bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-frequency and rare variants may contribute to elucidate the genetics of major depressive disorder
Authors: Yu Chenglong , Arcos-Burgos Mauricio , Baune Bernhard T. , Arolt Volker , Dannlowski Udo , Wong Ma-Li , Licinio Julio
Published: April 2018

Major depressive disorder (MDD) is a common but serious psychiatric disorder with significant levels of morbidity and mortality. Recent genome-wide association studies (GWAS) on common variants increase our understanding of MDD; however, the underlying genetic basis remains largely unknown. Many studies have been proposed to explore the genetics of complex diseases from a viewpoint of the “missing heritability” by considering low-frequency and rare variants, copy-number variations, and other types of genetic variants. Here we developed a novel computational and statistical strategy to investigate the “missing heritability” of MDD. We applied Hamming distance on common, low-frequency, and rare single-nucleotide polymorphism (SNP) sets to measure genetic distance between two individuals, and then built the multi-dimensional scaling (MDS) pictures. Whole-exome genotyping data from a Los Angeles Mexican-American cohort (203 MDD and 196 controls) and a European-ancestry cohort (473 MDD and 497 controls) were examined using our proposed methodology. MDS plots showed very significant separations between MDD cases and healthy controls for low-frequency SNP set (Pvalue < 2.2e−16) and rare SNP set (Pvalue = 7.681e−12). Our results suggested that low-frequency and rare variants may play more significant roles in the genetics of MDD.
A multiple myeloma-specific capture sequencing platform discovers novel translocations and frequent, risk-associated point mutations in IGLL5
Authors: White Brian S. , Lanc Irena , O’Neal Julie , Gupta Harshath , Fulton Robert S. , Schmidt Heather , Fronick Catrina , Belter Edward A. , Fiala Mark , King Justin , Ahmann Greg J. , DeRome Mary , Mardis Elaine R. , Vij Ravi , DiPersio John F. , Levy Joan , Auclair Daniel , Tomasson Michael H.
Published: April 2018

Multiple myeloma (MM) is a disease of copy number variants (CNVs), chromosomal translocations, and single-nucleotide variants (SNVs). To enable integrative studies across these diverse mutation types, we developed a capture-based sequencing platform to detect their occurrence in 465 genes altered in MM and used it to sequence 95 primary tumor-normal pairs to a mean depth of 104×. We detected cases of hyperdiploidy (23%), deletions of 1p (8%), 6q (21%), 8p (17%), 14q (16%), 16q (22%), and 17p (4%), and amplification of 1q (19%). We also detectedIGHandMYCtranslocations near expected frequencies and non-silent SNVs inNRAS(24%),KRAS(21%),FAM46C(17%),TP53(9%),DIS3(9%), andBRAF(3%). We discovered frequent mutations inIGLL5(18%) that were mutually exclusive ofRASmutations and associated with increased risk of disease progression (p = 0.03), suggesting thatIGLL5may be a stratifying biomarker. We identified novelIGLL5/IGHtranslocations in two samples. We subjected 15 of the pairs to ultra-deep sequencing (1259×) and found that although depth correlated with number of mutations detected (p = 0.001), depth past ~300× added little. The platform provides cost-effective genomic analysis for research and may be useful in individualizing treatment decisions in clinical settings.
Mechanically induced Ca2+ oscillations in osteocytes release extracellular vesicles and enhance bone formation
Authors: Morrell Andrea E. , Brown Genevieve N. , Robinson Samuel T. , Sattler Rachel L. , Baik Andrew D. , Zhen Gehua , Cao Xu , Bonewald Lynda F. , Jin Weiyang , Kam Lance C. , Guo X. Edward
Published: April 2018

The vast osteocytic network is believed to orchestrate bone metabolic activity in response to mechanical stimuli through production of sclerostin, RANKL, and osteoprotegerin (OPG). However, the mechanisms of osteocyte mechanotransduction remain poorly understood. We’ve previously shown that osteocyte mechanosensitivity is encoded through unique intracellular calcium (Ca2+) dynamics. Here, by simultaneously monitoring Ca2+ and actin dynamics in single cells exposed to fluid shear flow, we detected actin network contractions immediately upon onset of flow-induced Ca2+ transients, which were facilitated by smooth muscle myosin and further confirmed in native osteocytes ex vivo. Actomyosin contractions have been linked to the secretion of extracellular vesicles (EVs), and our studies demonstrate that mechanical stimulation upregulates EV production in osteocytes through immunostaining for the secretory vesicle marker Lysosomal-associated membrane protein 1 (LAMP1) and quantifying EV release in conditioned medium, both of which are blunted when Ca2+ signaling was inhibited by neomycin. Axial tibia compression was used to induce anabolic bone formation responses in mice, revealing upregulated LAMP1 and expected downregulation of sclerostin in vivo. This load-related increase in LAMP1 expression was inhibited in neomycin-injected mice compared to vehicle. Micro-computed tomography revealed significant load-related increases in both trabecular bone volume fraction and cortical thickness after two weeks of loading, which were blunted by neomycin treatment. In summary, we found mechanical stimulation of osteocytes activates Ca2+-dependent contractions and enhances the production and release of EVs containing bone regulatory proteins. Further, blocking Ca2+ signaling significantly attenuates adaptation to mechanical loading in vivo, suggesting a critical role for Ca2+-mediated signaling in bone adaptation.
Deregulation of ATG9A by impaired AR signaling induces autophagy in prostate stromal fibroblasts and promotes BPH progression
Authors: Jiang Chen-Yi , Yang Bo-Yu , Zhao Sheng , Shao Si-Hui , Bei Xiao-Yu , Shi Fei , Sun Qian , Deng Zheng , Wang Xiao-Hai , Han Bang-Min , Zhao Fu-Jun , Xia Shu-Jie , Ruan Yuan
Published: April 2018

The activation of androgen receptor (AR) signaling plays an essential role in both prostate stromal cells and epithelial cells during the development of benign prostatic hyperplasia (BPH). Here we demonstrated that androgen ablation after 5α-reductase inhibitor (5-ARI) treatment induced autophagy in prostate stromal fibroblasts inhibiting cell apoptosis. In addition, we found that ATG9A expression was increased after androgen ablation, which facilitated autophagic flux development. Knockdown of ATG9A not only inhibited autophagy notably in prostate stromal fibroblasts, but also reduced the volumes of prostate stromal fibroblast and epithelial cell recombinant grafts in nude mice. In conclusion, our findings suggested that ATG9A upregulation after long-term 5-ARI treatment constitutes a possible mechanism of BPH progression. Thus, combined treatment with 5-ARI and autophagy inhibitory agents would reduce the risk of BPH progression.
Astrocytic metabolic switch is a novel etiology for Cocaine and HIV-1 Tat-mediated neurotoxicity
Authors: Natarajaseenivasan Kalimuthusamy , Cotto Bianca , Shanmughapriya Santhanam , Lombardi Alyssa A. , Datta Prasun K. , Madesh Muniswamy , Elrod John W. , Khalili Kamel , Langford Dianne
Published: April 2018

Calcium (Ca2+) dynamics and oxidative signaling control mitochondrial bioenergetics in the central nervous system, where astrocytes are a major energy source for neurons. Cocaine use exacerbates HIV-associated neurocognitive disorders, but little is known about disruptions in astrocyte metabolism in this context. Our data show that the HIV protein Tat and cocaine induce a metabolic switch from glucose to fatty acid oxidation in astrocytes, thereby limiting lactate transport to neurons. Mechanistic analyses revealed increased Mitochondrial Ca2+ Uniporter (MCU)-mediated Ca2+ uptake in astrocytes exposed to Tat and cocaine due to oxidation of MCU. Since our data suggest that mitochondrial oxidation is dependent in part on MCU-mediated Ca2+ uptake, we targeted MCU to restore glycolysis in astrocytes to normalize extracellular lactate levels. Knocking down MCU in astrocytes prior to Tat and cocaine exposure prevented metabolic switching and protected neurons. These findings identify a novel molecular mechanism underlying neuropathogenesis in HIV and cocaine use.
Alarmin HMGB1 induces systemic and brain inflammatory exacerbation in post-stroke infection rat model
Authors: Kim Il-Doo , Lee Hahnbie , Kim Seung-Woo , Lee Hye-Kyung , Choi Juli , Han Pyung-Lim , Lee Ja-Kyeong
Published: April 2018

Post-stroke infection (PSI) is known to worsen functional outcomes of stroke patients and accounts to one-third of stroke-related deaths in hospital. In our previous reports, we demonstrated that massive release of high-mobility group box protein 1 (HMGB1), an endogenous danger signal molecule, is promoted by N-methyl-d-aspartic acid-induced acute damage in the postischemic brain, exacerbating neuronal damage by triggering delayed inflammatory processes. Moreover, augmentation of proinflammatory function of lipopolysaccharides (LPS) by HMGB1 via direct interaction has been reported. The aim of this study was to investigate the role of HMGB1 in aggravating inflammation in the PSI by exacerbating the function of LPS. PSI animal model was produced by administrating a low-dose LPS at 24 h post-middle cerebral artery occlusion (MCAO). Profound aggravations of inflammation, deterioration of behavioral outcomes, and infarct expansion were observed in LPS-injected MCAO animals, in which serum HMGB1 surge, especially disulfide type, occurred immediately after LPS administration and aggravated brain and systemic inflammations probably by acting in synergy with LPS. Importantly, blockage of HMGB1 function by delayed administrations of therapeutic peptides known to inhibit HMGB1 (HMGB1 A box, HPep1) or by treatment with LPS after preincubation with HMGB1 A box significantly ameliorated damages observed in the rat PSI model, demonstrating that HMGB1 plays a crucial role. Furthermore, administration of Rhodobacter sphaeroides LPS, a selective toll-like receptor 4 antagonist not only failed to exert these effects but blocked the effects of LPS, indicating its TLR4 dependence. Together, these results indicated that alarmin HMGB1 mediates potentiation of LPS function, exacerbating TLR4-dependent systemic and brain inflammation in a rat PSI model and there is a positive-feedback loop between augmentation of LPS function by HMGB1 and subsequent HMGB1 release/serum. Therefore, HMGB1 might be a valuable therapeutic target for preventing post-stroke infection.
NF-κB-driven improvement of EHD1 contributes to erlotinib resistance in EGFR-mutant lung cancers
Authors: Wang Xiaoyuan , Yin Hang , Zhang Hongxia , Hu Jing , Lu Hailing , Li Chunhong , Cao Mengru , Yan Shi , Cai Li
Published: April 2018

Acquired resistance to epidermal growth factor receptor-tyrosine-kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, is a critical obstacle in the treatment of EGFR mutant-positive non-small cell lung cancer (NSCLC). EHD1, a protein of the C-terminal Eps15 homology domain-containing (EHD) family, plays a role in regulating endocytic recycling, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we found that a lower EHD1 expression improved both EGFR-TKIs sensitivity, which is consistent with a lower CD133 expression, and progression-free survival in NSCLC patients. The overexpression of EHD1 markedly increased erlotinib resistance and lung cancer cell stemness in vitro and in vivo. Moreover, we demonstrated that miR-590 targeted the 3′-UTR of EHD1 and was regulated by NK-κB, resulting in downregulated EHD1 expression, increased erlotinib sensitivity and repressed NSCLC cancer stem-like properties in vitro and in vivo. We found that EHD1 was an important factor in EGFR-TKI resistance and the cancer stem-like cell phenotype of lung cancer, and these results suggest that targeting the NF-κB/miR-590/EHD1 pathway has potential therapeutic promise in EGFR-mutant NSCLC patients with acquired EGFR-TKI resistance.
Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma
Authors: Cheng Yusheng , Li Hui , Deng Yinan , Tai Yan , Zeng Kaining , Zhang Yingcai , Liu Wei , Zhang Qi , Yang Yang
Published: April 2018

Emerging evidence indicate that cancer-associated fibroblasts (CAFs) affect tumor progression by reshaping the tumor microenvironment. Neutrophils are prominent components of solid tumors and important in cancer progression. Whether the phenotype and function of neutrophils in hepatocellular carcinoma (HCC) are influenced by CAFs is not well understood. Herein, we investigated the effect of HCC-derived CAFs (HCC-CAFs) on the neutrophils and explored the biological role of this effect. We found that HCC-CAFs induced chemotaxis of neutrophils and protected them from spontaneous apoptosis. Neutrophils were activated by the conditioned medium from HCC-CAFs with increased expression of CD66b, PDL1, IL8, TNFa, and CCL2, and with decreased expression of CD62L. HCC-CAF-primed neutrophils impaired T-cell function through the PD1/PDL1 signaling pathway. We revealed that HCC-CAFs induced the activation of STAT3 pathways in neutrophils, which are essential for the survival and function of activated neutrophils. In addition, we demonstrated that HCC-CAF-derived IL6 was responsible for the STAT3 activation of neutrophils. Collectively, our results suggest that HCC-CAFs regulate the survival, activation, and function of neutrophils within HCC through an IL6–STAT3–PDL1 signaling cascade, which presents a novel mechanism for the role of CAFs in remodeling the cancer niche and provides a potential target for HCC therapy.
Tumor-associated macrophages-derived exosomes promote the migration of gastric cancer cells by transfer of functional Apolipoprotein E
Authors: Zheng Peiming , Luo Qin , Wang Weiwei , Li Junhua , Wang Tingting , Wang Ping , Chen Lei , Zhang Peng , Chen Hui , Liu Yi , Dong Ping , Xie Guohua , Ma Yanhui , Jiang Li , Yuan Xiangliang , Shen Lisong
Published: April 2018

Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment and have been shown to contribute to tumor aggressiveness. However, the detailed mechanisms underlying the pro-metastatic effect of TAMs on gastric cancer are not clearly defined. Here, we show that TAMs are enriched in gastric cancer. TAMs are characterized by M2-polarized phenotype and promote migration of gastric cancer cells in vitro and in vivo. Furthermore, we find that M2-derived exosomes determine the TAMs-mediated pro-migratory activity. Using mass spectrometry, we identify that apolipoprotein E (ApoE) is highly specific and effective protein in M2 macrophages-derived exosomes. Moreover, TAMs are uniquely immune cells population expressed ApoE in gastric cancer microenvironment. However, exosomes derived from M2 macrophages of Apoe
−/−
mice have no significant effect on the migration of gastric cancer cells in vitro and in vivo. Mechanistically, M2 macrophage-derived exosomes mediate an intercellular transfer of ApoE-activating PI3K-Akt signaling pathway in recipient gastric cancer cells to remodel the cytoskeleton-supporting migration. Collectively, our findings signify that the exosome-mediated transfer of functional ApoE protein from TAMs to the tumor cells promotes the migration of gastric cancer cells.
Two-thirds of global cropland area impacted by climate oscillations
Authors: Heino Matias , Puma Michael J. , Ward Philip J. , Gerten Dieter , Heck Vera , Siebert Stefan , Kummu Matti
Published: April 2018

The El Niño Southern Oscillation (ENSO) peaked strongly during the boreal winter 2015–2016, leading to food insecurity in many parts of Africa, Asia and Latin America. Besides ENSO, the Indian Ocean Dipole (IOD) and the North Atlantic Oscillation (NAO) are known to impact crop yields worldwide. Here we assess for the first time in a unified framework the relationships between ENSO, IOD and NAO and simulated crop productivity at the sub-country scale. Our findings reveal that during 1961–2010, crop productivity is significantly influenced by at least one large-scale climate oscillation in two-thirds of global cropland area. Besides observing new possible links, especially for NAO in Africa and the Middle East, our analyses confirm several known relationships between crop productivity and these oscillations. Our results improve the understanding of climatological crop productivity drivers, which is essential for enhancing food security in many of the most vulnerable places on the planet.
Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum
Authors: Fejzo Marlena S. , Sazonova Olga V. , Sathirapongsasuti J. Fah , Hallgrímsdóttir Ingileif B. , Vacic Vladimir , MacGibbon Kimber W. , Schoenberg Frederic P. , Mancuso Nicholas , Slamon Dennis J. , Mullin Patrick M. ,   23andMe Research Team, Agee Michelle , Alipanahi Babak , Auton Adam , Bell Robert K. , Bryc Katarzyna , Elson Sarah L. , Fontanillas Pierre , Furlotte Nicholas A. , Hinds David A. , Hromatka Bethann S. , Huber Karen E. , Kleinman Aaron , Litterman Nadia K. , McIntyre Matthew H. , Mountain Joanna L. , Noblin Elizabeth S. , Northover Carrie A. M. , Pitts Steven J. , Shelton Janie F. , Shringarpure Suyash , Tian Chao , Tung Joyce Y. , Wilson Catherine H.
Published: April 2018

Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, occurs in 0.3–2% of pregnancies and is associated with maternal and fetal morbidity. The cause of HG remains unknown, but familial aggregation and results of twin studies suggest that understanding the genetic contribution is essential for comprehending the disease etiology. Here, we conduct a genome-wide association study (GWAS) for binary (HG) and ordinal (severity of nausea and vomiting) phenotypes of pregnancy complications. Two loci, chr19p13.11 and chr4q12, are genome-wide significant (p < 5 × 10−8) in both association scans and are replicated in an independent cohort. The genes implicated at these two loci are GDF15 and IGFBP7 respectively, both known to be involved in placentation, appetite, and cachexia. While proving the casual roles of GDF15 and IGFBP7 in nausea and vomiting of pregnancy requires further study, this GWAS provides insights into the genetic risk factors contributing to the disease.
Drought drives rapid shifts in tropical rainforest soil biogeochemistry and greenhouse gas emissions
Authors: O’Connell Christine S. , Ruan Leilei , Silver Whendee L.
Published: April 2018

Climate change models predict more frequent and severe droughts in the humid tropics. How drought will impact tropical forest carbon and greenhouse gas dynamics is poorly understood. Here we report the effects of the severe 2015 Caribbean drought on soil moisture, oxygen, phosphorus (P), and greenhouse gas emissions in a humid tropical forest in Puerto Rico. Drought significantly decreases inorganic P concentrations, an element commonly limiting to net primary productivity in tropical forests, and significantly increases organic P. High-frequency greenhouse gas measurements show varied impacts across topography. Soil carbon dioxide emissions increase by 60% on slopes and 163% in valleys. Methane (CH4) consumption increases significantly during drought, but high CH4 fluxes post-drought offset this sink after 7 weeks. The rapid response and slow recovery to drought suggest tropical forest biogeochemistry is more sensitive to climate change than previously believed, with potentially large direct and indirect consequences for regional and global carbon cycles.
TRIM11 activates the proteasome and promotes overall protein degradation by regulating USP14
Authors: Chen Liang , Zhu Guixin , Johns Eleanor M. , Yang Xiaolu
Published: April 2018

The proteasome is a complex protease critical for protein quality control and cell regulation, and its dysfunction is associated with cancer and other diseases. However, the mechanisms that control proteasome activity  in normal and malignant cells remain unclear. Here we report that TRIM11 enhances degradation of aberrant and normal regulatory proteins, and augments overall rate of proteolysis. Mechanistically, TRIM11 binds to both the proteasome and USP14, a deubiquitinase that prematurely removes ubiquitins from proteasome-bound substrates and also noncatalytically inhibits the proteasome, and precludes their association, thereby increasing proteasome activity. TRIM11 promotes cell survival and is upregulated upon heat shock. Moreover, TRIM11 is required for tumor growth, and increased expression of TRIM11 correlates with poor clinical survival. These findings identify TRIM11 as an important activator of the proteasome, define a pathway that adjusts proteasome activity, and reveal a mechanism by which tumor cells acquire higher degradative power to support oncogenic growth.
A tiny Triassic saurian from Connecticut and the early evolution of the diapsid feeding apparatus
Authors: Pritchard Adam C. , Gauthier Jacques A. , Hanson Michael , Bever Gabriel S. , Bhullar Bhart-Anjan S.
Published: April 2018

Following the Permo–Triassic Extinction, large-bodied diapsid reptiles—with a body length >1 m—rapidly expanded their ecological roles. This diversification is reflected in enormous disparity in the development of the rostrum and adductor chamber. However, it is unclear how marked the diversity of the feeding apparatus was in contemporary small-bodied diapsids. Here we describe the remarkably small skull (2.5 cm long) of a saurian reptile, Colobops noviportensis, gen. et sp. nov., from the Triassic New Haven Arkose of Connecticut, USA. The taxon possesses an exceptionally reinforced snout and strikingly expanded supratemporal fossae for adductor musculature relative to any known Mesozoic or Recent diapsid of similar size. Our phylogenetic analyses support C. noviportensis as an early diverging pan-archosaur. Colobops noviportensis reveals extraordinary disparity of the feeding apparatus in small-bodied early Mesozoic diapsids, and a suite of morphologies, functionally related to a powerful bite, unknown in any small-bodied diapsid.
PHA-4/FoxA senses nucleolar stress to regulate lipid accumulation in Caenorhabditis elegans
Authors: Wu Jieyu , Jiang Xue , Li Yamei , Zhu Tingting , Zhang Jingjing , Zhang Zhiguo , Zhang Linqiang , Zhang Yuru , Wang Yanli , Zou Xiaoju , Liang Bin
Published: April 2018

The primary function of the nucleolus is ribosome biogenesis, which is an extremely energetically expensive process. Failures in ribosome biogenesis cause nucleolar stress with an altered energy status. However, little is known about the underlying mechanism linking nucleolar stress to energy metabolism. Here we show that nucleolar stress is triggered by inactivation of RSKS-1 (ribosomal protein S6 kinase), RRP-8 (ribosomal RNA processing 8), and PRO-2/3 (proximal proliferation), all of which are involved in ribosomal RNA processing or inhibition of rDNA transcription by actinomycin D (AD), leading to excessive lipid accumulation in Caenorhabditiselegans. The transcription factor PHA-4/FoxA acts as a sensor of nucleolar stress to bind to and transactivate the expression of the lipogenic genes pod-2 (acetyl-CoA carboxylase), fasn-1 (fatty acid synthase), and dgat-2 (diacylglycerol O-acyltransferase 2), consequently promoting lipid accumulation. Importantly, inactivation of pha-4 or dgat-2 is sufficient to abolish nucleolar stress-induced lipid accumulation and prolonged starvation survival. The results revealed a distinct PHA-4-mediated lipogenesis pathway that senses nucleolar stress and shifts excessive energy for storage as fat.
Aftershock sequences and seismic-like organization of acoustic events produced by a single propagating crack
Authors: Barés Jonathan , Dubois Alizée , Hattali Lamine , Dalmas Davy , Bonamy Daniel
Published: April 2018

Brittle fractures of inhomogeneous materials like rocks, concrete, or ceramics are of two types: Nominally brittle and driven by the propagation of a single dominant crack or quasi-brittle and resulting from the accumulation of many microcracks. The latter goes along with acoustic noise, whose analysis has revealed that events form aftershock sequences obeying characteristic laws reminiscent of those in seismology. Yet, their origin lacks explanation. Here we show that such a statistical organization is not only specific to the multi-cracking situations of quasi-brittle failure and seismology, but also rules the acoustic events produced by a propagating crack. This simpler situation has permitted us to relate these laws to the overall scale-free distribution of inter-event time and energy and to uncover their selection by the crack speed. These results provide a comprehensive picture of how acoustic events are organized upon material failure in the most fundamental of fracture states: single propagating cracks.
A lever-like transduction pathway for long-distance chemical- and mechano-gating of the mechanosensitive Piezo1 channel
Authors: Wang Yanfeng , Chi Shaopeng , Guo Huifang , Li Guang , Wang Li , Zhao Qiancheng , Rao Yu , Zu Liansuo , He Wei , Xiao Bailong
Published: April 2018

Piezo1 represents a prototype of eukaryotic mechanotransduction channels. The full-length 2547-residue mouse Piezo1 possesses a unique 38-transmembrane-helix (TM) topology and is organized into a three-bladed, propeller-shaped architecture, comprising a central ion-conducting pore, three peripheral blade-like structures, and three 90-Å-long intracellular beam-resembling structures that bridge the blades to the pore. However, how mechanical force and chemicals activate the gigantic Piezo1 machinery remains elusive. Here we identify a novel set of Piezo1 chemical activators, termed Jedi, which activates Piezo1 through the extracellular side of the blade instead of the C-terminal extracellular domain of the pore, indicating long-range allosteric gating. Remarkably, Jedi-induced activation of Piezo1 requires the key mechanotransduction components, including the two extracellular loops in the distal blade and the two leucine residues in the proximal end of the beam. Thus, Piezo1 employs the peripheral blade-beam-constituted lever-like apparatus as a designated transduction pathway for long-distance mechano- and chemical-gating of the pore.
Publisher Correction: Anderson light localization in biological nanostructures of native silk
Authors: Choi Seung Ho , Kim Seong-Wan , Ku Zahyun , Visbal-Onufrak Michelle A. , Kim Seong-Ryul , Choi Kwang-Ho , Ko Hakseok , Choi Wonshik , Urbas Augustine M. , Goo Tae-Won , Kim Young L.
Published: April 2018

The original PDF version of this Article contained errors in Equations 1 and 2. Both equations omitted all Γ terms. This has been corrected in the PDF version of the Article. The HTML version was correct from the time of publication.
Degradation of blue-phosphorescent organic light-emitting devices involves exciton-induced generation of polaron pair within emitting layers
Authors: Kim Sinheui , Bae Hye Jin , Park Sangho , Kim Wook , Kim Joonghyuk , Kim Jong Soo , Jung Yongsik , Sul Soohwan , Ihn Soo-Ghang , Noh Changho , Kim Sunghan , You Youngmin
Published: April 2018

Degradation of organic materials is responsible for the short operation lifetimes of organic light-emitting devices, but the mechanism by which such degradation is initiated has yet to be fully established. Here we report a new mechanism for degradation of emitting layers in blue-phosphorescent devices. We investigate binary mixtures of a wide bandgap host and a series of novel Ir(III) complex dopants having N-heterocyclocarbenic ligands. Our mechanistic study reveals the charge-neutral generation of polaron pairs (radical ion pairs) by electron transfer from the dopant to host excitons. Annihilation of the radical ion pair occurs by charge recombination, with such annihilation competing with bond scission. Device lifetime correlates linearly with the rate constant for the annihilation of the radical ion pair. Our findings demonstrate the importance of controlling exciton-induced electron transfer, and provide novel strategies to design materials for long-lifetime blue electrophosphorescence devices.
Lymphotoxin α fine-tunes T cell clonal deletion by regulating thymic entry of antigen-presenting cells
Authors: Lopes Noëlla , Charaix Jonathan , Cédile Oriane , Sergé Arnauld , Irla Magali
Published: April 2018

Medullary thymic epithelial cells (mTEC) purge the T cell repertoire of autoreactive thymocytes. Although dendritic cells (DC) reinforce this process by transporting innocuous peripheral self-antigens, the mechanisms that control their thymic entry remain unclear. Here we show that mTEC-CD4+thymocyte crosstalk regulates the thymus homing of SHPS-1+conventional DCs (cDC), plasmacytoid DCs (pDC) and macrophages. This homing process is controlled by lymphotoxin α (LTα), which negatively regulates CCL2, CCL8 and CCL12 chemokines in mTECs. Consequently,Ltα-deficient mice have increased expression of these chemokines that correlates with augmented classical NF-κB subunits and increased thymic recruitment of cDCs, pDCs and macrophages. This enhanced migration depends mainly on the chemokine receptor CCR2, and increases thymic clonal deletion. Altogether, this study identifies a fine-tuning mechanism of T cell repertoire selection and paves the way for therapeutic interventions to treat autoimmune disorders.
BAFF-neutralizing interaction of belimumab related to its therapeutic efficacy for treating systemic lupus erythematosus
Authors: Shin Woori , Lee Hyun Tae , Lim Heejin , Lee Sang Hyung , Son Ji Young , Lee Jee Un , Yoo Ki-Young , Ryu Seong Eon , Rhie Jaejun , Lee Ju Yeon , Heo Yong-Seok
Published: April 2018

BAFF, a member of the TNF superfamily, has been recognized as a good target for autoimmune diseases. Belimumab, an anti-BAFF monoclonal antibody, was approved by the FDA for use in treating systemic lupus erythematosus. However, the molecular basis of BAFF neutralization by belimumab remains unclear. Here our crystal structure of the BAFF–belimumab Fab complex shows the precise epitope and the BAFF-neutralizing mechanism of belimumab, and demonstrates that the therapeutic activity of belimumab involves not only antagonizing the BAFF–receptor interaction, but also disrupting the formation of the more active BAFF 60-mer to favor the induction of the less active BAFF trimer through interaction with the flap region of BAFF. In addition, the belimumab HCDR3 loop mimics the DxL(V/L) motif of BAFF receptors, thereby binding to BAFF in a similar manner as endogenous BAFF receptors. Our data thus provides insights for the design of new drugs targeting BAFF for the treatment of autoimmune diseases.
Poly-ligand profiling differentiates trastuzumab-treated breast cancer patients according to their outcomes
Authors: Domenyuk Valeriy , Gatalica Zoran , Santhanam Radhika , Wei Xixi , Stark Adam , Kennedy Patrick , Toussaint Brandon , Levenberg Symon , Wang Jie , Xiao Nianqing , Greil Richard , Rinnerthaler Gabriel , Gampenrieder Simon P. , Heimberger Amy B. , Berry Donald A. , Barker Anna , Quackenbush John , Marshall John L. , Poste George , Vacirca Jeffrey L. , Vidal Gregory A. , Schwartzberg Lee S. , Halbert David D. , Voss Andreas , Magee Daniel , Miglarese Mark R. , Famulok Michael , Mayer Günter , Spetzler David
Published: April 2018

Assessing the phenotypic diversity underlying tumour progression requires the identification of variations in the respective molecular interaction networks. Here we report proof-of-concept for a platform called poly-ligand profiling (PLP) that surveys these system states and distinguishes breast cancer patients who did or did not derive benefit from trastuzumab. We perform tissue-SELEX on breast cancer specimens to enrich single-stranded DNA (ssDNA) libraries that preferentially interact with molecular components associated with the two clinical phenotypes. Testing of independent sample sets verifies the ability of PLP to classify trastuzumab-treated patients according to their clinical outcomes with ROC-AUC of 0.78. Standard HER2 testing of the same patients gives a ROC-AUC of 0.47. Kaplan–Meier analysis reveals a median increase in benefit from trastuzumab-containing treatments of 300 days for PLP-positive compared to PLP-negative patients. If prospectively validated, PLP may increase success rates in precision oncology and clinical trials, thus improving both patient care and drug development.
Structural characterization of a highly-potent V3-glycan broadly neutralizing antibody bound to natively-glycosylated HIV-1 envelope
Authors: Barnes Christopher O. , Gristick Harry B. , Freund Natalia T. , Escolano Amelia , Lyubimov Artem Y. , Hartweger Harald , West Anthony P. , Cohen Aina E. , Nussenzweig Michel C. , Bjorkman Pamela J.
Published: April 2018

Broadly neutralizing antibodies (bNAbs) isolated from HIV-1-infected individuals inform HIV-1 vaccine design efforts. Developing bNAbs with increased efficacy requires understanding how antibodies interact with the native oligomannose and complex-type N-glycan shield that hides most protein epitopes on HIV-1 envelope (Env). Here we present crystal structures, including a 3.8-Å X-ray free electron laser dataset, of natively glycosylated Env trimers complexed with BG18, the most potent V3/N332gp120 glycan-targeting bNAb reported to date. Our structures show conserved contacts mediated by common D gene-encoded residues with the N332gp120 glycan and the gp120 GDIR peptide motif, but a distinct Env-binding orientation relative to PGT121/10-1074 bNAbs. BG18’s binding orientation provides additional contacts with N392gp120 and N386gp120 glycans near the V3-loop base and engages protein components of the V1-loop. The BG18-natively-glycosylated Env structures facilitate understanding of bNAb–glycan interactions critical for using V3/N332gp120 bNAbs therapeutically and targeting their epitope for immunogen design.
RodZ modulates geometric localization of the bacterial actin MreB to regulate cell shape
Authors: Colavin Alexandre , Shi Handuo , Huang Kerwyn Casey
Published: April 2018

In the rod-shaped bacterium Escherichia coli, the actin-like protein MreB localizes in a curvature-dependent manner and spatially coordinates cell-wall insertion to maintain cell shape, although the molecular mechanism by which cell width is regulated remains unknown. Here we demonstrate that the membrane protein RodZ regulates the biophysical properties of MreB and alters the spatial organization of E. coli cell-wall growth. The relative expression levels of MreB and RodZ change in a manner commensurate with variations in growth rate and cell width, and RodZ systematically alters the curvature-based localization of MreB and cell width in a concentration-dependent manner. We identify MreB mutants that alter the bending properties of MreB filaments in molecular dynamics simulations similar to RodZ binding, and show that these mutants rescue rod-like shape in the absence of RodZ alone or in combination with wild-type MreB. Thus, E. coli can control its shape and dimensions by differentially regulating RodZ and MreB to alter the patterning of cell-wall insertion, highlighting the rich regulatory landscape of cytoskeletal molecular biophysics.
Small tumor necrosis factor receptor biologics inhibit the tumor necrosis factor-p38 signalling axis and inflammation
Authors: Mukaro Violet R. , Quach Alex , Gahan Michelle E. , Boog Bernadette , Huang Zhi H. , Gao Xiuhui , Haddad Carol , Mahalingam Suresh , Hii Charles S. , Ferrante Antonio
Published: April 2018

Despite anti-TNF therapy advancements for inflammatory diseases such as rheumatoid arthritis, the burden of diseases remains high. An 11-mer TNF peptide, TNF70–80, is known to stimulate selective functional responses compared to the parent TNF molecule. Here, we show that TNF70–80binds to the TNF receptor, activating p38 MAP kinase through TNF receptor-associated factor 2. Using truncated TNFR mutants, we identify the sequence in TNFRI which enables p38 activation by TNF70–80. Peptides with this TNFRI sequence, such as TNFRI206–211bind to TNF and inhibit TNF-induced p38 activation, respiratory burst, cytokine production and adhesion receptor expression but not F-Met-Leu-Phe-induced respiratory burst in neutrophils. TNFRI206–211does not prevent TNF binding to TNFRI or TNF-induced stimulation of ERK, JNK and NF-κB. TNFRI206–211inhibits bacterial lipopolysaccharide-induced peritonitis, carrageenan-induced and antigen-induced paw inflammation, and respiratory syncytial virus-induced lung inflammation in mice. Our findings suggest a way of targeting TNF-p38 pathway to treat chronic inflammatory disorders.
Three-dimensional variations of the slab geometry correlate with earthquake distributions at the Cascadia subduction system
Authors: Gao Haiying
Published: April 2018

Significant along-strike variations of seismicity are observed at subduction zones, which are strongly influenced by physical properties of the plate interface and rheology of the crust and mantle lithosphere. However, the role of the oceanic side of the plate boundary on seismicity is poorly understood due to the lack of offshore instrumentations. Here tomographic results of the Cascadia subduction system, resolved with full-wave ambient noise simulation and inversion by integrating dense offshore and onshore seismic datasets, show significant variations of the oceanic lithosphere along strike and down dip from spreading centers to subduction. In central Cascadia, where seismicity is sparse, the slab is imaged as a large-scale low-velocity feature near the trench, which is attributed to a highly hydrated and strained oceanic lithosphere underlain by a layer of melts or fluids. The strong correlation suggests that the properties of the incoming oceanic plate play a significant role on seismicity.
Dissociating frontoparietal brain networks with neuroadaptive Bayesian optimization
Authors: Lorenz Romy , Violante Ines R. , Monti Ricardo Pio , Montana Giovanni , Hampshire Adam , Leech Robert
Published: April 2018

Understanding the unique contributions of frontoparietal networks (FPN) in cognition is challenging because they overlap spatially and are co-activated by diverse tasks. Characterizing these networks therefore involves studying their activation across many different cognitive tasks, which previously was only possible with meta-analyses. Here, we use neuroadaptive Bayesian optimization, an approach combining real-time analysis of functional neuroimaging data with machine-learning, to discover cognitive tasks that segregate ventral and dorsal FPN activity. We identify and subsequently refine two cognitive tasks, Deductive Reasoning and Tower of London, which maximally dissociate the dorsal from ventral FPN. We subsequently investigate these two FPNs in the context of a wider range of FPNs and demonstrate the importance of studying the whole activity profile across tasks to uniquely differentiate any FPN. Our findings deviate from previous meta-analyses and hypothesized functional labels for these FPNs. Taken together the results form the starting point for a neurobiologically-derived cognitive taxonomy.
Nuclear disarmament verification via resonant phenomena
Authors: Hecla Jake J. , Danagoulian Areg
Published: April 2018

Nuclear disarmament treaties are not sufficient in and of themselves to neutralize the existential threat of the nuclear weapons. Technologies are necessary for verifying the authenticity of the nuclear warheads undergoing dismantlement before counting them toward a treaty partner’s obligation. Here we present a concept that leverages isotope-specific nuclear resonance phenomena to authenticate a warhead’s fissile components by comparing them to a previously authenticated template. All information is encrypted in the physical domain in a manner that amounts to a physical zero-knowledge proof system. Using Monte Carlo simulations, the system is shown to reveal no isotopic or geometric information about the weapon, while readily detecting hoaxing attempts. This nuclear technique can dramatically increase the reach and trustworthiness of future nuclear disarmament treaties.
Helraiser intermediates provide insight into the mechanism of eukaryotic replicative transposition
Authors: Grabundzija Ivana , Hickman Alison B. , Dyda Fred
Published: April 2018

Helitrons are eukaryotic DNA transposons that have profoundly affected genome variability via capture and mobilization of host genomic sequences. Defining their mode of action is therefore important for understanding how genome landscapes evolve. Sequence similarities with certain prokaryotic mobile elements suggest a “rolling circle” mode of transposition, involving only a single transposon strand. Using the reconstituted Helraiser transposon to study Helitron transposition in cells and in vitro, we show that the donor site must be double-stranded and that single-stranded donors will not suffice. Nevertheless, replication and integration assays demonstrate the use of only one of the transposon donor strands. Furthermore, repeated reuse of Helraiser donor sites occurs following DNA synthesis. In cells, circular double-stranded intermediates that serve as transposon donors are generated and replicated by Helraiser transposase. Cell-free experiments demonstrate strand-specific cleavage and strand transfer, supporting observations made in cells.
High-speed and on-chip graphene blackbody emitters for optical communications by remote heat transfer
Authors: Miyoshi Yusuke , Fukazawa Yusuke , Amasaka Yuya , Reckmann Robin , Yokoi Tomoya , Ishida Kazuki , Kawahara Kenji , Ago Hiroki , Maki Hideyuki
Published: April 2018

High-speed light emitters integrated on silicon chips can enable novel architectures for silicon-based optoelectronics, such as on-chip optical interconnects, and silicon photonics. However, conventional light sources based on compound semiconductors face major challenges for their integration with a silicon-based platform because of their difficulty of direct growth on a silicon substrate. Here we report ultra-high-speed (100-ps response time), highly integrated graphene-based on-silicon-chip blackbody emitters in the near-infrared region including telecommunication wavelength. Their emission responses are strongly affected by the graphene contact with the substrate depending on the number of graphene layers. The ultra-high-speed emission can be understood by remote quantum thermal transport via surface polar phonons of the substrates. We demonstrated real-time optical communications, integrated two-dimensional array emitters, capped emitters operable in air, and the direct coupling of optical fibers to the emitters. These emitters can open new routes to on-Si-chip, small footprint, and high-speed emitters for highly integrated optoelectronics and silicon photonics.
Author Correction: Myoblasts and macrophages are required for therapeutic morpholino antisense oligonucleotide delivery to dystrophic muscle
Authors: Novak James S. , Hogarth Marshall W. , Boehler Jessica F. , Nearing Marie , Vila Maria C. , Heredia Raul , Fiorillo Alyson A. , Zhang Aiping , Hathout Yetrib , Hoffman Eric P. , Jaiswal Jyoti K. , Nagaraju Kanneboyina , Cirak Sebahattin , Partridge Terence A.
Published: April 2018

The originally published version of this Article contained an error in Figure 6. In panel b, the top graph (BrdU 21–24d) and the bottom graph (BrdU 28–31d) were inadvertently swapped. This error has now been corrected in both the PDF and HTML versions of the Article.
NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network
Authors: Anderson David J. , Kaplan David I. , Bell Katrina M. , Koutsis Katerina , Haynes John M. , Mills Richard J. , Phelan Dean G. , Qian Elizabeth L. , Leitoguinho Ana Rita , Arasaratnam Deevina , Labonne Tanya , Ng Elizabeth S. , Davis Richard P. , Casini Simona , Passier Robert , Hudson James E. , Porrello Enzo R. , Costa Mauro W. , Rafii Arash , Curl Clare L. , Delbridge Lea M. , Harvey Richard P. , Oshlack Alicia , Cheung Michael M. , Mummery Christine L. , Petrou Stephen , Elefanty Andrew G. , Stanley Edouard G. , Elliott David A.
Published: April 2018

Congenital heart defects can be caused by mutations in genes that guide cardiac lineage formation. Here, we show deletion of NKX2-5, a critical component of the cardiac gene regulatory network, in human embryonic stem cells (hESCs), results in impaired cardiomyogenesis, failure to activate VCAM1 and to downregulate the progenitor marker PDGFRα. Furthermore, NKX2-5 null cardiomyocytes have abnormal physiology, with asynchronous contractions and altered action potentials. Molecular profiling and genetic rescue experiments demonstrate that the bHLH protein HEY2 is a key mediator of NKX2-5 function during human cardiomyogenesis. These findings identify HEY2 as a novel component of the NKX2-5 cardiac transcriptional network, providing tangible evidence that hESC models can decipher the complex pathways that regulate early stage human heart development. These data provide a human context for the evaluation of pathogenic mutations in congenital heart disease.
Recurrent acquisition of cytosine methyltransferases into eukaryotic retrotransposons
Authors: de Mendoza Alex , Bonnet Amandine , Vargas-Landin Dulce B. , Ji Nanjing , Li Hongfei , Yang Feng , Li Ling , Hori Koichi , Pflueger Jahnvi , Buckberry Sam , Ohta Hiroyuki , Rosic Nedeljka , Lesage Pascale , Lin Senjie , Lister Ryan
Published: April 2018

Transposable elements are in a constant arms race with the silencing mechanisms of their host genomes. One silencing mechanism commonly used by many eukaryotes is dependent on cytosine methylation, a covalent modification of DNA deposited by C5 cytosine methyltransferases (DNMTs). Here, we report how two distantly related eukaryotic lineages, dinoflagellates and charophytes, have independently incorporated DNMTs into the coding regions of distinct retrotransposon classes. Concomitantly, we show that dinoflagellates of the genus Symbiodinium have evolved cytosine methylation patterns unlike any other eukaryote, with most of the genome methylated at CG dinucleotides. Finally, we demonstrate the ability of retrotransposon DNMTs to methylate CGs de novo, suggesting that retrotransposons could self-methylate retrotranscribed DNA. Together, this is an example of how retrotransposons incorporate host-derived genes involved in DNA methylation. In some cases, this event could have implications for the composition and regulation of the host epigenomic environment.
Multi-omics analysis reveals neoantigen-independent immune cell infiltration in copy-number driven cancers
Authors: McGrail Daniel J. , Federico Lorenzo , Li Yongsheng , Dai Hui , Lu Yiling , Mills Gordon B. , Yi Song , Lin Shiaw-Yih , Sahni Nidhi
Published: April 2018

To realize the full potential of immunotherapy, it is critical to understand the drivers of tumor infiltration by immune cells. Previous studies have linked immune infiltration with tumor neoantigen levels, but the broad applicability of this concept remains unknown. Here, we find that while this observation is true across cancers characterized by recurrent mutations, it does not hold for cancers driven by recurrent copy number alterations, such as breast and pancreatic tumors. To understand immune invasion in these cancers, we developed an integrative multi-omics framework, identifying the DNA damage response protein ATM as a driver of cytokine production leading to increased immune infiltration. This prediction was validated in numerous orthogonal datasets, as well as experimentally in vitro and in vivo by cytokine release and immune cell migration. These findings demonstrate diverse drivers of immune cell infiltration across cancer lineages and may facilitate the clinical adaption of immunotherapies across diverse malignancies.