bluuebunny/crossref_metadata_2025_split huggingface dataset:
Yap haploinsufficiency leads to Müller cell dysfunction and late-onset cone dystrophy
Authors: Masson Christel , García-García Diana , Bitard Juliette , Grellier Élodie-Kim , Roger Jérôme E. , Perron Muriel 
Published: August 2020

AbstractHippo signalling regulates eye growth during embryogenesis through its effectors YAP and TAZ. Taking advantage of a Yap heterozygous mouse line, we here sought to examine its function in adult neural retina, where YAP expression is restricted to Müller glia. We first discovered an unexpected temporal dynamic of gene compensation. At postnatal stages, Taz upregulation occurs, leading to a gain of function-like phenotype characterised by EGFR signalling potentiation and delayed cell-cycle exit of retinal progenitors. In contrast, Yap+/− adult retinas no longer exhibit TAZ-dependent dosage compensation. In this context, Yap haploinsufficiency in aged individuals results in Müller glia dysfunction, late-onset cone degeneration, and reduced cone-mediated visual response. Alteration of glial homeostasis and altered patterns of cone opsins were also observed in Müller cell-specific conditional Yap-knockout aged mice. Together, this study highlights a novel YAP function in Müller cells for the maintenance of retinal tissue homeostasis and the preservation of cone integrity. It also suggests that YAP haploinsufficiency should be considered and explored as a cause of cone dystrophies in human.
DPP8/9 inhibitors activate the CARD8 inflammasome in resting lymphocytes
Authors: Johnson Darren C. , Okondo Marian C. , Orth Elizabeth L. , Rao Sahana D. , Huang Hsin-Che , Ball Daniel P. , Bachovchin Daniel A. 
Published: August 2020

AbstractCanonical inflammasomes are innate immune signaling platforms that are formed in response to intracellular pathogen-associated signals and trigger caspase-1-dependent pyroptosis. Inflammasome formation and signaling is thought to mainly occur in myeloid cells, and in particular monocytes and macrophages. Here we show that small molecule inhibitors of dipeptidyl peptidases 8 and 9 (DPP8/9), which activate the related CARD8 and NLRP1 inflammasomes, also activate pyroptosis in human and rodent resting lymphocytes. We found that both CD4+and CD8+T cells were particularly sensitive to these inhibitors, although the sensitivity of T cells, like macrophages, varied considerably between species. In human T cells, we show that CARD8 mediates DPP8/9 inhibitor-induced pyroptosis. Intriguingly, although activated human T cells express the key proteins known to be required for CARD8-mediated pyroptosis, these cells were completely resistant to DPP8/9 inhibitors. Overall, these data show that resting lymphoid cells can activate at least one inflammasome, revealing additional cell types and states poised to undergo rapid pyroptotic cell death in response to danger-associated signals.
SIDT1-dependent absorption in the stomach mediates host uptake of dietary and orally administered microRNAs
Authors: Chen Qun , Zhang Fan , Dong Lei , Wu Huimin , Xu Jie , Li Hanqin , Wang Jin , Zhou Zhen , Liu Chunyan , Wang Yanbo , Liu Yuyan , Lu Liangsheng , Wang Chen , Liu Minghui , Chen Xi , Wang Cheng , Zhang Chunni , Li Dangsheng , Zen Ke , Wang Fangyu , Zhang Qipeng , Zhang Chen-Yu 
Published: August 2020

AbstractDietary microRNAs have been shown to be absorbed by mammals and regulate host gene expression, but the absorption mechanism remains unknown. Here, we show that SIDT1 expressed on gastric pit cells in the stomach is required for the absorption of dietary microRNAs. SIDT1-deficient mice show reduced basal levels and impaired dynamic absorption of dietary microRNAs. Notably, we identified the stomach as the primary site for dietary microRNA absorption, which is dramatically attenuated in the stomachs of SIDT1-deficient mice. Mechanistic analyses revealed that the uptake of exogenous microRNAs by gastric pit cells is SIDT1 and low-pH dependent. Furthermore, oral administration of plant-derived miR2911 retards liver fibrosis, and this protective effect was abolished in SIDT1-deficient mice. Our findings reveal a major mechanism underlying the absorption of dietary microRNAs, uncover an unexpected role of the stomach and shed light on developing small RNA therapeutics by oral delivery.
Stunting in infancy, pubertal trajectories and adult body composition: the Birth to Twenty Plus cohort, South Africa
Authors: Chidumwa Glory , Said-Mohamed Rihlat , Nyati Lukhanyo H. , Mpondo Feziwe , Chikowore Tinashe , Prioreschi Alessandra , Kagura Juliana , Ware Lisa J. , Micklesfield Lisa K. , Norris Shane A. 
Published: August 2020

Abstract
Background/objectives
Childhood rapid growth and earlier puberty onset have been associated with adult obesity. However, the association between childhood stunting, pubertal timing and adult obesity is unclear. We examined whether the relationship between stunting at age 2 years (y) and body composition at 23 years is mediated by adolescent body mass index, and pubertal development, using the Birth-to-Twenty Plus cohort (South Africa).

Subjects/methods
For 1036 participants, data on anthropometrics between birth and 23 years, maternal factors, and pubertal development (Tanner scale at 9–16 years) were collected. Stunting at 2 years (height-for-age z-score < −2), 5–18 years BMI-for-age trajectories, pubertal development trajectories, and DXA-derived fat mass (FM) and fat free mass (FFM) at 23 years were determined. Data were analysed using hierarchical regressions and structural equation models.

Results
Stunting was directly associated with slower pubertal development and with shorter adult stature, but was not associated with adolescent BMI trajectories, adult FM or FFM. However, stunting was indirectly associated with adult FM and FFM through the direct associations between slower pubertal development and lower FM and between shorter height and lower FFM. BMI trajectories were independently associated with FM and FFM.

Conclusions
Being stunted in this population predicted adult body composition through slower pubertal development and shorter adult stature.
A Japanese boy with NAA10-related syndrome and hypertrophic cardiomyopathy
Authors: Shishido Ayumi , Morisada Naoya , Tominaga Kenta , Uemura Hiroyasu , Haruna Akiko , Hanafusa Hiroaki , Nozu Kandai , Iijima Kazumoto 
Published: August 2020

AbstractNAA10-related syndrome is an extremely rare X-chromosomal disorder, the symptoms of which include intellectual disability (ID), ocular anomalies, or congenital heart diseases, such as hypertrophic cardiomyopathy (HCM). Here, we describe a 4-year-old Japanese male patient who exhibited mild ID, HCM, and specific facial features. A hemizygous mutation (NM_003491.3: c.455_458del, p. Thr152Argfs*6) in exon 7 of NAA10 was detected. We recommend that patients undergo precise medical follow-up considering the characteristics of NAA10-related syndrome.
SLIT2/ROBO1-signaling inhibits macropinocytosis by opposing cortical cytoskeletal remodeling
Authors: Bhosle Vikrant K. , Mukherjee Tapas , Huang Yi-Wei , Patel Sajedabanu , Pang Bo Wen , Liu Guang-Ying , Glogauer Michael , Wu Jane Y. , Philpott Dana J. , Grinstein Sergio , Robinson Lisa A. 
Published: August 2020

AbstractMacropinocytosis is essential for myeloid cells to survey their environment and for growth of RAS-transformed cancer cells. Several growth factors and inflammatory stimuli are known to induce macropinocytosis, but its endogenous inhibitors have remained elusive. Stimulation of Roundabout receptors by Slit ligands inhibits directional migration of many cell types, including immune cells and cancer cells. We report that SLIT2 inhibits macropinocytosis in vitro and in vivo by inducing cytoskeletal changes in macrophages. In mice, SLIT2 attenuates the uptake of muramyl dipeptide, thereby preventing NOD2-dependent activation of NF-κB and consequent secretion of pro-inflammatory chemokine, CXCL1. Conversely, blocking the action of endogenous SLIT2 enhances CXCL1 secretion. SLIT2 also inhibits macropinocytosis in RAS-transformed cancer cells, thereby decreasing their survival in nutrient-deficient conditions which resemble tumor microenvironment. Our results identify SLIT2 as a physiological inhibitor of macropinocytosis and challenge the conventional notion that signals that enhance macropinocytosis negatively regulate cell migration, and vice versa.
Distinct fibroblast subsets regulate lacteal integrity through YAP/TAZ-induced VEGF-C in intestinal villi
Authors: Hong Seon Pyo , Yang Myung Jin , Cho Hyunsoo , Park Intae , Bae Hosung , Choe Kibaek , Suh Sang Heon , Adams Ralf H. , Alitalo Kari , Lim Daesik , Koh Gou Young 
Published: August 2020

AbstractEmerging evidence suggests that intestinal stromal cells (IntSCs) play essential roles in maintaining intestinal homeostasis. However, the extent of heterogeneity within the villi stromal compartment and how IntSCs regulate the structure and function of specialized intestinal lymphatic capillary called lacteal remain elusive. Here we show that selective hyperactivation or depletion of YAP/TAZ in PDGFRβ+ IntSCs leads to lacteal sprouting or regression with junctional disintegration and impaired dietary fat uptake. Indeed, mechanical or osmotic stress regulates IntSC secretion of VEGF-C mediated by YAP/TAZ. Single-cell RNA sequencing delineated novel subtypes of villi fibroblasts that upregulate Vegfc upon YAP/TAZ activation. These populations of fibroblasts were distributed in proximity to lacteal, suggesting that they constitute a peri-lacteal microenvironment. Our findings demonstrate the heterogeneity of IntSCs and reveal that distinct subsets of villi fibroblasts regulate lacteal integrity through YAP/TAZ-induced VEGF-C secretion, providing new insights into the dynamic regulatory mechanisms behind lymphangiogenesis and lymphatic remodeling.
Scavenging of reactive dicarbonyls with 2-hydroxybenzylamine reduces atherosclerosis in hypercholesterolemic Ldlr−/− mice
Authors: Tao Huan , Huang Jiansheng , Yancey Patricia G. , Yermalitsky Valery , Blakemore John L. , Zhang Youmin , Ding Lei , Zagol-Ikapitte Irene , Ye Fei , Amarnath Venkataraman , Boutaud Olivier , Oates John A. , Roberts L. Jackson , Davies Sean S. , Linton MacRae F. 
Published: August 2020

AbstractLipid peroxidation generates reactive dicarbonyls including isolevuglandins (IsoLGs) and malondialdehyde (MDA) that covalently modify proteins. Humans with familial hypercholesterolemia (FH) have increased lipoprotein dicarbonyl adducts and dysfunctional HDL. We investigate the impact of the dicarbonyl scavenger, 2-hydroxybenzylamine (2-HOBA) on HDL function and atherosclerosis in Ldlr−/− mice, a model of FH. Compared to hypercholesterolemic Ldlr−/− mice treated with vehicle or 4-HOBA, a nonreactive analogue, 2-HOBA decreases atherosclerosis by 60% in en face aortas, without changing plasma cholesterol. Ldlr−/− mice treated with 2-HOBA have reduced MDA-LDL and MDA-HDL levels, and their HDL display increased capacity to reduce macrophage cholesterol. Importantly, 2-HOBA reduces the MDA- and IsoLG-lysyl content in atherosclerotic aortas versus 4-HOBA. Furthermore, 2-HOBA reduces inflammation and plaque apoptotic cells and promotes efferocytosis and features of stable plaques. Dicarbonyl scavenging with 2-HOBA has multiple atheroprotective effects in a murine FH model, supporting its potential as a therapeutic approach for atherosclerotic cardiovascular disease.
Widespread protein lysine acetylation in gut microbiome and its alterations in patients with Crohn’s disease
Authors: Zhang Xu , Ning Zhibin , Mayne Janice , Yang Yidai , Deeke Shelley A. , Walker Krystal , Farnsworth Charles L. , Stokes Matthew P. , Couture Jean-François , Mack David , Stintzi Alain , Figeys Daniel 
Published: August 2020

AbstractLysine acetylation (Kac), an abundant post-translational modification (PTM) in prokaryotes, regulates various microbial metabolic pathways. However, no studies have examined protein Kac at the microbiome level, and it remains unknown whether Kac level is altered in patient microbiomes. Herein, we use a peptide immuno-affinity enrichment strategy coupled with mass spectrometry to characterize protein Kac in the microbiome, which successfully identifies 35,200 Kac peptides from microbial or human proteins in gut microbiome samples. We demonstrate that Kac is widely distributed in gut microbial metabolic pathways, including anaerobic fermentation to generate short-chain fatty acids. Applying to the analyses of microbiomes of patients with Crohn’s disease identifies 52 host and 136 microbial protein Kac sites that are differentially abundant in disease versus controls. This microbiome-wide acetylomic approach aids in advancing functional microbiome research.
Demonstration of chip-based coupled degenerate optical parametric oscillators for realizing a nanophotonic spin-glass
Authors: Okawachi Yoshitomo , Yu Mengjie , Jang Jae K. , Ji Xingchen , Zhao Yun , Kim Bok Young , Lipson Michal , Gaeta Alexander L. 
Published: August 2020

AbstractThe need for solving optimization problems is prevalent in various physical applications, including neuroscience, network design, biological systems, socio-economics, and chemical reactions. Many of these are classified as non-deterministic polynomial-time hard and thus become intractable to solve as the system scales to a large number of elements. Recent research advances in photonics have sparked interest in using a network of coupled degenerate optical parametric oscillators (DOPOs) to effectively find the ground state of the Ising Hamiltonian, which can be used to solve other combinatorial optimization problems through polynomial-time mapping. Here, using the nanophotonic silicon-nitride platform, we demonstrate a spatial-multiplexed DOPO system using continuous-wave pumping. We experimentally demonstrate the generation and coupling of two microresonator-based DOPOs on a single chip. Through a reconfigurable phase link, we achieve both in-phase and out-of-phase operation, which can be deterministically achieved at a fast regeneration speed of 400 kHz with a large phase tolerance.
Cryo-EM structure of an activated VIP1 receptor-G protein complex revealed by a NanoBiT tethering strategy
Authors: Duan Jia , Shen Dan-dan , Zhou X. Edward , Bi Peng , Liu Qiu-feng , Tan Yang-xia , Zhuang You-wen , Zhang Hui-bing , Xu Pei-yu , Huang Si-Jie , Ma Shan-shan , He Xin-heng , Melcher Karsten , Zhang Yan , Xu H. Eric , Jiang Yi 
Published: August 2020

AbstractVasoactive intestinal polypeptide receptor (VIP1R) is a widely expressed class B G protein-coupled receptor and a drug target for the treatment of neuronal, metabolic, and inflammatory diseases. However, our understanding of its mechanism of action and the potential of drug discovery targeting this receptor is limited by the lack of structural information of VIP1R. Here we report a cryo-electron microscopy structure of human VIP1R bound to PACAP27 and Gs heterotrimer, whose complex assembly is stabilized by a NanoBiT tethering strategy. Comparison with other class B GPCR structures reveals that PACAP27 engages VIP1R with its N-terminus inserting into the ligand binding pocket at the transmembrane bundle of the receptor, which subsequently couples to the G protein in a receptor-specific manner. This structure has provided insights into the molecular basis of PACAP27 binding and VIP receptor activation. The methodology of the NanoBiT tethering may help to provide structural information of unstable complexes.
Reductive cyanation of organic chlorides using CO2 and NH3 via Triphos–Ni(I) species
Authors: Dong Yanan , Yang Peiju , Zhao Shizhen , Li Yuehui 
Published: August 2020

AbstractCyano-containing compounds constitute important pharmaceuticals, agrochemicals and organic materials. Traditional cyanation methods often rely on the use of toxic metal cyanides which have serious disposal, storage and transportation issues. Therefore, there is an increasing need to develop general and efficient catalytic methods for cyanide-free production of nitriles. Here we report the reductive cyanation of organic chlorides using CO2/NH3 as the electrophilic CN source. The use of tridentate phosphine ligand Triphos allows for the nickel-catalyzed cyanation of a broad array of aryl and aliphatic chlorides to produce the desired nitrile products in good yields, and with excellent functional group tolerance. Cheap and bench-stable urea was also shown as suitable CN source, suggesting promising application potential. Mechanistic studies imply that Triphos-Ni(I) species are responsible for the reductive C-C coupling approach involving isocyanate intermediates. This method expands the application potential of reductive cyanation in the synthesis of functionalized nitrile compounds under cyanide-free conditions, which is valuable for safe synthesis of (isotope-labeled) drugs.
Micro-environmental sensing by bone marrow stroma identifies IL-6 and TGFβ1 as regulators of hematopoietic ageing
Authors: Valletta Simona , Thomas Alexander , Meng Yiran , Ren Xiying , Drissen Roy , Sengül Hilal , Di Genua Cristina , Nerlov Claus 
Published: August 2020

AbstractHematopoietic ageing involves declining erythropoiesis and lymphopoiesis, leading to frequent anaemia and decreased adaptive immunity. How intrinsic changes to the hematopoietic stem cells (HSCs), an altered microenvironment and systemic factors contribute to this process is not fully understood. Here we use bone marrow stromal cells as sensors of age-associated changes to the bone marrow microenvironment, and observe up-regulation of IL-6 and TGFβ signalling-induced gene expression in aged bone marrow stroma. Inhibition of TGFβ signalling leads to reversal of age-associated HSC platelet lineage bias, increased generation of lymphoid progenitors and rebalanced HSC lineage output in transplantation assays. In contrast, decreased erythropoiesis is not an intrinsic property of aged HSCs, but associated with decreased levels and functionality of erythroid progenitor populations, defects ameliorated by TGFβ-receptor and IL-6 inhibition, respectively. These results show that both HSC-intrinsic and -extrinsic mechanisms are involved in age-associated hematopoietic decline, and identify therapeutic targets that promote their reversal.
Discovery of flat seismic reflections in the mantle beneath the young Juan de Fuca Plate
Authors: Qin Yanfang , Singh Satish C. , Grevemeyer Ingo , Marjanović Milena , Roger Buck W. 
Published: August 2020

AbstractCrustal properties of young oceanic lithosphere have been examined extensively, but the nature of the mantle lithosphere underneath remains elusive. Using a novel wide-angle seismic imaging technique, here we show the presence of two sub-horizontal reflections at ∼11 and ∼14.5 km below the seafloor over the 0.51–2.67 Ma old Juan de Fuca Plate. We find that the observed reflectors originate from 300–600-m-thick layers, with an ∼7–8% drop in P-wave velocity. They could be explained either by the presence of partially molten sills or frozen gabbroic sills. If partially molten, the shallower sill would define the base of a thin lithosphere with the constant thickness (11 km), requiring the presence of a mantle thermal anomaly extending up to 2.67 Ma. In contrast, if these reflections were frozen melt sills, they would imply the presence of thick young oceanic lithosphere (20–25 km), and extremely heterogeneous upper mantle.
CRISPR GUARD protects off-target sites from Cas9 nuclease activity using short guide RNAs
Authors: Coelho Matthew A. , De Braekeleer Etienne , Firth Mike , Bista Michal , Lukasiak Sebastian , Cuomo Maria Emanuela , Taylor Benjamin J. M. 
Published: August 2020

AbstractPrecise genome editing using CRISPR-Cas9 is a promising therapeutic avenue for genetic diseases, although off-target editing remains a significant safety concern. Guide RNAs shorter than 16 nucleotides in length effectively recruit Cas9 to complementary sites in the genome but do not permit Cas9 nuclease activity. Here we describe CRISPR Guide RNA Assisted Reduction of Damage (CRISPR GUARD) as a method for protecting off-targets sites by co-delivery of short guide RNAs directed against off-target loci by competition with the on-target guide RNA. CRISPR GUARD reduces off-target mutagenesis while retaining on-target editing efficiencies with Cas9 and base editor. However, we discover that short guide RNAs can also support base editing if they contain cytosines within the deaminase activity window. We explore design rules and the universality of this method through in vitro studies and high-throughput screening, revealing CRISPR GUARD as a rapidly implementable strategy to improve the specificity of genome editing for most genomic loci. Finally, we create an online tool for CRISPR GUARD design.
Electronic correlations and transport in iron at Earth’s core conditions
Authors: Pourovskii L. V. , Mravlje J. , Pozzo M. , Alfè D. 
Published: August 2020

AbstractThe transport properties of iron under Earth’s inner core conditions are essential input for the geophysical modelling but are poorly constrained experimentally. Here we show that the thermal and electrical conductivity of iron at those conditions remains high even if the electron-electron-scattering (EES) is properly taken into account. This result is obtained by ab initio simulations taking into account consistently both thermal disorder and electronic correlations. Thermal disorder suppresses the non-Fermi-liquid behavior of the body-centered cubic iron phase, hence, reducing the EES; the total calculated thermal conductivity of this phase is 220 Wm−1 K−1 with the EES reduction not exceeding 20%. The EES and electron-lattice scattering are intertwined resulting in breaking of the Matthiessen’s rule with increasing EES. In the hexagonal close-packed iron the EES is also not increased by thermal disorder and remains weak. Our main finding thus holds for the both likely iron phases in the inner core.
Intra-articular corticosteroid knee injection induces a reduction in meniscal thickness with no treatment effect on cartilage volume: a case–control study
Authors: Pelletier Jean-Pierre , Raynauld Jean-Pierre , Abram François , Dorais Marc , Paiement Patrice , Martel-Pelletier Johanne 
Published: August 2020

AbstractAlthough intra-articular corticosteroid injections (IACI) are commonly used for the treatment of knee osteoarthritis (OA), there is controversy regarding possible deleterious effects on joint structure. In this line, this study investigates the effects of IACI on the evolution of knee OA structural changes and pain. Participants for this nested case–control study were from the Osteoarthritis Initiative. Knees of participants who had received an IACI and had magnetic resonance images (MRI) were named cases (n = 93), and each matched with one control (n = 93). Features assessed at the yearly visits and their changes within the follow-up period were from MRI (cartilage volume, meniscal thickness, bone marrow lesions, bone curvature, and synovial effusion size), X-ray (joint space width), and clinical (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain score) data. Participants who received IACI experienced a transient and significantly greater rate of loss of the meniscal thickness (p = 0.006) and joint space width (p = 0.011) in the knee medial compartment in the year they received the injection, compared to controls. No significant effect of the IACI was found on the rate of cartilage loss nor on any other knee structural changes or WOMAC pain post-treatment. In conclusion, a single IACI in knee OA was shown to be safe with no negative impact on structural changes, but there was a transient meniscal thickness reduction, a phenomenon for which the clinical relevance is at present unknown.