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Revealing enigmatic mucus structures in the deep sea using DeepPIV 期刊论文
NATURE, 2020, 583 (7814) : 78-+
作者:  Nguyen, Ngoc Uyen Nhi;  Canseco, Diana C.;  Xiao, Feng;  Nakada, Yuji;  Li, Shujuan;  Lam, Nicholas T.;  Muralidhar, Shalini A.;  Savla, Jainy J.;  Hill, Joseph A.;  Le, Victor;  Zidan, Kareem A.;  El-Feky, Hamed W.;  Wang, Zhaoning;  Ahmed, Mahmoud Salama;  Hubbi, Maimon E.;  Menendez-Montes, Ivan
收藏  |  浏览/下载:13/0  |  提交时间:2020/06/09

Advanced deep-sea imaging tools yield insights into the structure and function of mucus filtration houses built by midwater giant larvaceans.


Many animals build complex structures to aid in their survival, but very few are built exclusively from materials that animals create (1,2). In the midwaters of the ocean, mucoid structures are readily secreted by numerous animals, and serve many vital functions(3,4). However, little is known about these mucoid structures owing to the challenges of observing them in the deep sea. Among these mucoid forms, the '  houses'  of larvaceans are marvels of nature(5), and in the ocean twilight zone giant larvaceans secrete and build mucus filtering structures that can reach diameters of more than 1 m(6). Here we describe in situ laser-imaging technology(7) that reconstructs three-dimensional models of mucus forms. The models provide high-resolution views of giant larvacean houses and elucidate the role that house structure has in food capture and predator avoidance. Now that tools exist to study mucus structures found throughout the ocean, we can shed light on some of nature'  s most complex forms.


  
Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease 期刊论文
NATURE, 2020, 577 (7790) : 399-+
作者:  Gate, David;  Saligrama, Naresha;  Leventhal, Olivia;  Yang, Andrew C.;  Unger, Michael S.;  Middeldorp, Jinte;  Chen, Kelly;  Lehallier, Benoit;  Channappa, Divya;  De Los Santos, Mark B.;  McBride, Alisha;  Pluvinage, John;  Elahi, Fanny;  Tam, Grace Kyin-Ye;  Kim, Yongha;  Greicius, Michael;  Wagner, Anthony D.;  Aigner, Ludwig;  Galasko, Douglas R.;  Davis, Mark M.;  Wyss-Coray, Tony
收藏  |  浏览/下载:6/0  |  提交时间:2020/07/03

Alzheimer'  s disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function(1). However, little is known about the contribution of the adaptive immune response in Alzheimer'  s disease(2). Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer'  s disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer'  s disease that consists of increased numbers of CD8(+) T effector memory CD45RA(+) (T-EMRA) cells. In a second cohort, we found that CD8(+) T-EMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8(+) T-EMRA cells in the cerebrospinal fluid of patients with Alzheimer'  s disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer'  s disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer'  s disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.


  
An Alternative BEM for Simulating the Flow Behavior of a Leaky Confined Fractured Aquifer With the Use of the Semianalytical Approach 期刊论文
WATER RESOURCES RESEARCH, 2020, 56 (5)
作者:  Luo, Wanjing;  Wang, Junlei;  Wang, Lei;  Zhou, Y.
收藏  |  浏览/下载:7/0  |  提交时间:2020/07/02
boundary element method  continuously confined fractured aquifer  discretely confined fractured aquifer  Green'  s function  transient flow behavior  
AI tracks a beating heart's function over time 期刊论文
NATURE, 2020, 580 (7802)
作者:  Ball, Philip
收藏  |  浏览/下载:8/0  |  提交时间:2020/07/03

Clinicians use ultrasound videos of heartbeats to assess subtle changes in the heart'  s pumping function. A method that uses artificial intelligence might simplify these complex assessments when heartbeats are out of rhythm.


  
Sialylation of immunoglobulin E is a determinant of allergic pathogenicity 期刊论文
NATURE, 2020, 582 (7811) : 265-+
作者:  Abdul-Masih, Michael;  Banyard, Gareth;  Bodensteiner, Julia;  Bordier, Emma;  Bowman, Dominic M.;  Dsilva, Karan;  Fabry, Matthias;  Hawcroft, Calum;  Mahy, Laurent;  Marchant, Pablo;  Raskin, Gert;  Reggiani, Maddalena;  Shenar, Tomer;  Tkachenko, Andrew;  Van Winckel, Hans;  Vermeylen, Lore;  Sana, Hugues
收藏  |  浏览/下载:17/0  |  提交时间:2020/07/03

A specific type of glycosylation-sialylation-is more common on immunoglobulin E from individuals with a peanut allergys than from non-atopic people, suggesting that it has a role in regulating anaphylaxis.


Approximately one-third of the world'  s population suffers from allergies(1). Exposure to allergens crosslinks immunoglobulin E (IgE) antibodies that are bound to mast cells and basophils, triggering the release of inflammatory mediators, including histamine(2). Although IgE is absolutely required for allergies, it is not understood why total and allergen-specific IgE concentrations do not reproducibly correlate with allergic disease(3-5). It is well-established that glycosylation of IgG dictates its effector function and has disease-specific patterns. However, whether IgE glycans differ in disease states or affect biological activity is completely unknown(6). Here we perform an unbiased examination of glycosylation patterns of total IgE from individuals with a peanut allergy and from non-atopic individuals without allergies. Our analysis reveals an increase in sialic acid content on total IgE from individuals with a peanut allergy compared with non-atopic individuals. Removal of sialic acid from IgE attenuates effector-cell degranulation and anaphylaxis in several functional models of allergic disease. Therapeutic interventions-including removing sialic acid from cell-bound IgE with a neuraminidase enzyme targeted towards the IgE receptor Fc epsilon RI, and administering asialylated IgE-markedly reduce anaphylaxis. Together, these results establish IgE glycosylation, and specifically sialylation, as an important regulator of allergic disease.


  
Extra help for neuron grafts 期刊论文
NATURE, 2020, 582 (7810) : 39-40
作者:  Raz, Mical
收藏  |  浏览/下载:7/0  |  提交时间:2020/07/03

Grafts of stem-cell-derived precursors of dopamine neurons could be used to treat Parkinson'  s disease, but this approach has limitations. Injecting a growth factor three weeks after transplantation can overcome some of these limits.


Steps to improve function and survival of dopamine-neuron transplants.


  
A conserved dendritic-cell regulatory program limits antitumour immunity 期刊论文
NATURE, 2020, 580 (7802) : 257-+
作者:  Perry, Rachel J.;  Zhang, Dongyan;  Guerra, Mateus T.;  Brill, Allison L.;  Goedeke, Leigh;  Nasiri, Ali R.;  Rabin-Court, Aviva;  Wang, Yongliang;  Peng, Liang;  Dufour, Sylvie;  Zhang, Ye;  Zhang, Xian-Man;  Butrico, Gina M.;  Toussaint, Keshia;  Nozaki, Yuichi;  Cline, Gary W.;  Petersen, Kitt Falk;  Nathanson, Michael H.;  Ehrlich, Barbara E.;  Shulman, Gerald I.
收藏  |  浏览/下载:26/0  |  提交时间:2020/07/03

After taking up tumour-associated antigens, dendritic cells in mouse and human tumours upregulate a regulatory gene program that limits dendritic cell immunostimulatory function, and modulating this program can rescue antitumor immunity in mice.


Checkpoint blockade therapies have improved cancer treatment, but such immunotherapy regimens fail in a large subset of patients. Conventional type 1 dendritic cells (DC1s) control the response to checkpoint blockade in preclinical models and are associated with better overall survival in patients with cancer, reflecting the specialized ability of these cells to prime the responses of CD8(+) T cells(1-3). Paradoxically, however, DC1s can be found in tumours that resist checkpoint blockade, suggesting that the functions of these cells may be altered in some lesions. Here, using single-cell RNA sequencing in human and mouse non-small-cell lung cancers, we identify a cluster of dendritic cells (DCs) that we name '  mature DCs enriched in immunoregulatory molecules'  (mregDCs), owing to their coexpression of immunoregulatory genes (Cd274, Pdcd1lg2 and Cd200) and maturation genes (Cd40, Ccr7 and Il12b). We find that the mregDC program is expressed by canonical DC1s and DC2s upon uptake of tumour antigens. We further find that upregulation of the programmed death ligand 1 protein-a key checkpoint molecule-in mregDCs is induced by the receptor tyrosine kinase AXL, while upregulation of interleukin (IL)-12 depends strictly on interferon-gamma and is controlled negatively by IL-4 signalling. Blocking IL-4 enhances IL-12 production by tumour-antigen-bearing mregDC1s, expands the pool of tumour-infiltrating effector T cells and reduces tumour burden. We have therefore uncovered a regulatory module associated with tumour-antigen uptake that reduces DC1 functionality in human and mouse cancers.


  
General synthesis of two-dimensional van der Waals heterostructure arrays 期刊论文
NATURE, 2020: 368-+
作者:  Bloch, Joel S.;  Pesciullesi, Giorgio;  Boilevin, Jeremy;  Nosol, Kamil;  Irobalieva, Rossitza N.;  Darbre, Tamis;  Aebi, Markus;  Kossiakoff, Anthony A.;  Reymond, Jean-Louis;  Locher, Kaspar P.
收藏  |  浏览/下载:62/0  |  提交时间:2020/07/03

Two-dimensional van der Waals heterostructures (vdWHs) have attracted considerable interest(1-4). However, most vdWHs reported so far are created by an arduous micromechanical exfoliation and manual restacking process(5), which-although versatile for proof-of-concept demonstrations(6-16) and fundamental studies(17-30)-is clearly not scalable for practical technologies. Here we report a general synthetic strategy for two-dimensional vdWH arrays between metallic transition-metal dichalcogenides (m-TMDs) and semiconducting TMDs (s-TMDs). By selectively patterning nucleation sites on monolayer or bilayer s-TMDs, we precisely control the nucleation and growth of diverse m-TMDs with designable periodic arrangements and tunable lateral dimensions at the predesignated spatial locations, producing a series of vdWH arrays, including VSe2/WSe2, NiTe2/WSe2, CoTe2/WSe2, NbTe2/WSe2, VS2/WSe2, VSe2/MoS2 and VSe2/WS2. Systematic scanning transmission electron microscopy studies reveal nearly ideal vdW interfaces with widely tunable moire superlattices. With the atomically clean vdW interface, we further show that the m-TMDs function as highly reliable synthetic vdW contacts for the underlying WSe2 with excellent device performance and yield, delivering a high ON-current density of up to 900 microamperes per micrometre in bilayer WSe2 transistors. This general synthesis of diverse two-dimensional vdWH arrays provides a versatile material platform for exploring exotic physics and promises a scalable pathway to high-performance devices.


A general strategy for the synthesis of two-dimensional van der Waals heterostructure arrays is used to produce high-performance electronic devices, showing the potential of this scalable approach for practical technologies.


  
Two conserved epigenetic regulators prevent healthy ageing 期刊论文
NATURE, 2020
作者:  Yoshida, Kenichi;  Gowers, Kate H. C.;  Lee-Six, Henry;  Chandrasekharan, Deepak P.;  Coorens, Tim;  Maughan, Elizabeth F.;  Beal, Kathryn;  Menzies, Andrew;  Millar, Fraser R.;  Anderson, Elizabeth;  Clarke, Sarah E.;  Pennycuick, Adam;  Thakrar, Ricky M.;  Butler, Colin R.;  Kakiuchi, Nobuyuki;  Hirano, Tomonori;  Hynds, Robert E.;  Stratton, Michael R.;  Martincorena, Inigo;  Janes, Sam M.;  Campbell, Peter J.
收藏  |  浏览/下载:34/0  |  提交时间:2020/07/03

It has long been assumed that lifespan and healthspan correlate strongly, yet the two can be clearly dissociated(1-6). Although there has been a global increase in human life expectancy, increasing longevity is rarely accompanied by an extended healthspan(4,7). Thus, understanding the origin of healthy behaviours in old people remains an important and challenging task. Here we report a conserved epigenetic mechanism underlying healthy ageing. Through genome-wide RNA-interference-based screening of genes that regulate behavioural deterioration in ageing Caenorhabditis elegans, we identify 59 genes as potential modulators of the rate of age-related behavioural deterioration. Among these modulators, we found that a neuronal epigenetic reader, BAZ-2, and a neuronal histone 3 lysine 9 methyltransferase, SET-6, accelerate behavioural deterioration in C. elegans by reducing mitochondrial function, repressing the expression of nuclear-encoded mitochondrial proteins. This mechanism is conserved in cultured mouse neurons and human cells. Examination of human databases(8,9) shows that expression of the human orthologues of these C. elegans regulators, BAZ2B and EHMT1, in the frontal cortex increases with age and correlates positively with the progression of Alzheimer'  s disease. Furthermore, ablation of Baz2b, the mouse orthologue of BAZ-2, attenuates age-dependent body-weight gain and prevents cognitive decline in ageing mice. Thus our genome-wide RNA-interference screen in C. elegans has unravelled conserved epigenetic negative regulators of ageing, suggesting possible ways to achieve healthy ageing.


Two epigenetic regulators-identified in an RNA interference screen in Caenhorhabditis elegans, and conserved in mammals-diminish mitochondrial function and accelerate the age-related deterioration of behaviour.


  
Structural basis of ligand recognition and self-activation of orphan GPR52 期刊论文
NATURE, 2020
作者:  Liu, Guoxia;  Papa, Arianne;  Katchman, Alexander N.;  Zakharov, Sergey I.;  Roybal, Daniel;  Hennessey, Jessica A.;  Kushner, Jared;  Yang, Lin;  Chen, Bi-Xing;  Kushnir, Alexander;  Dangas, Katerina;  Gygi, Steven P.;  Pitt, Geoffrey S.;  Colecraft, Henry M.;  Ben-Johny, Manu;  Kalocsay, Marian;  Marx, Steven O.
收藏  |  浏览/下载:10/0  |  提交时间:2020/07/03

Structures of the orphan G-protein-coupled receptor GPR52 in ligand-free, G-protein-coupled and ligand-bound states reveal that extracellular loop 2 occupies the orthosteric binding pocket and functions as a built-in agonist to activate the receptor.


GPR52 is a class-A orphan G-protein-coupled receptor that is highly expressed in the brain and represents a promising therapeutic target for the treatment of Huntington'  s disease and several psychiatric disorders(1,2). Pathological malfunction of GPR52 signalling occurs primarily through the heterotrimeric G(s) protein(2), but it is unclear how GPR52 and G(s) couple for signal transduction and whether a native ligand or other activating input is required. Here we present the high-resolution structures of human GPR52 in three states: a ligand-free state, a G(s)-coupled self-activation state and a potential allosteric ligand-bound state. Together, our structures reveal that extracellular loop 2 occupies the orthosteric binding pocket and operates as a built-in agonist, conferring an intrinsically high level of basal activity to GPR52(3). A fully active state is achieved when G(s) is coupled to GPR52 in the absence of an external agonist. The receptor also features a side pocket for ligand binding. These insights into the structure and function of GPR52 could improve our understanding of other self-activated GPCRs, enable the identification of endogenous and tool ligands, and guide drug discovery efforts that target GPR52.