bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteasome-independent polyubiquitin linkage regulates synapse scaffolding, efficacy, and plasticity
Authors: Ma Qi , Ruan Hongyu , Peng Lisheng , Zhang Mingjie , Gack Michaela U. , Yao Wei-Dong 
Published: October 2017

Significance
A well-investigated mechanism regulating synapse protein turnover and remodeling is the classical ubiquitin–proteasome system by which polyubiquitin (polyUb) chains linked through ubiquitin lysine 48 (K48) tag substrates for proteasomal degradation. Little is known about the role of nondegradable polyUb linkages, e.g., K63-linked chains, in the synapse, although these chains represent the second most abundant polyUb linkage in mammalian brain. We identified a bona fide K63-polyUb substrate in PSD-95, a major postsynaptic scaffold. K63-polyUb conjugation markedly augments PSD-95’s scaffolding capability and promotes its synaptic targeting and anchorage. We identify a K63-linkage–specific E3 ligase–deubiquitinase complex that controls activity-dependent assembly and disassembly of K63-polyUb chains on PSD-95. We show that this unconventional polyUb linkage promotes synapse maturation, efficacy, and plasticity.
Actin retrograde flow actively aligns and orients ligand-engaged integrins in focal adhesions
Authors: Swaminathan Vinay , Kalappurakkal Joseph Mathew , Mehta Shalin B. , Nordenfelt Pontus , Moore Travis I. , Koga Nobuyasu , Baker David A. , Oldenbourg Rudolf , Tani Tomomi , Mayor Satyajit , Springer Timothy A. , Waterman Clare M. 
Published: October 2017

Significance
Integrins are adhesion receptors linking cells to their environment, which function as sensors of physical and chemical information to regulate development, immune response, and vascular function. How integrins receive and transduce directional forces including flow or tissue tension has remained elusive. We used polarization-based microscopy techniques to discover that activated αVβ3 integrins are aligned with one another in focal adhesions in migrating fibroblasts. Integrin coalignment is sensitive to mechanical resistance of its ligand and coupling to a dynamic F-actin cytoskeleton, consistent with the “cytoskeleton force model” for integrin activation. Our work suggests that activated integrins are actively ordered at the molecular scale by cellular forces, which may underlie their ability to sense directional forces in their environment to mediate critical functions.
Long-term restoration of visual function in end-stage retinal degeneration using subretinal human melanopsin gene therapy
Authors: De Silva Samantha R. , Barnard Alun R. , Hughes Steven , Tam Shu K. E. , Martin Chris , Singh Mandeep S. , Barnea-Cramer Alona O. , McClements Michelle E. , During Matthew J. , Peirson Stuart N. , Hankins Mark W. , MacLaren Robert E. 
Published: October 2017

Significance
Inherited retinal degenerations may result in blindness due to a progressive loss of photoreceptor cells. We assess subretinal delivery of human melanopsin using an adeno-associated viral vector to remaining retinal cells in a model of end-stage retinal degeneration. Human melanopsin, being already present in the eye, is unlikely to generate an immune response when introduced via gene therapy. Furthermore, this method of delivery has been proven to be safe in clinical trials and may be more effective at delivering vector in primates than the alternative method of intravitreal injection. We demonstrate long-term vector expression and restoration of visual function, indicating that this therapy could be stable and efficacious in the treatment of patients with end-stage retinal degenerations.
Cross-activating c-Met/β1 integrin complex drives metastasis and invasive resistance in cancer
Authors: Jahangiri Arman , Nguyen Alan , Chandra Ankush , Sidorov Maxim K. , Yagnik Garima , Rick Jonathan , Han Sung Won , Chen William , Flanigan Patrick M. , Schneidman-Duhovny Dina , Mascharak Smita , De Lay Michael , Imber Brandon , Park Catherine C. , Matsumoto Kunio , Lu Kan , Bergers Gabriele , Sali Andrej , Weiss William A. , Aghi Manish K. 
Published: October 2017

Significance
Invasion is a major cause of cancer mortality, as exemplified by metastatic spread of peripheral malignancies or local intracranial invasion of glioblastoma. While individual mediators of invasion are identified, functional or structural interactions between these mediators remain undefined. We identified a structural cross-activating c-Met/β1 integrin complex that promotes breast cancer metastases and invasive resistance of glioblastoma to the antiangiogenic therapy bevacizumab. We show that tumor cells adapt to their microenvironmental stressors by usurping c-Met and β1 integrin, with c-Met displacing α5 integrin from β1 integrin to form a c-Met/β1 complex with far greater fibronectin affinity than α5β1 integrin. These findings challenge conventional thinking about integrin–ligand interactions and define a molecular target for disrupting metastases or invasive oncologic resistance.
Autophagy is required for endothelial cell alignment and atheroprotection under physiological blood flow
Authors: Vion Anne-Clemence , Kheloufi Marouane , Hammoutene Adel , Poisson Johanne , Lasselin Juliette , Devue Cecile , Pic Isabelle , Dupont Nicolas , Busse Johanna , Stark Konstantin , Lafaurie-Janvore Julie , Barakat Abdul I. , Loyer Xavier , Souyri Michele , Viollet Benoit , Julia Pierre , Tedgui Alain , Codogno Patrice , Boulanger Chantal M. , Rautou Pierre-Emmanuel 
Published: October 2017

SignificanceAtherosclerotic plaques tend to develop preferentially in areas of the vasculature exposed to low and disturbed shear stress (SS), but the mechanisms are not fully understood. In this study, we demonstrate that inefficient autophagy contributes to the development of atherosclerotic plaques in low-SS areas. Defective endothelial autophagy not only curbs endothelial alignment with the direction of blood flow, but also promotes an inflammatory, apoptotic, and senescent phenotype. Furthermore, genetic inactivation of endothelial autophagy in a murine model of atherosclerosis increases plaque burden exclusively in high-SS areas that are normally resistant to atherosclerotic plaque development. Altogether, these findings underline the role of endothelial autophagic flux activation by SS as an atheroprotective mechanism.
Interhost dispersal alters microbiome assembly and can overwhelm host innate immunity in an experimental zebrafish model
Authors: Burns Adam R. , Miller Elizabeth , Agarwal Meghna , Rolig Annah S. , Milligan-Myhre Kathryn , Seredick Steve , Guillemin Karen , Bohannan Brendan J. M. 
Published: October 2017

Significance
Manipulating the microbial communities associated with animals to improve host health requires a comprehensive understanding of the mechanisms driving microbiome variation, which a strict focus on host-specific factors has been insufficient in providing. We performed an experiment to test whether the movement, or dispersal, of microorganisms among zebrafish hosts could alter the effects of important host factors, using a dispersal-based model to guide the interpretation of results. We observed that interhost dispersal can alter the diversity and composition of microbial communities and overwhelm the effects of the host’s innate immune system. These findings suggest that dispersal is an important mechanism driving microbiome variation and should be considered in future microbiome research.
YAP/TAZ-CDC42 signaling regulates vascular tip cell migration
Authors: Sakabe Masahide , Fan Jieqing , Odaka Yoshinobu , Liu Ning , Hassan Aishlin , Duan Xin , Stump Paige , Byerly Luke , Donaldson Megan , Hao Jiukuan , Fruttiger Marcus , Lu Qing Richard , Zheng Yi , Lang Richard A. , Xin Mei 
Published: October 2017

Significance
New blood vessel formation is a physiological process seen in development, as well as in wound healing and tumorigenesis. Although the process of blood vasculature formation has been well documented, little is known about the molecular mechanisms that regulate endothelial migration during vascular network formation. In this study, we identified a critical role for Hippo effectors YAP and TAZ in the regulation of vascular network remodeling through controlling endothelial cell (EC) proliferation, filopodia formation, and cell migration. We found a striking cytoplasmic function of YAP in the regulation of EC migration through controlling the Rho family GTPase CDC42 activity. These findings identify a previously unrecognized YAP/TAZ function involved in the vascular network remodeling during angiogenesis.
Asynchronous warming and δ
18
O evolution of deep Atlantic water masses during the last deglaciation
Authors: Zhang Jiaxu , Liu Zhengyu , Brady Esther C. , Oppo Delia W. , Clark Peter U. , Jahn Alexandra , Marcott Shaun A. , Lindsay Keith 
Published: October 2017

Significance
The reorganizations of deep Atlantic water masses are widely thought to regulate glacial–interglacial climate changes. However, the pattern of reorganizations and their impact on ocean tracer transport remain poorly constrained by marine proxies. Our modeling study, which simulates the coevolution of water masses and oxygen isotopes during the last deglaciation, suggests that deglacial meltwater input causes both northern- and southern-sourced deep water transports to decrease. This reorganization pattern leads to asynchronous warming between the deep North and South Atlantic, which might have caused the observed deglacial phasing difference in deep water oxygen isotope records between these ocean basins. We further propose a mechanism to explain the early warming in the northern North Atlantic.
Spontaneous self-dislodging of freezing water droplets and the role of wettability
Authors: Graeber Gustav , Schutzius Thomas M. , Eghlidi Hadi , Poulikakos Dimos 
Published: October 2017

Significance
Freezing of water on surfaces is ubiquitous in nature and technology; however, to control ice aggregation and rationally design icephobic surfaces, which passively inhibit ice formation and accretion, a deeper fundamental understanding of the interaction of forming ice with the underlying substrate and environment is necessary. In this work, we report the phenomenon of self-dislodging freezing water droplets, explain its physics, and develop surfaces which inhibit ice aggregation through passive ice self-removal. Successful experiments on a palette of material classes underpin the general applicability and robustness of the effect to control surface icing, and can guide further research in the field of icephobicity.
Why pens have rubbery grips
Authors: Dzidek Brygida , Bochereau Séréna , Johnson Simon A. , Hayward Vincent , Adams Michael J. 
Published: October 2017

Significance
Why does gripping a pen, tool, or handle feel more secure when it is coated with a rubbery material? The keratin of the skin outer layer is stiff and rough at a small scale. When encountering a smooth, stiff, and impermeable surface, such as polished metal or glass, the actual contact area is initially small as is the friction. Because the keratin softens when it is hydrated by the moisture secreted from the sweat pores, it requires many seconds for the contact area to increase to the value reached almost instantaneously with a soft material, such as a rubber. This mechanism might be used by our tactile sense to identify materials and has implications for the design of tactile displays.
Soilborne fungi have host affinity and host-specific effects on seed germination and survival in a lowland tropical forest
Authors: Sarmiento Carolina , Zalamea Paul-Camilo , Dalling James W. , Davis Adam S. , Stump Simon M. , U’Ren Jana M. , Arnold A. Elizabeth 
Published: October 2017

SignificanceThe remarkable diversity of trees in tropical forests is thought to be maintained by natural enemies such as fungal pathogens, which must exhibit sufficient host specificity to differentially impact survival of co-occurring host species. Little is known about the specificity of fungi that infect seeds of tropical trees. Here we show that communities of seed-associated fungi are structured more by plant species than by soil type, forest characteristics, or time in soil. These fungi have host-specific impacts on seed viability and germination. In this way, highly diverse communities of soilborne fungi directly impact a critical component of reproduction in tropical trees—seeds—with the potential to contribute to maintaining diversity in some of the richest terrestrial communities on Earth.
Complement-activation fragment C4a mediates effector functions by binding as untethered agonist to protease-activated receptors 1 and 4
Authors: Wang HongBin , Ricklin Daniel , Lambris John D. 
Published: October 2017

SignificanceHow C4a transduces signaling and generates various biological functions has long been unresolved. Using a cell-based reporter assay, we screened C4a against a panel of 168 known and 73 orphan G protein-coupled receptors and now provide evidence that C4a is a ligand for protease-activated receptor (PAR)1 and PAR4. In human endothelial cells, our assessment of ERK activation and calcium mobilization in the presence of various antagonists and inhibitors suggests that C4a-mediated cell activation is mediated through PAR1 and PAR4. Our results demonstrate that C4a is a nontraditional agonist for PAR1 and PAR4 whose direct functional effects indicate a potentially significant direct linkage between the complement, coagulation, and endothelial barrier systems.
Mycobacterium tuberculosisis protected from NADPH oxidase and LC3-associated phagocytosis by the LCP protein CpsA
Authors: Köster Stefan , Upadhyay Sandeep , Chandra Pallavi , Papavinasasundaram Kadamba , Yang Guozhe , Hassan Amir , Grigsby Steven J. , Mittal Ekansh , Park Heidi S. , Jones Victoria , Hsu Fong-Fu , Jackson Mary , Sassetti Christopher M. , Philips Jennifer A. 
Published: October 2017

SignificanceMycobacterium tuberculosis(Mtb), the causative agent of the disease tuberculosis, grows in macrophages, cells that normally kill bacteria. Recent work has defined a macrophage pathway called “LC3-associated phagocytosis” (LAP) that can eliminate other microbes. LAP is characterized by the recruitment of NADPH oxidase to phagosomes, followed by phagosomal association with LC3 and delivery of the bacteria to a degradative lysosome. Here, we show that LAP does not effectively clear Mtb. The ability of Mtb to inhibit LAP and therefore cause disease depends upon CpsA, a member of the LytR-CpsA-Psr (LCP) protein family, which has previously been implicated in cell-wall metabolism. We demonstrate that Mtb CpsA plays an unexpected role in antagonizing host innate immunity by inhibiting NADPH oxidase and LAP.
Nucleus accumbens feedforward inhibition circuit promotes cocaine self-administration
Authors: Yu Jun , Yan Yijin , Li King-Lun , Wang Yao , Huang Yanhua H. , Urban Nathaniel N. , Nestler Eric J. , Schlüter Oliver M. , Dong Yan 
Published: October 2017

Significance
The nucleus accumbens (NAc) regulates cue-induced motivated behaviors, a process that requires fine-tuned functional output of medium spiny principal neurons (MSNs). Our present study reveals that, although contributing <1% of the NAc shell (NAcSh) neuronal population, fast-spiking interneurons (FSIs) form an inhibitory feedforward circuit to dictate the functional output of NAc MSNs. Cocaine self-administration, a rodent model mimicking human cocaine seeking and taking, persistently potentiates the driving force to this FSI-embedded feedforward circuit. Functionally mimicking this effect of cocaine in vivo expedites the acquisition of cocaine self-administration. These results demonstrate a previously unidentified role of an FSI-mediated NAcSh feedforward circuit in cue-induced cocaine seeking and taking.
Mycobacterium tuberculosisinhibits human innate immune responses via the production of TLR2 antagonist glycolipids
Authors: Blanc Landry , Gilleron Martine , Prandi Jacques , Song Ok-ryul , Jang Mi-Seon , Gicquel Brigitte , Drocourt Daniel , Neyrolles Olivier , Brodin Priscille , Tiraby Gérard , Vercellone Alain , Nigou Jérôme 
Published: October 2017

SignificanceTo secure their colonization and survival, pathogens have evolved tactics to undermine host immune responses. Most particularly,Mycobacterium tuberculosisinhibits the activation of macrophages, one of whose roles is to recognize and kill invading microorganisms. Here, we used a library ofM. tuberculosismutants to infect macrophages and uncover molecular mechanisms by which the pathogen modulates the function of these immune cells. We found thatM. tuberculosisproduces cell envelope glycolipids that are antagonists of a macrophage receptor, named TLR2, which is dedicated to the recognition of pathogens, thereby preventing its efficient recognition by the immune system.
Time-resolved measurements of an ion channel conformational change driven by a membrane phase transition
Authors: Stevenson Paul , Tokmakoff Andrei 
Published: October 2017

Significance
Membranes act as a host matrix to many different biomolecules, such as membrane proteins. As highly dynamic structures, membranes have many modes of fluctuation accessible under physiological conditions. By inducing a phase transition that thins a membrane with a temperature jump and monitoring the response of a model ion channel, we are able to track in a time-resolved manner how this protein responds to fast structural changes in the membrane.
Engineering of tomato for the sustainable production of ketocarotenoids and its evaluation in aquaculture feed
Authors: Nogueira Marilise , Enfissi Eugenia M. A. , Martínez Valenzuela Maria E. , Menard Guillaume N. , Driller Richard L. , Eastmond Peter J. , Schuch Wolfgang , Sandmann Gerhard , Fraser Paul D. 
Published: October 2017

Significance
Ketocarotenoids are high-value pigments used in the food and feed industry to confer color. Aquaculture is a good example, where the addition of carotenoids to the feed is essential for the coloration of trout or salmon flesh, and thus product viability. In this study, complex engineering has been carried out to produce a renewable source of ketocarotenoids for use as feed additives. Production in tomato fruit has enabled the testing of this “generally recognized as safe” material with low-energy minimal bioprocessing in aquaculture trials to demonstrate production, technical, and economic feasibility of the system. This achievement represents a potential paradigm in the bioproduction of specialty and bulk chemicals without our reliance on fossil fuel-derived chemical processes.
An anion-immobilized composite electrolyte for dendrite-free lithium metal anodes
Authors: Zhao Chen-Zi , Zhang Xue-Qiang , Cheng Xin-Bing , Zhang Rui , Xu Rui , Chen Peng-Yu , Peng Hong-Jie , Huang Jia-Qi , Zhang Qiang 
Published: October 2017

Significance
The Li metal electrode is regarded as a “Holy Grail” anode for next-generation batteries due to its extremely high theoretical capacity and lowest reduction potential. Unfortunately, uncontrolled dendrite growth leads to serious safety issues. This work realizes a dendrite-free Li metal anode by introducing an anion-immobilized composite solid electrolyte, where anions are tethered to polymer chains and ceramic particles. Immobilized anions contribute to uniform distribution of Li ions and dendrite-free Li deposition. The flexible electrolyte can be applied in all–solid-state Li metal batteries with excellent specific capacities. This work demonstrates a concept to adjust ion distribution based on solid-state electrolytes for safe dendrite-free Li anodes, paving the way to practical Li metal batteries.
Detection of isolated protein-bound metal ions by single-particle cryo-STEM
Authors: Elad Nadav , Bellapadrona Giuliano , Houben Lothar , Sagi Irit , Elbaum Michael 
Published: October 2017

Significance
Trace metal ions play essential roles in the function of many proteins. Examples include iron in oxygen transport, zinc in proteolytic enzymes and nucleic acid binding, and calcium in signaling and muscle contraction. Current structural methods are not optimal to detect protein-bound metals, which may be observed only after determination of the protein structure to atomic resolution. Elastic scattering contrast in annular dark-field scanning transmission electron microscopy (STEM) is particularly sensitive to atomic number. Using 3D reconstructions generated from cryo-STEM images, we detect isolated Zn and Fe bound to ferritin at very low stoichiometry. The different patterns obtained reflect physiological interactions of these metals with ferritin. The demonstration also raises the potential for specific protein labeling with heavy atoms.
Molecular origin of the weak susceptibility of kinesin velocity to loads and its relation to the collective behavior of kinesins
Authors: Wang Qian , Diehl Michael R. , Jana Biman , Cheung Margaret S. , Kolomeisky Anatoly B. , Onuchic José N. 
Published: October 2017

Significance
Successful functioning of biological systems depends on efficient cellular transport supported by several classes of active biological molecules known as motor proteins. Although they have been intensively studied using various experimental methods, their molecular properties remain not fully understood. We developed a theoretical approach by using structure-based molecular dynamics simulations. It allowed us to understand at the molecular level the effect of external forces on kinesin motor proteins. It is shown that a force-regulated coupling between the neck linker and the ATP binding site of a kinesin accounts for experimentally observed weak susceptibility to loads. Our framework helps us to rationalize the low cooperativity among kinesins. The presented method is a powerful tool in clarifying microscopic features of motor proteins.
Ab initio theory and modeling of water
Authors: Chen Mohan , Ko Hsin-Yu , Remsing Richard C. , Calegari Andrade Marcos F. , Santra Biswajit , Sun Zhaoru , Selloni Annabella , Car Roberto , Klein Michael L. , Perdew John P. , Wu Xifan 
Published: October 2017

Significance
Water is vital to our everyday life, but its structure at a molecular level is still not fully understood from either experiment or theory. The latter is hampered by our inability to construct a purely predictive, first principles model. The difficulty in modeling water lies in capturing the delicate interplay among the many strong and weak forces that govern its behavior and phase diagram. Herein, molecular simulations with a recently proposed nonempirical quantum mechanical approach (the SCAN density functional) yield an excellent description of the structural, electronic, and dynamic properties of liquid water. SCAN (strongly constrained and appropriately normed)-based approaches, which describe diverse types of bonds in materials on an equal, accurate footing, will likely enable efficient and reliable modeling of aqueous phase chemistry.
Critical role for PI3-kinase in regulating the use of proteins as an amino acid source
Authors: Palm Wilhelm , Araki Jingwen , King Bryan , DeMatteo Raymond G. , Thompson Craig B. 
Published: October 2017

SignificanceMammalian cells can take up monomeric amino acids through cell-surface transporters or recover amino acids through macropinocytosis and lysosomal catabolism of extracellular proteins. In mammalian cells, nutrient uptake is regulated by growth factors. Yet how growth-factor signaling orchestrates different nutrient uptake routes is unclear. Here, we establish a central role for growth-factor–activated phosphatidylinositol 3-kinase (PI3-kinase) signaling in promoting cellular amino acid uptake and show that distinct effector branches regulate expression of amino acid transporters, and macropinocytosis and lysosomal catabolism of ingested proteins. Therefore, PI3-kinase signaling supports cell proliferation in the presence of various amino acid sources. These findings suggest that oncogenic PI3-kinase pathway activation is a selective advantage for tumor cells proliferating in fluctuating nutrient environments.