one of the filovirus species that cause deadly hemorrhagic fever in humans, with mortality rates up to 90%. Neutralizing antibodies represent ideal candidates to prevent or treat virus disease. However, no antibody has been approved for MARV treatment to date. In this study, we identified a novel human antibody named AF-03 that targeted MARV glycoprotein (GP). AF-03 possessed
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Repulsive Sema3E-Plexin-D1 signaling coordinates both axonal extension and steering via activating an autoregulatory factor, Mtss1 eLife (IF 7.7) Pub Date : 2024-03-25
Axon guidance molecules are critical for neuronal pathfinding because they regulate directionality and growth pace during nervous system development. However, the molecular mechanisms coordinating proper axonal extension and turning are poorly understood. Here, Metastasis Suppressor 1 (Mtss1), a membrane protrusion protein, ensured axonal extension while sensitizing axons to the Semaphorin 3E (Sema3E)-Plexin-D1
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A stable microtubule bundle formed through an orchestrated multistep process controls quiescence exit eLife (IF 7.7) Pub Date : 2024-03-25
Cells fine-tune microtubule assembly in both space and time to give rise to distinct edifices with specific cellular functions. In proliferating cells, microtubules are highly dynamics, and proliferation cessation often leads to their stabilization. One of the most stable microtubule structures identified to date is the nuclear bundle assembled in quiescent yeast. In this article, we characterize the
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Fetal liver macrophages contribute to the hematopoietic stem cell niche by controlling granulopoiesis eLife (IF 7.7) Pub Date : 2024-03-25 Amir Hossein Kayvanjoo, Iva Splichalova, David Alejandro Bejarano, Hao Huang, Katharina Mauel, Nikola Makdissi, David Heider, Hui Ming Tew, Nora Reka Balzer, Eric Greto, Collins Osei-Sarpong, Kevin Baßler, Joachim L Schultze, Stefan Uderhardt, Eva Kiermaier, Marc Beyer, Andreas Schlitzer, Elvira Mass
During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche
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A novel machine learning algorithm selects proteome signature to specifically identify cancer exosomes eLife (IF 7.7) Pub Date : 2024-03-26 Bingrui Li, Fernanda G Kugeratski, Raghu Kalluri
Non-invasive early cancer diagnosis remains challenging due to the low sensitivity and specificity of current diagnostic approaches. Exosomes are membrane-bound nanovesicles secreted by all cells that contain DNA, RNA, and proteins that are representative of the parent cells. This property, along with the abundance of exosomes in biological fluids makes them compelling candidates as biomarkers. However
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Synthetic eco-evolutionary dynamics in simple molecular environment eLife (IF 7.7) Pub Date : 2024-03-26 Luca Casiraghi, Francesco Mambretti, Anna Tovo, Elvezia Maria Paraboschi, Samir Suweis, Tommaso Bellini
The understanding of eco-evolutionary dynamics, and in particular the mechanism of coexistence of species, is still fragmentary and in need of test bench model systems. To this aim we developed a variant of SELEX in vitro selection to study the evolution of a population of ∼1015 single-strand DNA oligonucleotide ‘individuals’. We begin with a seed of random sequences which we select via affinity capture
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Emergence of catalytic function in prebiotic information-coding polymers eLife (IF 7.7) Pub Date : 2024-03-26 Alexei V Tkachenko, Sergei Maslov
Life as we know it relies on the interplay between catalytic activity and information processing carried out by biological polymers. Here we present a plausible pathway by which a pool of prebiotic information-coding oligomers could acquire an early catalytic function, namely sequence-specific cleavage activity. Starting with a system capable of non-enzymatic templated replication, we demonstrate that
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Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment eLife (IF 7.7) Pub Date : 2024-03-26 Hideo Hagihara, Hirotaka Shoji, Satoko Hattori, Giovanni Sala, Yoshihiro Takamiya, Mika Tanaka, Masafumi Ihara, Mihiro Shibutani, Izuho Hatada, Kei Hori, Mikio Hoshino, Akito Nakao, Yasuo Mori, Shigeo Okabe, Masayuki Matsushita, Anja Urbach, Yuta Katayama, Akinobu Matsumoto, Keiichi I Nakayama, Shota Katori, Takuya Sato, Takuji Iwasato, Haruko Nakamura, Yoshio Goshima, Matthieu Raveau, Tetsuya Tatsukawa
Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia
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Disruption of awake sharp-wave ripples does not affect memorization of locations in repeated-acquisition spatial memory tasks eLife (IF 7.7) Pub Date : 2024-03-26 Lies Deceuninck, Fabian Kloosterman
Storing and accessing memories is required to successfully perform day-to-day tasks, for example for engaging in a meaningful conversation. Previous studies in both rodents and primates have correlated hippocampal cellular activity with behavioral expression of memory. A key role has been attributed to awake hippocampal replay - a sequential reactivation of neurons representing a trajectory through
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Dysregulation of mTOR signaling mediates common neurite and migration defects in both idiopathic and 16p11.2 deletion autism neural precursor cells eLife (IF 7.7) Pub Date : 2024-03-25 Smrithi Prem, Bharati Dev, Cynthia Peng, Monal Mehta, Rohan Alibutud, Robert J Connacher, Madeline St Thomas, Xiaofeng Zhou, Paul Matteson, Jinchuan Xing, James H Millonig, Emanuel DiCicco-Bloom
Autism spectrum disorder (ASD) is defined by common behavioral characteristics, raising the possibility of shared pathogenic mechanisms. Yet, vast clinical and etiological heterogeneity suggests personalized phenotypes. Surprisingly, our iPSC studies find that six individuals from two distinct ASD-subtypes, idiopathic and 16p11.2 deletion, have common reductions in neural precursor cell (NPC) neurite
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Assembly of neuron- and radial glial-cell-derived extracellular matrix molecules promotes radial migration of developing cortical neurons eLife (IF 7.7) Pub Date : 2024-03-21 Ayumu Mubuchi, Mina Takechi, Shunsuke Nishio, Tsukasa Matsuda, Yoshifumi Itoh, Chihiro Sato, Ken Kitajima, Hiroshi Kitagawa, Shinji Miyata
Radial neuronal migration is a key neurodevelopmental event for proper cortical laminar organization. The multipolar-to-bipolar transition, a critical step in establishing neuronal polarity during radial migration, occurs in the subplate/intermediate zone (SP/IZ), a distinct region of the embryonic cerebral cortex. It has been known that the extracellular matrix (ECM) molecules are enriched in the
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Comparative brain-wide mapping of ketamine- and isoflurane-activated nuclei and functional networks in the mouse brain eLife (IF 7.7) Pub Date : 2024-03-21 Yue Hu, Wenjie Du, Jiangtao Qi, Huoqing Luo, Zhao Zhang, Mengqiang Luo, Yingwei Wang
Ketamine (KET) and isoflurane (ISO) are two widely used general anesthetics, yet their distinct and shared neurophysiological mechanisms remain elusive. In this study, we conducted a comparative analysis of the effects of KET and ISO on c-Fos expression across the mouse brain, utilizing hierarchical clustering and c-Fos-based functional network analysis to evaluate the responses of individual brain
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Targeting host deoxycytidine kinase mitigates Staphylococcus aureus abscess formation eLife (IF 7.7) Pub Date : 2024-03-21 Volker Winstel, Evan R Abt, Thuc M Le, Caius G Radu
Host-directed therapy (HDT) is an emerging approach to overcome antimicrobial resistance in pathogenic microorganisms. Specifically, HDT targets host-encoded factors required for pathogen replication and survival without interfering with microbial growth or metabolism, thereby eliminating the risk of resistance development. By applying HDT and a drug repurposing approach, we demonstrate that (R)-DI-87
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Paradoxical imbalance between activated lymphocyte protein synthesis capacity and rapid division rate eLife (IF 7.7) Pub Date : 2024-03-21 Mina O Seedhom, Devin Dersh, Jaroslav Holly, Mariana Pavon-Eternod, Jiajie Wei, Matthew Angel, Lucas Shores, Alexandre David, Jefferson Santos, Heather Hickman, Jonathan W Yewdell
Rapid lymphocyte cell division places enormous demands on the protein synthesis machinery. Flow cytometric measurement of puromycylated ribosome-associated nascent chains after treating cells or mice with translation initiation inhibitors reveals that ribosomes in resting lymphocytes in vitro and in vivo elongate at typical rates for mammalian cells. Intriguingly, elongation rates can be increased
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The Hippo kinase cascade regulates a contractile cell behavior and cell density in a close unicellular relative of animals eLife (IF 7.7) Pub Date : 2024-03-22 Jonathan E Phillips, Duojia Pan
The genomes of close unicellular relatives of animals encode orthologs of many genes that regulate animal development. However, little is known about the function of such genes in unicellular organisms or the evolutionary process by which these genes came to function in multicellular development. The Hippo pathway, which regulates cell proliferation and tissue size in animals, is present in some of
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Structural mechanisms for VMAT2 inhibition by tetrabenazine eLife (IF 7.7) Pub Date : 2024-03-22 Michael P Dalton, Mary Hongying Cheng, Ivet Bahar, Jonathan A Coleman
The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson’s disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for
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Caveolin-1 protects endothelial cells from extensive expansion of transcellular tunnel by stiffening the plasma membrane eLife (IF 7.7) Pub Date : 2024-03-22 Camille Morel, Eline Lemerle, Feng-Ching Tsai, Thomas Obadia, Nishit Srivastava, Maud Marechal, Audrey Salles, Marvin Albert, Caroline Stefani, Yvonne Benito, François Vandenesch, Christophe Lamaze, Stéphane Vassilopoulos, Matthieu Piel, Patricia Bassereau, David Gonzalez-Rodriguez, Cecile Leduc, Emmanuel Lemichez
Large transcellular pores elicited by bacterial mono-ADP-ribosyltransferase (mART) exotoxins inhibiting the small RhoA GTPase compromise the endothelial barrier. Recent advances in biophysical modeling point toward membrane tension and bending rigidity as the minimal set of mechanical parameters determining the nucleation and maximal size of transendothelial cell macroaperture (TEM) tunnels induced
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Quantification of sporozoite expelling by Anopheles mosquitoes infected with laboratory and naturally circulating P. falciparum gametocytes eLife (IF 7.7) Pub Date : 2024-03-22 Chiara Andolina, Wouter Graumans, Moussa Guelbeogo, Geert-Jan van Gemert, Jordache Ramijth, Soré Harouna, Zongo Soumanaba, Rianne Stoter, Marga Vegte-Bolmer, Martina Pangos, Photini Sinnis, Katharine Collins, Sarah G Staedke, Alfred B Tiono, Chris Drakeley, Kjerstin Lanke, Teun Bousema
It is currently unknown whether all Plasmodium falciparum-infected mosquitoes are equally infectious. We assessed sporogonic development using cultured gametocytes in the Netherlands and naturally circulating strains in Burkina Faso. We quantified the number of sporozoites expelled into artificial skin in relation to intact oocysts, ruptured oocysts, and residual salivary gland sporozoites. In laboratory
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Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation eLife (IF 7.7) Pub Date : 2024-03-22 Wayne Mitchell, Ludger JE Goeminne, Alexander Tyshkovskiy, Sirui Zhang, Julie Y Chen, Joao A Paulo, Kerry A Pierce, Angelina H Choy, Clary B Clish, Steven P Gygi, Vadim N Gladyshev
Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the
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Purine nucleosides replace cAMP in allosteric regulation of PKA in trypanosomatid pathogens eLife (IF 7.7) Pub Date : 2024-03-22 Veronica Teresa Ober, George Boniface Githure, Yuri Volpato Santos, Sidney Becker, Gabriel Moya Munoz, Jérôme Basquin, Frank Schwede, Esben Lorentzen, Michael Boshart
Cyclic nucleotide binding domains (CNB) confer allosteric regulation by cAMP or cGMP to many signaling proteins, including PKA and PKG. PKA of phylogenetically distant Trypanosoma is the first exception as it is cyclic nucleotide-independent and responsive to nucleoside analogues (Bachmaier et al., 2019). Here, we show that natural nucleosides inosine, guanosine and adenosine are nanomolar affinity
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A myristoyl switch at the plasma membrane triggers cleavage and oligomerization of Mason-Pfizer monkey virus matrix protein eLife (IF 7.7) Pub Date : 2024-03-22 Markéta Častorálová, Jakub Sýs, Jan Prchal, Anna Pavlů, Lucie Prokopová, Zina Briki, Martin Hubálek, Tomas Ruml
For most retroviruses, including HIV, association with the plasma membrane (PM) promotes the assembly of immature particles, which occurs simultaneously with budding and maturation. In these viruses, maturation is initiated by oligomerization of polyprotein precursors. In contrast, several retroviruses, such as Mason-Pfizer monkey virus (M-PMV), assemble in the cytoplasm into immature particles that
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Murine alveolar macrophages rapidly accumulate intranasally administered SARS-CoV-2 Spike protein leading to neutrophil recruitment and damage eLife (IF 7.7) Pub Date : 2024-03-20 Chung Park, Il-Young Hwang, Serena Li-Sue Yan, Sinmanus Vimonpatranon, Danlan Wei, Don Van Ryk, Alexandre Girard, Claudia Cicala, James Arthos, John H Kehrl
The trimeric SARS-CoV-2 Spike protein mediates viral attachment facilitating cell entry. Most COVID-19 vaccines direct mammalian cells to express the Spike protein or deliver it directly via inoculation to engender a protective immune response. The trafficking and cellular tropism of the Spike protein in vivo and its impact on immune cells remains incompletely elucidated. In this study, we inoculated
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Inhibition of CERS1 in skeletal muscle exacerbates age-related muscle dysfunction eLife (IF 7.7) Pub Date : 2024-03-20 Martin Wohlwend, Pirkka-Pekka Laurila, Ludger JE Goeminne, Tanes Lima, Ioanna Daskalaki, Xiaoxu Li, Giacomo von Alvensleben, Barbara Crisol, Renata Mangione, Hector Gallart-Ayala, Olivier Burri, Stephen Butler, Jonathan Morris, Nigel Turner, Julijana Ivanisevic, Johan Auwerx
Age-related muscle wasting and dysfunction render the elderly population vulnerable and incapacitated, while underlying mechanisms are poorly understood. Here, we implicate the CERS1 enzyme of the de novo sphingolipid synthesis pathway in the pathogenesis of age-related skeletal muscle impairment. In humans, CERS1 abundance declines with aging in skeletal muscle cells and, correlates with biological
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Distinctive whole-brain cell types predict tissue damage patterns in thirteen neurodegenerative conditions eLife (IF 7.7) Pub Date : 2024-03-21
For over a century, brain research narrative has mainly centered on neuron cells. Accordingly, most neurodegenerative studies focus on neuronal dysfunction and their selective vulnerability, while we lack comprehensive analyses of other major cell types’ contribution. By unifying spatial gene expression, structural MRI, and cell deconvolution, here we describe how the human brain distribution of canonical
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Memory-specific encoding activities of the ventral tegmental area dopamine and GABA neurons eLife (IF 7.7) Pub Date : 2024-03-21 Vasileios Glykos, Shigeyoshi Fujisawa
Although the midbrain dopamine (DA) system plays a crucial role in higher cognitive functions, including updating and maintaining short-term memory, the encoding properties of the somatic spiking activity of ventral tegmental area (VTA) DA neurons for short-term memory computations have not yet been identified. Here, we probed and analyzed the activity of optogenetically identified DA and GABA neurons
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The stability of the primed pool of synaptic vesicles and the clamping of spontaneous neurotransmitter release rely on the integrity of the C-terminal half of the SNARE domain of syntaxin-1A eLife (IF 7.7) Pub Date : 2024-03-21 Andrea Salazar Lázaro, Thorsten Trimbuch, Gülçin Vardar, Christian Rosenmund
The SNARE proteins are central in membrane fusion and, at the synapse, neurotransmitter release. However, their involvement in the dual regulation of the synchronous release while maintaining a pool of readily releasable vesicles remains unclear. Using a chimeric approach, we performed a systematic analysis of the SNARE domain of STX1A by exchanging the whole SNARE domain or its N- or C-terminus subdomains
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A latent clinical-anatomical dimension relating metabolic syndrome to brain structure and cognition eLife (IF 7.7) Pub Date : 2024-03-21 Marvin Petersen, Felix Hoffstaedter, Felix L Nägele, Carola Mayer, Maximilian Schell, D Leander Rimmele, Birgit-Christiane Zyriax, Tanja Zeller, Simone Kühn, Jürgen Gallinat, Jens Fiehler, Raphael Twerenbold, Amir Omidvarnia, Kaustubh R Patil, Simon B Eickhoff, Goetz Thomalla, Bastian Cheng
The link between metabolic syndrome (MetS) and neurodegenerative as well as cerebrovascular conditions holds substantial implications for brain health in at-risk populations. This study elucidates the complex relationship between MetS and brain health by conducting a comprehensive examination of cardiometabolic risk factors, brain morphology, and cognitive function in 40,087 individuals. Multivariate
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The Toxoplasma monocarboxylate transporters are involved in the metabolism within the apicoplast and are linked to parasite survival eLife (IF 7.7) Pub Date : 2024-03-19 Hui Dong, Jiong Yang, Kai He, Wen-Bin Zheng, De-Hua Lai, Jing Liu, Hui-Yong Ding, Rui-Bin Wu, Kevin M Brown, Geoff Hide, Zhao-Rong Lun, Xing-Quan Zhu, Shaojun Long
The apicoplast is a four-membrane plastid found in the apicomplexans, which harbors biosynthesis and organelle housekeeping activities in the matrix. However, the mechanism driving the flux of metabolites, in and out, remains unknown. Here, we used TurboID and genome engineering to identify apicoplast transporters in Toxoplasma gondii. Among the many novel transporters, we show that one pair of apicomplexan
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Rho GTPase signaling and mDia facilitate endocytosis via presynaptic actin eLife (IF 7.7) Pub Date : 2024-03-19 Kristine Oevel, Svea Hohensee, Atul Kumar, Irving Rosas-Brugada, Francesca Bartolini, Tolga Soykan, Volker Haucke
Neurotransmission at synapses is mediated by the fusion and subsequent endocytosis of synaptic vesicle membranes. Actin has been suggested to be required for presynaptic endocytosis but the mechanisms that control actin polymerization and its mode of action within presynaptic nerve terminals remain poorly understood. We combine optical recordings of presynaptic membrane dynamics and ultrastructural
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Structural basis for the preservation of a subset of topologically associating domains in interphase chromosomes upon cohesin depletion eLife (IF 7.7) Pub Date : 2024-03-19 Davin Jeong, Guang Shi, Xin Li, D Thirumalai
Compartment formation in interphase chromosomes is a result of spatial segregation between euchromatin and heterochromatin on a few megabase pairs (Mbp) scale. On the sub-Mbp scales, topologically associating domains (TADs) appear as interacting domains along the diagonal in the ensemble averaged Hi-C contact map. Hi-C experiments showed that most of the TADs vanish upon deleting cohesin, while the
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A previously undescribed scene-selective site is the key to encoding ego-motion in naturalistic environments eLife (IF 7.7) Pub Date : 2024-03-20 Bryan Kennedy, Sarala N Malladi, Roger BH Tootell, Shahin Nasr
Current models of scene processing in the human brain include three scene-selective areas: the parahippocampal place area (or the temporal place areas), the restrosplenial cortex (or the medial place area), and the transverse occipital sulcus (or the occipital place area). Here, we challenged this model by showing that at least one other scene-selective site can also be detected within the human posterior
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Structural dynamics of the active HER4 and HER2/HER4 complexes is finely tuned by different growth factors and glycosylation eLife (IF 7.7) Pub Date : 2024-03-18 Raphael Trenker, Devan Diwanji, Tanner Bingham, Kliment A Verba, Natalia Jura
Human Epidermal growth factor Receptor 4 (HER4 or ERBB4) carries out essential functions in the development and maintenance of the cardiovascular and nervous systems. HER4 activation is regulated by a diverse group of extracellular ligands including the neuregulin (NRG) family and betacellulin (BTC), which promote HER4 homodimerization or heterodimerization with other HER receptors. Important cardiovascular
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Unlocking the power of virtual networking for early-career researchers eLife (IF 7.7) Pub Date : 2024-03-19
Many successful researchers in the biomedical sciences have benefitted from mentors and networks earlier in their career. However, early-career researchers from minoritized and underrepresented groups do not have the same access to potential mentors and networks as many of their peers. In this article we describe how ‘cold emails’ and social media platforms – notably Twitter/X and LinkedIn – can be
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Spatiotemporal dissection of the Golgi apparatus and the ER-Golgi intermediate compartment in budding yeast eLife (IF 7.7) Pub Date : 2024-03-19 Takuro Tojima, Yasuyuki Suda, Natsuko Jin, Kazuo Kurokawa, Akihiko Nakano
Cargo traffic through the Golgi apparatus is mediated by cisternal maturation, but it remains largely unclear how the cis-cisternae, the earliest Golgi sub-compartment, is generated and how the Golgi matures into the trans-Golgi network (TGN). Here, we use high-speed and high-resolution confocal microscopy to analyze the spatiotemporal dynamics of a diverse set of proteins that reside in and around
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Transformer-based spatial–temporal detection of apoptotic cell death in live-cell imaging eLife (IF 7.7) Pub Date : 2024-03-18 Alain Pulfer, Diego Ulisse Pizzagalli, Paolo Armando Gagliardi, Lucien Hinderling, Paul Lopez, Romaniya Zayats, Pau Carrillo-Barberà, Paola Antonello, Miguel Palomino-Segura, Benjamin Grädel, Mariaclaudia Nicolai, Alessandro Giusti, Marcus Thelen, Luca Maria Gambardella, Thomas T Murooka, Olivier Pertz, Rolf Krause, Santiago Fernandez Gonzalez
Intravital microscopy has revolutionized live-cell imaging by allowing the study of spatial–temporal cell dynamics in living animals. However, the complexity of the data generated by this technology has limited the development of effective computational tools to identify and quantify cell processes. Amongst them, apoptosis is a crucial form of regulated cell death involved in tissue homeostasis and
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Single-cell RNA sequencing unveils the hidden powers of zebrafish kidney for generating both hematopoiesis and adaptive antiviral immunity eLife (IF 7.7) Pub Date : 2024-03-18 Chongbin Hu, Nan Zhang, Yun Hong, Ruxiu Tie, Dongdong Fan, Aifu Lin, Ye Chen, Li-xin Xiang, Jian-zhong Shao
The vertebrate kidneys play two evolutionary conserved roles in waste excretion and osmoregulation. Besides, the kidney of fish is considered as a functional ortholog of mammalian bone marrow that serves as a hematopoietic hub for generating blood cell lineages and immunological responses. However, knowledge about the properties of kidney hematopoietic cells, and the functionality of the kidney in
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Linking environmental factors and gene regulation eLife (IF 7.7) Pub Date : 2024-03-18 Signe Penner-Goeke, Elisabeth B Binder
A technique called mSTARR-seq sheds light on how DNA methylation may shape responses to external stimuli by altering the activity of sequences that control gene expression.
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Caspase-1 activates gasdermin A in non-mammals eLife (IF 7.7) Pub Date : 2024-03-18 Zachary Paul Billman, Stephen Bela Kovacs, Bo Wei, Kidong Kang, Ousmane H Cissé, Edward A Miao
Gasdermins oligomerize to form pores in the cell membrane, causing regulated lytic cell death called pyroptosis. Mammals encode five gasdermins that can trigger pyroptosis: GSDMA, B, C, D, and E. Caspase and granzyme proteases cleave the linker regions of and activate GSDMB, C, D, and E, but no endogenous activation pathways are yet known for GSDMA. Here, we perform a comprehensive evolutionary analysis
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Habitat loss weakens the positive relationship between grassland plant richness and above-ground biomass eLife (IF 7.7) Pub Date : 2024-03-18 Yongzhi Yan, Scott Jarvie, Qing Zhang
Habitat loss and fragmentation per se have been shown to be a major threat to global biodiversity and ecosystem function. However, little is known about how habitat loss and fragmentation per se alters the relationship between biodiversity and ecosystem function (BEF relationship) in the natural landscape context. Based on 130 landscapes identified by a stratified random sampling in the agro-pastoral
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Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model eLife (IF 7.7) Pub Date : 2024-03-18
Down syndrome (DS) is characterized by skeletal and brain structural malformations, cognitive impairment, altered hippocampal metabolite concentration and gene expression imbalance. These alterations were usually investigated separately, and the potential rescuing effects of green tea extracts enriched in epigallocatechin-3-gallate (GTE-EGCG) provided disparate results due to different experimental
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Dynamic 1D search and processive nucleosome translocations by RSC and ISW2 chromatin remodelers eLife (IF 7.7) Pub Date : 2024-03-18 Jee Min Kim, Claudia C Carcamo, Sina Jazani, Zepei Xie, Xinyu A Feng, Maryam Yamadi, Matthew Poyton, Katie L Holland, Jonathan B Grimm, Luke D Lavis, Taekjip Ha, Carl Wu
Eukaryotic gene expression is linked to chromatin structure and nucleosome positioning by ATP-dependent chromatin remodelers that establish and maintain nucleosome-depleted regions (NDRs) near transcription start sites. Conserved yeast RSC and ISW2 remodelers exert antagonistic effects on nucleosomes flanking NDRs, but the temporal dynamics of remodeler search, engagement, and directional nucleosome