bluuebunny/crossref_metadata_2025 huggingface dataset:
Transgenerational transmission of hedonic behaviors and metabolic phenotypes induced by maternal overnutrition
Authors: Sarker Gitalee , Berrens Rebecca , von Arx Judith , Pelczar Pawel , Reik Wolf , Wolfrum Christian , Peleg-Raibstein Daria
Published: September 2018

Maternal overnutrition has been associated with increased susceptibility to develop obesity and neurological disorders later in life. Most epidemiological as well as experimental studies have focused on the metabolic consequences across generations following an early developmental nutritional insult. Recently, it has been shown that maternal high-fat diet (HFD) affects third-generation female body mass via the paternal lineage. We showed here that the offspring born to HFD ancestors displayed addictive-like behaviors as well as obesity and insulin resistance up to the third generation in the absence of any further exposure to HFD. These findings, implicate that the male germ line is a major player in transferring phenotypic traits. These behavioral and physiological alterations were paralleled by reduced striatal dopamine levels and increased dopamine 2 receptor density. Interestingly, by the third generation a clear gender segregation emerged, where females showed addictive-like behaviors while male HFD offspring showed an obesogenic phenotype. However, methylome profiling of F1 and F2 sperm revealed no significant difference between the offspring groups, suggesting that the sperm methylome might not be the major carrier for the transmission of the phenotypes observed in our mouse model. Together, our study for the first time demonstrates that maternal HFD insult causes sustained alterations of the mesolimbic dopaminergic system suggestive of a predisposition to develop obesity and addictive-like behaviors across multiple generations.
Exposure to childhood abuse is associated with human sperm DNA methylation
Authors: Roberts Andrea L. , Gladish Nicole , Gatev Evan , Jones Meaghan J. , Chen Ying , MacIsaac Julia L. , Tworoger Shelley S. , Austin S. Bryn , Tanrikut Cigdem , Chavarro Jorge E. , Baccarelli Andrea A. , Kobor Michael S.
Published: September 2018

Offspring of persons exposed to childhood abuse are at higher risk of neurodevelopmental and physical health disparities across the life course. Animal experiments have indicated that paternal environmental stressors can affect sperm DNA methylation and gene expression in an offspring. Childhood abuse has been associated with epigenetic marks in human blood, saliva, and brain tissue, with statistically significant methylation differences ranging widely. However, no studies have examined the association of childhood abuse with DNA methylation in gametes. We examined the association of childhood abuse with DNA methylation in human sperm. Combined physical, emotional, and sexual abuse in childhood was characterized as none, medium, or high. DNA methylation was assayed in 46 sperm samples from 34 men in a longitudinal non-clinical cohort using HumanMethylation450 BeadChips. We performed principal component analysis and examined the correlation of principal components with abuse exposure. Childhood abuse was associated with a component that captured 6.2% of total variance in DNA methylation (p < 0.05). Next, we investigated the regions differentially methylated by abuse exposure. We identified 12 DNA regions differentially methylated by childhood abuse, containing 64 probes and including sites on genes associated with neuronal function (MAPT,CLU), fat cell regulation (PRDM16), and immune function (SDK1). We examined adulthood health behaviors, mental health, and trauma exposure as potential mediators of an association between abuse and DNAm, and found that mental health and trauma exposure partly mediated the association. Finally, we constructed a parsimonious epigenetic marker for childhood abuse using a machine learning approach, which identified three probes that predicted high vs. no childhood abuse in 71% of participants. Our results suggested that childhood abuse is associated with sperm DNA methylation, which may have implications for offspring development. Larger samples are needed to identify with greater confidence specific genomic regions differentially methylated by childhood abuse.
Bi-directional genetic modulation of GSK-3β exacerbates hippocampal neuropathology in experimental status epilepticus
Authors: Engel Tobias , Gómez-Sintes Raquel , Alves Mariana , Jimenez-Mateos Eva M. , Fernández-Nogales Marta , Sanz-Rodriguez Amaya , Morgan James , Beamer Edward , Rodríguez-Matellán Alberto , Dunleavy Mark , Sano Takanori , Avila Jesus , Medina Miguel , Hernandez Felix , Lucas José J. , Henshall David C.
Published: September 2018

Glycogen synthase kinase-3 (GSK-3) is ubiquitously expressed throughout the brain and involved in vital molecular pathways such as cell survival and synaptic reorganization and has emerged as a potential drug target for brain diseases. A causal role for GSK-3, in particular the brain-enriched GSK-3β isoform, has been demonstrated in neurodegenerative diseases such as Alzheimer’s and Huntington’s, and in psychiatric diseases. Recent studies have also linked GSK-3 dysregulation to neuropathological outcomes in epilepsy. To date, however, there has been no genetic evidence for the involvement of GSK-3 in seizure-induced pathology. Status epilepticus (prolonged, damaging seizure) was induced via a microinjection of kainic acid into the amygdala of mice. Studies were conducted using two transgenic mouse lines: a neuron-specific GSK-3β overexpression and a neuron-specific dominant-negative GSK-3β (GSK-3β-DN) expression in order to determine the effects of increased or decreased GSK-3β activity, respectively, on seizures and attendant pathological changes in the hippocampus. GSK-3 inhibitors were also employed to support the genetic approach. Status epilepticus resulted in a spatiotemporal regulation of GSK-3 expression and activity in the hippocampus, with decreased GSK-3 activity evident in non-damaged hippocampal areas. Consistent with this, overexpression of GSK-3β exacerbated status epilepticus-induced neurodegeneration in mice. Surprisingly, decreasing GSK-3 activity, either via overexpression of GSK-3β-DN or through the use of specific GSK-3 inhibitors, also exacerbated hippocampal damage and increased seizure severity during status epilepticus. In conclusion, our results demonstrate that the brain has limited tolerance for modulation of GSK-3 activity in the setting of epileptic brain injury. These findings caution against targeting GSK-3 as a treatment strategy for epilepsy or other neurologic disorders where neuronal hyperexcitability is an underlying pathomechanism.
LncRNA SNHG15 acts as a ceRNA to regulate YAP1-Hippo signaling pathway by sponging miR-200a-3p in papillary thyroid carcinoma
Authors: Wu Dong-Mei , Wang Shan , Wen Xin , Han Xin-Rui , Wang Yong-Jian , Shen Min , Fan Shao-Hua , Zhang Zi-Feng , Shan Qun , Li Meng-Qiu , Hu Bin , Lu Jun , Chen Gui-Quan , Zheng Yuan-Lin
Published: September 2018

Over the past decade, lncRNAs have been widely reported in human malignant tumors, including papillary thyroid carcinoma. LncRNA SNHG15 has been validated to be a tumor facilitator in several types of malignancies. The present study focused on the biological role of SNHG15 in papillary thyroid carcinoma. Based on the result of qPCR analysis, we identified the strong expression of SNHG15 in human papillary thyroid carcinoma tissues and cell lines. Moreover, Kaplan–Meier method was utilized to analyze the internal relevance between SNHG15 expression and overall survival rate of patients with papillary thyroid carcinoma. Loss-of-function assays were designed and conducted to determine the inhibitory effects of silenced SNHG15 on the cell growth and migration in papillary thyroid carcinoma. The mechanical investigation indicated that SNHG15 upregulated YAP1 by sponging miR-200a-3p. Moreover, results of gain-of-function assays validated the anti-oncogenic function of miR-200a-3p in papillary thyroid carcinoma. Finally, results of rescue assays validated the function of SNHG15-miR-200a-3p-YAP1 axis in papillary thyroid carcinoma. YAP1 is known as an oncogene and a core factor of Hippo pathway. Here, we demonstrated that SNHG15 inactivated Hippo signaling pathway in papillary thyroid carcinoma. In summary, our findings demonstrated that SNHG15 serves as a competitively endogenous RNA (ceRNA) to regulate YAP1-Hippo signaling pathway by sponging miR-200a-3p in papillary thyroid carcinoma.
CCN6-mediated MMP-9 activation enhances metastatic potential of human chondrosarcoma
Authors: Tzeng Huey-En , Tang Chih-Hsin , Wu Sz-Hua , Chen Hsien-Te , Fong Yi-Chin , Lu Yung-Chang , Chen Wei-Cheng , Huang Hsien-Da , Lin Chih-Yang , Wang Shih-Wei
Published: September 2018

Chondrosarcomas are primary malignant bone tumors that have a poor prognosis. WNT1-inducible signaling pathway protein-3 (WISP-3, also termed CCN6) belongs to the CCN family of proteins and is implicated in the regulation of various cellular functions, such as cell proliferation, differentiation, and migration. It is unknown as to whether CCN6 affects human chondrosarcoma metastasis. We show how CCN6 promotes chondrosarcoma cell migration and invasion via matrix metallopeptidase-9 (MMP)-9 expression. These effects were abolished by pretreatment of chondrosarcoma cells with PI3K, Akt, mTOR, and NF-κB inhibitors or short interfering (si)RNAs. Our investigations indicate that CCN6 facilitates metastasis through the PI3K/Akt/mTOR/NF-κB signaling pathway. CCN6 and MMP-9 expression was markedly increased in the highly migratory JJ012(S10) cell line compared with the primordial cell line (JJ012) in both in vitro and in vivo experiments. CCN6 knockdown suppressed MMP-9 production in JJ012(S10) cells and attenuated cell migration and invasion ability. Importantly, CCN6 knockdown profoundly inhibited chondrosarcoma cell metastasis to lung. Our findings reveal an important mechanism underlying CCN6-induced metastasis and they highlight the clinical significance between CCN6 and MMP-9 in regard to human chondrosarcoma. CCN6 appears to be a promising therapeutic target in chondrosarcoma metastasis.
Polybrene induces neural degeneration by bidirectional Ca2+ influx-dependent mitochondrial and ER–mitochondrial dynamics
Authors: Bao Feixiang , Shi Hongyan , Gao Mi , Yang Liang , Zhou Lingyan , Zhao Qiuge , Wu Yi , Chen Keshi , Xiang Ge , Long Qi , Guo Jingyi , Zhang Jian , Liu Xingguo
Published: September 2018

Hexadimethrine bromide (Polybrene) was once used clinically as a heparin neutralizer and has recently found use as a promoter in virus-mediated gene therapy trials and gene transfer in research. However, the potential for tissue-specific toxicity of polybrene at low doses has been ignored so far. Here, we found that after intracerebroventricular (ICV) polybrene injection, mice showed disability of movement accompanied neural death and gliosis in brain, and in human neurons, polybrene induces concentration-dependent neuritic beading and fragmentation. Mechanistically, polybrene induces a rapid voltage-dependent calcium channel (VDCC)-mediated influx of extracellular Ca2+. The elevated cytoplasmic Ca2+ activates DRP1, which leads to mitochondrial fragmentation and metabolic dysfunction. At the same time, Ca2+ influx induces endoplasmic reticulum (ER) fragmentation and tightened associations between ER and mitochondria, which makes mitochondria prone to Ca2+ overloading and ensuing permeability transition. These results reveal an unexpected neuronal toxicity of polybrene, wherein Ca2+ influx serves as a regulator for both mitochondrial dynamics and ER–mitochondrial remodeling.
MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis
Authors: Fernández-Ramos David , Fernández-Tussy Pablo , Lopitz-Otsoa Fernando , Gutiérrez-de-Juan Virginia , Navasa Nicolás , Barbier-Torres Lucía , Zubiete-Franco Imanol , Simón Jorge , Fernández Agustín F. , Arbelaiz Ander , Aransay Ana M. , Lavín José Luis , Beraza Naiara , Perugorria María J. , Banales Jesus M. , Villa Erica , Fraga Mario F. , Anguita Juan , Avila Matias A. , Berasain Carmen , Iruzibieta Paula , Crespo Javier , Lu Shelly C. , Varela-Rey Marta , Mato José M. , Delgado Teresa C. , Martínez-Chantar María L.
Published: September 2018

Glycine N-methyltransferase (GNMT) is the most abundant methyltransferase in the liver and a master regulator of the transmethylation flux. GNMT downregulation leads to loss of liver function progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Moreover, GNMT deficiency aggravates cholestasis-induced fibrogenesis. To date, little is known about the mechanisms underlying downregulation of GNMT levels in hepatic fibrosis and cirrhosis. On this basis, microRNAs are epigenetic regulatory elements that play important roles in liver pathology. In this work, we aim to study the regulation of GNMT by microRNAs during liver fibrosis and cirrhosis. Luciferase assay on the 3ʹUTR-Gnmt was used to confirm in silico analysis showing that GNMT is potentially targeted by the microRNA miR-873-5p. Correlation between GNMT and miR-873-5p in human cholestasis and cirrhosis together with miR-873-5p inhibition in vivo in different mouse models of liver cholestasis and fibrosis [bile duct ligation and Mdr2 (Abcb4)-/- mouse] were then assessed. The analysis of liver tissue from cirrhotic and cholestatic patients, as well as from the animal models, showed that miR-873-5p inversely correlated with the expression of GNMT. Importantly, high circulating miR-873-5p was also detected in cholestastic and cirrhotic patients. Preclinical studies with anti-miR-873-5p treatment in bile duct ligation and Mdr2-/- mice recovered GNMT levels in association with ameliorated inflammation and fibrosis mainly by counteracting hepatocyte apoptosis and cholangiocyte proliferation. In conclusion, miR-873-5p emerges as a novel marker for liver fibrosis, cholestasis, and cirrhosis and therapeutic approaches based on anti-miR-873-5p may be effective treatments for liver fibrosis and cholestatic liver disease.
Distinct multilevel misregulations of Parkin and PINK1 revealed in cell and animal models of TDP-43 proteinopathy
Authors: Sun Xing , Duan Yongjia , Qin Caixia , Li Jian-Chiuan , Duan Gang , Deng Xue , Ni Jiangxia , Cao Xu , Xiang Ke , Tian Kuili , Chen Chun-Hong , Li Ang , Fang Yanshan
Published: September 2018

Parkin and PINK1 play an important role in mitochondrial quality control, whose malfunction may also be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Excessive TDP-43 accumulation is a pathological hallmark of ALS and is associated with Parkin protein reduction in spinal cord neurons from sporadic ALS patients. In this study, we reveal that Parkin and PINK1 are differentially misregulated in TDP-43 proteinopathy at RNA and protein levels. Using knock-in flies, mouse primary neurons, and TDP-43Q331K transgenic mice, we further unveil that TDP-43 downregulates Parkin mRNA, which involves an unidentified, intron-independent mechanism and requires the RNA-binding and the protein–protein interaction functions of TDP-43. Unlike Parkin, TDP-43 does not regulate PINK1 at an RNA level. Instead, excess of TDP-43 causes cytosolic accumulation of cleaved PINK1 due to impaired proteasomal activity, leading to compromised mitochondrial functions. Consistent with the alterations at the molecular and cellular levels, we show that transgenic upregulation of Parkin but downregulation of PINK1 suppresses TDP-43-induced degenerative phenotypes in a Drosophila model of ALS. Together, these findings highlight the challenge associated with the heterogeneity and complexity of ALS pathogenesis, while pointing to Parkin–PINK1 as a common pathway that may be differentially misregulated in TDP-43 proteinopathy.
C-Abl is not actıvated in DNA damage-induced and Tap63-mediated oocyte apoptosıs in human ovary
Authors: Bildik Gamze , Acılan Ceyda , Sahin Gizem Nur , Karahuseyinoglu Sercin , Oktem Ozgur
Published: September 2018

There is a controversy in literature as to whether c-Abl is crucial for the induction of TAp63-mediated apoptosis and whether that inhibition of c-Abl with imatinib, which was designed to inhibit the oncogenic kinase BCR-ABL and c-kit, protects oocytes from chemotherapy-induced apoptosis in mice. No human data are available on this issue. We therefore aimed to explore whether genomic damage induced by chemotherapy drug cisplatin activates c-Abl along with TAp63 and the inhibition of c-Abl with imatinib prevents cisplatin-induced oocyte death and follicle loss in human ovary. Exposure to cisplatin induced DNA damage, activated TAp63 and SAPK/JNK pathway, and triggered apoptosis in the oocytes and granulosa cells. However, TAp63 activation after cisplatin was not associated with any increase in the expression of c-Abl. Imatinib did not prevent cisplatin-induced apoptosis of the granulosa cells or oocytes. Moreover, treatment with this drug resulted in the formation of bizarre shaped follicles lacking oocytes and increased follicular atresia by inducing apoptosis of granulosa cells and oocytes. Similar toxic effects were observed when ovarian tissue samples were incubated with a c-kit antagonist drug anti-CD117, but not with another c-Abl tyrosine kinase inhibitor GNF-2, which lacks an inhibitory action on c-kit. Intraperitoneal administration of imatinib to the xenografted animals produced similar histomorphological abnormalities in the follicles in human ovarian grafts and did not prevent cisplatin-induced follicle loss when co-administered with cisplatin. Our findings provide, for the first time, a molecular evidence for ovarian toxicity of this drug in human. Furthermore, this study together with two previous case reports of a severely compromised ovarian response to gonadotropin stimulation and premature ovarian failure in patients, while receiving imatinib, further heighten the concerns about its potential gonadotoxicity on human ovary and urge caution in its use in young female patients.
Structural basis for broad neutralization of ebolaviruses by an antibody targeting the glycoprotein fusion loop
Authors: Janus Benjamin M. , van Dyk Nydia , Zhao Xuelian , Howell Katie A. , Soto Cinque , Aman M. Javad , Li Yuxing , Fuerst Thomas R. , Ofek Gilad
Published: September 2018

The severity of the 2014–2016 ebolavirus outbreak in West Africa expedited clinical development of therapeutics and vaccines though the countermeasures on hand were largely monospecific and lacked efficacy against other ebolavirus species that previously emerged. Recent studies indicate that ebolavirus glycoprotein (GP) fusion loops are targets for cross-protective antibodies. Here we report the 3.72 Å resolution crystal structure of one such cross-protective antibody, CA45, bound to the ectodomain of Ebola virus (EBOV) GP. The CA45 epitope spans multiple faces of the fusion loop stem, across both GP1 and GP2 subunits, with ~68% of residues identical across > 99.5% of known ebolavirus isolates. Extensive antibody interactions within a pan-ebolavirus small-molecule inhibitor binding cavity on GP define this cavity as a novel site of immune vulnerability. The structure elucidates broad ebolavirus neutralization through a highly conserved epitope on GP and further enables rational design and development of broadly protective vaccines and therapeutics.
Magnetized fast isochoric laser heating for efficient creation of ultra-high-energy-density states
Authors: Sakata Shohei , Lee Seungho , Morita Hiroki , Johzaki Tomoyuki , Sawada Hiroshi , Iwasa Yuki , Matsuo Kazuki , Law King Fai Farley , Yao Akira , Hata Masayasu , Sunahara Atsushi , Kojima Sadaoki , Abe Yuki , Kishimoto Hidetaka , Syuhada Aneez , Shiroto Takashi , Morace Alessio , Yogo Akifumi , Iwata Natsumi , Nakai Mitsuo , Sakagami Hitoshi , Ozaki Tetsuo , Yamanoi Kohei , Norimatsu Takayoshi , Nakata Yoshiki , Tokita Shigeki , Miyanaga Noriaki , Kawanaka Junji , Shiraga Hiroyuki , Mima Kunioki , Nishimura Hiroaki , Bailly-Grandvaux Mathieu , Santos João Jorge , Nagatomo Hideo , Azechi Hiroshi , Kodama Ryosuke , Arikawa Yasunobu , Sentoku Yasuhiko , Fujioka Shinsuke
Published: September 2018

Fast isochoric heating of a pre-compressed plasma core with a high-intensity short-pulse laser is an attractive and alternative approach to create ultra-high-energy-density states like those found in inertial confinement fusion (ICF) ignition sparks. Laser-produced relativistic electron beam (REB) deposits a part of kinetic energy in the core, and then the heated region becomes the hot spark to trigger the ignition. However, due to the inherent large angular spread of the produced REB, only a small portion of the REB collides with the core. Here, we demonstrate a factor-of-two enhancement of laser-to-core energy coupling with the magnetized fast isochoric heating. The method employs a magnetic field of hundreds of Tesla that is applied to the transport region from the REB generation zone to the core which results in guiding the REB along the magnetic field lines to the core. This scheme may provide more efficient energy coupling compared to the conventional ICF scheme.
UBL3 modification influences protein sorting to small extracellular vesicles
Authors: Ageta Hiroshi , Ageta-Ishihara Natsumi , Hitachi Keisuke , Karayel Ozge , Onouchi Takanori , Yamaguchi Hisateru , Kahyo Tomoaki , Hatanaka Ken , Ikegami Koji , Yoshioka Yusuke , Nakamura Kenji , Kosaka Nobuyoshi , Nakatani Masashi , Uezumi Akiyoshi , Ide Tomihiko , Tsutsumi Yutaka , Sugimura Haruhiko , Kinoshita Makoto , Ochiya Takahiro , Mann Matthias , Setou Mitsutoshi , Tsuchida Kunihiro
Published: September 2018

Exosomes, a type of small extracellular vesicles (sEVs), derived from multivesicular bodies (MVBs), mediate cell-to-cell communication by transporting proteins, mRNAs, and miRNAs. However, the molecular mechanism by which proteins are sorted to sEVs is not fully understood. Here, we report that ubiquitin-like 3 (UBL3)/membrane-anchored Ub-fold protein (MUB) acts as a posttranslational modification (PTM) factor that regulates protein sorting to sEVs. We find that UBL3 modification is indispensable for sorting of UBL3 to MVBs and sEVs. We also observe a 60% reduction of total protein levels in sEVs purified from Ubl3-knockout mice compared with those from wild-type mice. By performing proteomics analysis, we find 1241 UBL3-interacting proteins, including Ras. We also show that UBL3 directly modifies Ras and oncogenic RasG12V mutant, and that UBL3 expression enhances sorting of RasG12V to sEVs via UBL3 modification. Collectively, these results indicate that PTM by UBL3 influences the sorting of proteins to sEVs.
Genome-wide association study of 23,500 individuals identifies 7 loci associated with brain ventricular volume
Authors: Vojinovic Dina , Adams Hieab H. , Jian Xueqiu , Yang Qiong , Smith Albert Vernon , Bis Joshua C. , Teumer Alexander , Scholz Markus , Armstrong Nicola J. , Hofer Edith , Saba Yasaman , Luciano Michelle , Bernard Manon , Trompet Stella , Yang Jingyun , Gillespie Nathan A. , van der Lee Sven J. , Neumann Alexander , Ahmad Shahzad , Andreassen Ole A. , Ames David , Amin Najaf , Arfanakis Konstantinos , Bastin Mark E. , Becker Diane M. , Beiser Alexa S. , Beyer Frauke , Brodaty Henry , Bryan R. Nick , Bülow Robin , Dale Anders M. , De Jager Philip L. , Deary Ian J. , DeCarli Charles , Fleischman Debra A. , Gottesman Rebecca F. , van der Grond Jeroen , Gudnason Vilmundur , Harris Tamara B. , Homuth Georg , Knopman David S. , Kwok John B. , Lewis Cora E. , Li Shuo , Loeffler Markus , Lopez Oscar L. , Maillard Pauline , El Marroun Hanan , Mather Karen A. , Mosley Thomas H. , Muetzel Ryan L. , Nauck Matthias , Nyquist Paul A. , Panizzon Matthew S. , Pausova Zdenka , Psaty Bruce M. , Rice Ken , Rotter Jerome I. , Royle Natalie , Satizabal Claudia L. , Schmidt Reinhold , Schofield Peter R. , Schreiner Pamela J. , Sidney Stephen , Stott David J. , Thalamuthu Anbupalam , Uitterlinden Andre G. , Valdés Hernández Maria C. , Vernooij Meike W. , Wen Wei , White Tonya , Witte A. Veronica , Wittfeld Katharina , Wright Margaret J. , Yanek Lisa R. , Tiemeier Henning , Kremen William S. , Bennett David A. , Jukema J. Wouter , Paus Tomas , Wardlaw Joanna M. , Schmidt Helena , Sachdev Perminder S. , Villringer Arno , Grabe Hans Jörgen , Longstreth W T , van Duijn Cornelia M. , Launer Lenore J. , Seshadri Sudha , Ikram M Arfan , Fornage Myriam
Published: September 2018

The volume of the lateral ventricles (LV) increases with age and their abnormal enlargement is a key feature of several neurological and psychiatric diseases. Although lateral ventricular volume is heritable, a comprehensive investigation of its genetic determinants is lacking. In this meta-analysis of genome-wide association studies of 23,533 healthy middle-aged to elderly individuals from 26 population-based cohorts, we identify 7 genetic loci associated with LV volume. These loci map to chromosomes 3q28, 7p22.3, 10p12.31, 11q23.1, 12q23.3, 16q24.2, and 22q13.1 and implicate pathways related to tau pathology, S1P signaling, and cytoskeleton organization. We also report a significant genetic overlap between the thalamus and LV volumes (ρgenetic = −0.59, p-value = 3.14 × 10−6), suggesting that these brain structures may share a common biology. These genetic associations of LV volume provide insights into brain morphology.
A scalable online tool for quantitative social network assessment reveals potentially modifiable social environmental risks
Authors: Dhand Amar , White Charles C. , Johnson Catherine , Xia Zongqi , De Jager Philip L.
Published: September 2018

Social networks are conduits of support, information, and health behavior flows. Existing measures of social networks used in clinical research are typically summative scales of social support or artificially truncated networks of ≤ 5 people. Here, we introduce a quantitative social network assessment tool on a secure open-source web platform, readily deployable in large-scale clinical studies. The tool maps an individual’s personal network, including specific persons, their relationships to each other, and their health habits. To demonstrate utility, we used the tool to measure the social networks of 1493 persons at risk of multiple sclerosis. We examined each person’s social network in relation to self-reported neurological disability. We found that the characteristics of persons surrounding the participant, such as negative health behaviors, were strongly associated with the individual’s functional disability. This quantitative assessment reveals the key elements of individuals’ social environments that could be targeted in clinical trials.
Structural analysis of HTL and D14 proteins reveals the basis for ligand selectivity in Striga
Authors: Xu Yuqun , Miyakawa Takuya , Nosaki Shohei , Nakamura Akira , Lyu Ying , Nakamura Hidemitsu , Ohto Umeharu , Ishida Hanako , Shimizu Toshiyuki , Asami Tadao , Tanokura Masaru
Published: September 2018

HYPOSENSITIVE TO LIGHT (HTL) and DWARF14 (D14) mediate the perception of karrikin and strigolactone, which stimulates germination of the parasitic weed Striga. However, their role in parasitic seeds is poorly understood, and the basis for their differing responsiveness remains unclear. Here, we show that Striga hermonthica HTL proteins (ShHTLs) in ‘conserved’ and ‘intermediate’ clades are able to bind karrikin. The ‘divergent’ clade is able to hydrolyze strigolactone. Unexpectedly, we find that ShD14 is also capable of hydrolyzing strigolactone. Through comparative analysis of ShHTLs and ShD14 crystal structures, we provide insights into the basis for their selectivity. Moreover, we show that both ShD14 and divergent clade ShHTLs, but not conserved and intermediate clade ShHTLs, can interact with the putative downstream signaling component ShMAX2 in the presence of the synthetic strigolactone, rac-GR24. These findings provide insight into how strigolactone is perceived and how ligand specificity is determined.
A bioinspired multilegged soft millirobot that functions in both dry and wet conditions
Authors: Lu Haojian , Zhang Mei , Yang Yuanyuan , Huang Qiang , Fukuda Toshio , Wang Zuankai , Shen Yajing
Published: September 2018

Developing untethered millirobots that can adapt to harsh environments with high locomotion efficiency is of interest for emerging applications in various industrial and biomedical settings. Despite recent success in exploiting soft materials to impart sophisticated functions which are not available in conventional rigid robotics, it remains challenging to achieve superior performances in both wet and dry conditions. Inspired by the flexible, soft, and elastic leg/foot structures of many living organisms, here we report an untethered soft millirobot decorated with multiple tapered soft feet architecture. Such robot design yields superior adaptivity to various harsh environments with ultrafast locomotion speed (>40 limb length/s), ultra-strong carrying capacity (>100 own weight), and excellent obstacle-crossing ability (stand up 90° and across obstacle >10 body height). Our work represents an important advance in the emerging area of bio-inspired robotics and will find a wide spectrum of applications.
Author Correction: The acoustic phase resonances and surface waves supported by a compound rigid grating
Authors: Beadle Joseph G. , Starkey Timothy , Dockrey Joseph A. , Sambles J. Roy , Hibbins Alastair P.
Published: September 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
Multi-omics integrative analysis with genome-scale metabolic model simulation reveals global cellular adaptation of Aspergillus niger under industrial enzyme production condition
Authors: Lu Hongzhong , Cao Weiqiang , Liu Xiaoyun , Sui Yufei , Ouyang Liming , Xia Jianye , Huang Mingzhi , Zhuang Yingping , Zhang Siliang , Noorman Henk , Chu Ju
Published: September 2018

Oxygen limitation is regarded as a useful strategy to improve enzyme production by mycelial fungus like Aspergillus niger. However, the intracellular metabolic response of A. niger to oxygen limitation is still obscure. To address this, the metabolism of A. niger was studied using multi-omics integrated analysis based on the latest GEMs (genome-scale metabolic model), including metabolomics, fluxomics and transcriptomics. Upon sharp reduction of the oxygen supply, A. niger metabolism shifted to higher redox level status, as well as lower energy supply, down-regulation of genes for fatty acid synthesis and a rapid decrease of the specific growth rate. The gene expression of the glyoxylate bypass was activated, which was consistent with flux analysis using the A. niger GEMs iHL1210. The increasing flux of the glyoxylate bypass was assumed to reduce the NADH formation from TCA cycle and benefit maintenance of the cellular redox balance under hypoxic conditions. In addition, the relative fluxes of the EMP pathway were increased, which possibly relieved the energy demand for cell metabolism. The above multi-omics integrative analysis provided new insights on metabolic regulatory mechanisms of A. niger associated with enzyme production under oxygen-limited condition, which will benefit systematic design and optimization of the A. niger microbial cell factory.
Methylation deregulation of miRNA promoters identifies miR124-2 as a survival biomarker in Breast Cancer in very young women
Authors: Oltra Sara S. , Peña-Chilet Maria , Vidal-Tomas Victoria , Flower Kirsty , Martinez María Teresa , Alonso Elisa , Burgues Octavio , Lluch Ana , Flanagan James M. , Ribas Gloria
Published: September 2018

MiRNAs are part of the epigenetic machinery, and are also epigenetically modified by DNA methylation. MiRNAs regulate expression of different genes, so any alteration in their methylation status may affect their expression. We aimed to identify methylation differences in miRNA encoding genes in breast cancer affecting women under 35 years old (BCVY), in order to identify potential biomarkers in these patients. In Illumina Infinium MethylationEPIC BeadChip samples (metEPICVal), we analysed the methylation of 9,961 CpG site regulators of miRNA-encoding genes present in the array. We identified 193 differentially methylated CpG sites in BCVY (p-value < 0.05 and methylation differences ±0.1) that regulated 83 unique miRNA encoding genes. We validated 10 CpG sites using two independent datasets based on Infinium Human Methylation 450k array. We tested gene expression of miRNAs with differential methylation in BCVY in a meta-analysis using The Cancer Genome Atlas (TCGA), Clariom D and Affymetrix datasets. Five miRNAs (miR-9, miR-124-2, miR-184, miR-551b and miR-196a-1) were differently expressed (FDRp-value < 0.01). Finally, only miR-124-2 shows a significantly different gene expression by quantitative real-time PCR. MiR-124-hypomethylation presents significantly better survival rates for older patients as opposed to the worse prognosis observed in BCVY, identifying it as a potential specific survival biomarker in BCVY.
Mutagenic assessment of chemotherapy and Smac mimetic drugs in cells with defective DNA damage response pathways
Authors: Miles Mark A. , Hawkins Christine J.
Published: September 2018

DNA damaging therapies can spur the formation of therapy-related cancers, due to mis-repair of lesions they create in non-cancerous cells. This risk may be amplified in patients with impaired DNA damage responses. We disabled key DNA damage response pathways using genetic and pharmacological approaches, and assessed the impact of these deficiencies on the mutagenicity of chemotherapy drugs or the “Smac mimetic” GDC-0152, which kills tumor cells by targeting XIAP, cIAP1 and 2. Doxorubicin and cisplatin provoked mutations in more surviving cells deficient in ATM, p53 or the homologous recombination effector RAD51 than in wild type cells, but suppressing non-homologous end joining (NHEJ) by disabling DNA-PKcs prevented chemotherapy-induced mutagenesis. Vincristine-induced mutagenesis required p53 and DNA-PKcs but was not affected by ATM status, consistent with it provoking ATM-independent p53-mediated activation of caspases and CAD, which creates DNA lesions in surviving cells that could be mis-repaired by NHEJ. Encouragingly, GDC-0152 failed to stimulate mutations in cells with proficient or defective DNA damage response pathways. This study highlights the elevated oncogenic risk associated with treating DNA repair-deficient patients with genotoxic anti-cancer therapies, and suggests a potential advantage for Smac mimetic drugs over traditional therapies: a reduced risk of therapy-related cancers.
Molecular fingerprinting of nanoparticles in complex media with non-contact photoacoustics: beyond the light scattering limit
Authors: Pelivanov Ivan , Petrova Elena , Yoon Soon Joon , Qian Zhaoxia , Guye Kathryn , O’Donnell Matthew
Published: September 2018

Optical instruments can probe physical systems even to the level of individual molecules. In particular, every molecule, solution, and structure such as a living cell has a unique absorption spectrum representing a molecular fingerprint. This spectrum can help identify a particular molecule from others or quantify its concentration; however, scattering limits molecular fingerprinting within a complex compound and must be overcome. Here, we present a new, non-contact photoacoustic (PA)-based method that can almost completely remove the influence of background light scattering on absorption measurements in heterogeneous highly scattering solutions and, furthermore, separate the intrinsic absorption of nanoscale objects from their scattering. In particular, we measure pure absorption spectra for solutions of gold nanorods (GNRs) as an example of a plasmonic agent and show that these spectra differ from the extinction measured with conventional UV-VIS spectrophotometry. Finally, we show how the original GNR absorption changes when nanoparticles are internalized by cells.
Publisher Correction: Concurrent guiding of light and heat by transformation optics and transformation thermodynamics via soft matter
Authors: Barros Wallysson K. P. , Pereira Erms
Published: September 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Direct RNA Sequencing of the Coding Complete Influenza A Virus Genome
Authors: Keller Matthew W. , Rambo-Martin Benjamin L. , Wilson Malania M. , Ridenour Callie A. , Shepard Samuel S. , Stark Thomas J. , Neuhaus Elizabeth B. , Dugan Vivien G. , Wentworth David E. , Barnes John R.
Published: September 2018

For the first time, a coding complete genome of an RNA virus has been sequenced in its original form. Previously, RNA was sequenced by the chemical degradation of radiolabeled RNA, a difficult method that produced only short sequences. Instead, RNA has usually been sequenced indirectly by copying it into cDNA, which is often amplified to dsDNA by PCR and subsequently analyzed using a variety of DNA sequencing methods. We designed an adapter to short highly conserved termini of the influenza A virus genome to target the (-) sense RNA into a protein nanopore on the Oxford Nanopore MinION sequencing platform. Utilizing this method with total RNA extracted from the allantoic fluid of influenza rA/Puerto Rico/8/1934 (H1N1) virus infected chicken eggs (EID50 6.8 × 109), we demonstrate successful sequencing of the coding complete influenza A virus genome with 100% nucleotide coverage, 99% consensus identity, and 99% of reads mapped to influenza A virus. By utilizing the same methodology one can redesign the adapter in order to expand the targets to include viral mRNA and (+) sense cRNA, which are essential to the viral life cycle, or other pathogens. This approach also has the potential to identify and quantify splice variants and base modifications, which are not practically measurable with current methods.
Direct IR Absorption Spectra of Propargyl Cation Isolated in Solid Argon
Authors: Chin Chih-Hao , Lin Meng-Yeh , Huang Tzu-Ping , Wu Pei-Zhen , Wu Yu-Jong
Published: September 2018

The direct infrared (IR) absorption spectra of propargyl cations were recorded. These cations were generated via the electron bombardment of a propyne/Ar matrix sample during matrix deposition. Secondary photolysis with selected ultraviolet (UV) light was used for grouping the observed bands of various products. The band assignment of the propargyl cation in solid Ar was performed according by referring to the previous infrared photodissociation (IRPD) and velocity-map imaging photoelectron (VMI-PE) data, and via theoretical predictions of the anharmonic vibrational wavenumbers, band intensities, and deuterium-substituted isotopic ratios. Almost all the IR active bands with an observable intensity were recorded and the ν11 mode was reported for the first time.
Group-based rewiring rules of binary opinion competition dynamics
Authors: Jin Cheng , Yin Chunji , Jin Xiaogang , Min Yong , Li Yixiao , Chen Nuole , Huang Jiaxuan
Published: September 2018

The dynamics of competing opinions on networks has attracted multi-disciplinary research. Most modelling approaches assume uniform or heterogeneous behaviour among all individuals, while the role of distinctive group behaviour is rarely addressed. Here, we consider competition occurring between two opinion groups with bound rewiring rules, i.e., opinion-preferred rewiring, degree-preferred rewiring and random rewiring. When two opinions share a balanced initial proportion, opinion-preferred rewiring is superior to the other rules under low rewiring rates, and coexistence occurs under high rewiring rates. For unbalanced proportions, the best response rule for the minority/majority is unfixed, and this depends on the initial proportion and rewiring frequency. Furthermore, we find evolution processes for all competing cases belong to two categories. Evolution Category I shows an obvious correlation between opinion proportions and the density of discordant edges (connecting nodes with different opinions), and these trends can be effectively described by numerical approximations. However, for Evolution Category II, no such correlation exists for individuals or linking pairs, and an analysis of local structures reveals the emergence of large numbers of open triads with the same opinions, denoting group prevalence. This work broadens the understanding of opinion competition and inspires exploring group strategies employed in social dynamic systems.
Bipolar lophotrichous Helicobacter suis combine extended and wrapped flagella bundles to exhibit multiple modes of motility
Authors: Constantino Maira A. , Jabbarzadeh Mehdi , Fu Henry C. , Shen Zeli , Fox James G. , Haesebrouck Freddy , Linden Sara K. , Bansil Rama
Published: September 2018

The swimming strategies of unipolar flagellated bacteria are well known but little is known about how bipolar bacteria swim. Here we examine the motility of Helicobacter suis, a bipolar gastric-ulcer-causing bacterium that infects pigs and humans. Phase-contrast microscopy of unlabeled bacteria reveals flagella bundles in two conformations, extended away from the body (E) or flipped backwards and wrapped (W) around the body. We captured videos of the transition between these two states and observed three different swimming modes in broth: with one bundle rotating wrapped around the body and the other extended (EW), both extended (EE), and both wrapped (WW). Only EW and WW modes were seen in porcine gastric mucin. The EW mode displayed ballistic trajectories while the other two displayed superdiffusive random walk trajectories with slower swimming speeds. Separation into these two categories was also observed by tracking the mean square displacement of thousands of trajectories at lower magnification. Using the Method of Regularized Stokeslets we numerically calculate the swimming dynamics of these three different swimming modes and obtain good qualitative agreement with the measurements, including the decreased speed of the less frequent modes. Our results suggest that the extended bundle dominates the swimming dynamics.
Psychological Profile in Coronary Artery By-Pass Graft Patients vs. Valve Replacement Patients Entering Cardiac Rehabilitation after Surgery
Authors: Modica Maddalena , Castiglioni Paolo , Minotti Anna , Faini Andrea , Racca Vittorio , Ferratini Maurizio
Published: September 2018

Anxiety and depression are thought to influence the genesis of ischemic diseases and not of valvular diseases, but little is known on the psychological profile of cardiac patients after surgery. Aim of this study was to investigate differences in disease experience and mood between patients undergoing cardiac rehabilitation after coronary artery by-pass graft (CABG) or after valve replacement (VR). We studied 1,179 CABG and 737 VR patients who completed the Illness Behaviour Questionnaire and the Hospital Anxiety and Depression Scale after surgery. We tested the independent effect of the type of surgery by multivariate analysis and between-group differences in prevalence of clinically relevant scores. Relevant scores in the psychosomatic concern scale were more frequent in CABG than in VR patients. After correction by age, sex, education and marital status, scores of disease conviction and psychosomatic concern were higher in CABG patients, scores of denial were higher in VR patients. Unexpectedly, anxiety and depression scores did not differ between groups. Results suggest providing psychological support for anxiety and depression to both VR and CABG patients during cardiac rehabilitation, and planning differentiated interventions of cardiac rehabilitation and secondary prevention tailored to the specific psychological reactions of CABG and VR patients.
Micropatterning of planar metal electrodes by vacuum filling microfluidic channel geometries
Authors: Chatzimichail Stelios , Supramaniam Pashiini , Ces Oscar , Salehi-Reyhani Ali
Published: September 2018

We present a simple, facile method to micropattern planar metal electrodes defined by the geometry of a microfluidic channel network template. By introducing aqueous solutions of metal into reversibly adhered PDMS devices by desiccation instead of flow, we are able to produce difficult to pattern “dead end” or discontinuous features with ease. We characterize electrodes fabricated using this method and perform electrical lysis of mammalian cancer cells and demonstrate their use as part of an antibody capture assay for GFP. Cell lysis in microwell arrays is achieved using the electrodes and the protein released is detected using an antibody microarray. We show how the template channels used as part of the workflow for patterning the electrodes may be produced using photolithography-free methods, such as laser micromachining and PDMS master moulding, and demonstrate how the use of an immiscible phase may be employed to create electrode spacings on the order of 25–50 μm, that overcome the current resolution limits of such methods. This work demonstrates how the rapid prototyping of electrodes for use in total analysis systems can be achieved on the bench with little or no need for centralized facilities.
Biolistic-delivery-based transient CRISPR/Cas9 expression enables in planta genome editing in wheat
Authors: Hamada Haruyasu , Liu Yuelin , Nagira Yozo , Miki Ryuji , Taoka Naoaki , Imai Ryozo
Published: September 2018

The current application of genome editing to crop plants is limited to cultivars that are amenable to in vitro culture and regeneration. Here, we report an in planta genome-editing which does not require callus culture and regeneration. Shoot apical meristems (SAMs) contain a subepidermal cell layer, L2, from which germ cells later develop during floral organogenesis. The biolistic delivery of gold particles coated with plasmids expressing CRISPR/Cas9 components designed to target TaGASR7 were bombarded into SAM-exposed embryos of imbibed seeds. Bombarded embryos showing transient GFP expression within SAM were selected and grown into adult plants. Mutations in the target gene were assessed in fifth-leaf tissue by cleaved amplified polymorphic sequence analysis. Eleven (5.2%) of the 210 bombarded plants carried mutant alleles, and the mutations of three (1.4%) of these were inherited in the next generation. Genotype analysis of T1 plants identified plants homozygous for the three homeologous genes, which were all derived from one T0 plant. These plants showed no detectable integration of the Cas9 and guide RNA genes, indicating that transient expression of CRISPR/Cas9 introduced the mutations. Together, our current method can be used to achieve in planta genome editing in wheat using CRISPR/Cas9 and suggests possible applications to other recalcitrant plant species and variations.