bluuebunny/crossref_metadata_2025 huggingface dataset:
The Role of the Stratosphere in Subseasonal to Seasonal Prediction: 2. Predictability Arising From Stratosphere‐Troposphere Coupling
Authors: Domeisen Daniela I. V. , Butler Amy H. , Charlton‐Perez Andrew J. , Ayarzagüena Blanca , Baldwin Mark P. , Dunn‐Sigouin Etienne , Furtado Jason C. , Garfinkel Chaim I. , Hitchcock Peter , Karpechko Alexey Yu. , Kim Hera , Knight Jeff , Lang Andrea L. , Lim Eun‐Pa , Marshall Andrew , Roff Greg , Schwartz Chen , Simpson Isla R. , Son Seok‐Woo , Taguchi Masakazu
Published: November 2019

The stratosphere can have a significant impact on winter surface weather on subseasonal to seasonal (S2S) timescales. This study evaluates the ability of current operational S2S prediction systems to capture two important links between the stratosphere and troposphere: (1) changes in probabilistic prediction skill in the extratropical stratosphere by precursors in the tropics and the extratropical troposphere and (2) changes in surface predictability in the extratropics after stratospheric weak and strong vortex events. Probabilistic skill exists for stratospheric events when including extratropical tropospheric precursors over the North Pacific and Eurasia, though only a limited set of models captures the Eurasian precursors. Tropical teleconnections such as the Madden‐Julian Oscillation, the Quasi‐Biennial Oscillation, and El Niño–Southern Oscillation increase the probabilistic skill of the polar vortex strength, though these are only captured by a limited set of models. At the surface, predictability is increased over the United States, Russia, and the Middle East for weak vortex events, but not for Europe, and the change in predictability is smaller for strong vortex events for all prediction systems. Prediction systems with poorly resolved stratospheric processes represent this skill to a lesser degree. Altogether, the analyses indicate that correctly simulating stratospheric variability and stratosphere‐troposphere dynamical coupling are critical elements for skillful S2S wintertime predictions.
Summertime Atmospheric Boundary Layer Gradients of O2 and CO2 over the Southern Ocean
Authors: Morgan Eric J. , Stephens Britton B. , Long Matthew C. , Keeling Ralph F. , Bent Jonathan D. , McKain Kathryn , Sweeney Colm , Hoecker‐Martínez Martín S. , Kort Eric A.
Published: November 2019

We present airborne observations of the vertical gradient of atmospheric oxygen (δ(O2/N2)) and carbon dioxide (CO2) through the atmospheric boundary layer (BL) over the Drake Passage region of the Southern Ocean, during the O2/N2 Ratio and CO2 Airborne Southern Ocean Study, from 15 January to 29 February 2016. Gradients were predominately anticorrelated, with excesses of δ(O2/N2) and depletions of CO2 found within the boundary layer, relative to a mean reference height of 1.7 km. Through analysis of the molar ratio of the gradients (GR), the behavior of other trace gases measured in situ, and modeling experiments with the Community Earth System Model, we found that the main driver of gradients was air‐sea exchange of O2 and CO2 driven by biological processes, more so than solubility effects. An exception to this was in the eastern Drake Passage, where positive GRs were occasionally observed, likely due to the dominance of thermal forcing on the air‐sea flux of both species. GRs were more spatially consistent than the magnitudes of the gradients, suggesting that GRs can provide integrated process constraints over broad spatial scales. Based on the model simulation within a domain bounded by 45°S, 75°S, 100°W, and 45°W, we show that the sampling density of the campaign was such that the observed mean GR (± standard error), −4.0± 0.8 mol O2 per mol CO2, was a reasonable proxy for both the mean GR and the mean molar ratio of air‐sea fluxes of O2 and CO2 during the O2/N2 Ratio and CO2 Airborne Southern Ocean Study.
The Importance of Monitoring Interval for Rockfall Magnitude‐Frequency Estimation
Authors: Williams Jack G. , Rosser Nick J. , Hardy Richard J. , Brain Matthew J.
Published: November 2019

Rockfalls commonly exhibit power law volume‐frequency distributions, where fewer large events are observed relative to more numerous small events. Within most inventories, the smallest rockfalls are the most difficult to detect and so may not be adequately represented. A primary challenge occurs when neighboring events within a single monitoring interval are recorded as one, producing ambiguity in event location, timing, volume, and frequency. Identifying measurement intervals that minimize these uncertainties is therefore essential. To address this, we use an hourly data set comprising 8,987 3‐D point clouds of a cliff that experiences frequent rockfalls. Multiple rockfall inventories are derived from this data set using change detections for the same 10‐month period, but over different monitoring intervals. The power law describing the probability distribution of rockfall volumes is highly sensitive to monitoring interval. The exponent,β, is stable for intervals >12 hr but increases nonlinearly over progressively short timescales. This change is manifested as an increase in observed rockfall numbers, from 1.4 × 103(30 day intervals) to 1.4 × 104(1 hr intervals), and a threefold reduction in mean rockfall volume. When the monitoring interval exceeds 4 hr, the geometry of detected rockfalls becomes increasingly similar to that of blocks defined by rock mass structure. This behavior change reveals a time‐dependent component to rockfall occurrence, where smaller rockfalls (identifiable from more frequent monitoring) are more sensitive to progressive deformation of the rock mass. Acquiring complete inventories and attributing discrete controls over rockfall occurrence may therefore only be achievable with high‐frequency monitoring, dependent upon local lithology.
Prostaglandin D2 stimulates phenotypic changes in vascular smooth muscle cells
Authors: Lee Hye Sun , Yun Sung Ji , Ha Jung Min , Jin Seo Yeon , Ha Hong Koo , Song Sang Heon , Kim Chi Dae , Bae Sun Sik
Published: November 2019

Since chronic inflammation is associated with the pathogenesis of atherosclerosis, inflammatory cytokines might contribute to the phenotypic modulation of vascular smooth muscle cells (VSMCs). Tumor necrosis factor α (TNFα) facilitated the transformation of contractile VSMCs to the synthetic phenotype, as determined by the expression of marker proteins and a collagen gel contraction assay. Western blot analysis and a cyclooxygenase-2 (COX2) promoter assay revealed that TNFα stimulation resulted in the induction of COX2. The overexpression, silencing, or pharmacological inhibition of COX2 significantly affected TNFα-induced phenotypic conversion, and of the tested prostaglandins, only PGD2significantly induced phenotypic conversion. ERK was significantly activated by PGD2stimulation, and the pharmacological inhibition of ERK blocked the PGD2-induced phenotypic conversion of VSMCs. However, antagonists or agonists of PGD2receptors did not affect VSMC conversion. In contrast, spontaneously dehydrated forms of PGD2, such as PGJ2, Δ12-PGJ2, and 15-d-PGJ2, strongly induced phenotypic conversion. A reporter gene assay showed that TNFα, PGD2, and 15-d-PGJ2significantly activated the peroxisome proliferator-responsive element (PPRE) promoter. In addition, the overexpression or silencing of peroxisome proliferator-activated receptor δ (PPARδ) significantly influenced 15-d-PGJ2-induced phenotypic conversion. Finally, atherosclerotic neointima formation was significantly suppressed in mice lacking TNFα. In addition, mice fed celecoxib exhibited complete inhibition of carotid artery ligation-induced neointima formation. This study shows that PGD2regulates the phenotypic conversion of VSMCs by generating an endogenous ligand of PPAR, and that this leads to neointima formation in occlusive arterial disease.
Boosting therapeutic potency of antibodies by taming Fc domain functions
Authors: Kang Tae Hyun , Jung Sang Taek
Published: November 2019

Monoclonal antibodies (mAbs) are one of the most widely used drug platforms for infectious diseases or cancer therapeutics because they selectively target pathogens, infectious cells, cancerous cells, and even immune cells. In this way, they mediate the elimination of target molecules and cells with fewer side effects than other therapeutic modalities. In particular, cancer therapeutic mAbs can recognize cell-surface proteins on target cells and then kill the targeted cells by multiple mechanisms that are dependent upon a fragment crystallizable (Fc) domain interacting with effector Fc gamma receptors, including antibody-dependent cell-mediated cytotoxicity and antibody-dependent cell-mediated phagocytosis. Extensive engineering efforts have been made toward tuning Fc functions by either reinforcing (e.g. for targeted therapy) or disabling (e.g. for immune checkpoint blockade therapy) effector functions and prolonging the serum half-lives of antibodies, as necessary. In this report, we review Fc engineering efforts to improve therapeutic potency, and propose future antibody engineering directions that can fulfill unmet medical needs.
Microplasma direct writing for site-selective surface functionalization of carbon microelectrodes
Authors: Thiha Aung , Ibrahim Fatimah , Muniandy Shalini , Madou Marc J.
Published: November 2019

Carbon micro- and nanoelectrodes fabricated by carbon microelectromechanical systems (carbon MEMS) are increasingly used in various biosensors and supercapacitor applications. Surface modification of as-produced carbon electrodes with oxygen functional groups is sometimes necessary for biofunctionalization or to improve electrochemical properties. However, conventional surface treatment methods have a limited ability for selective targeting of parts of a surface area for surface modification without using complex photoresist masks. Here, we report microplasma direct writing as a simple, low-cost, and low-power technique for site-selective plasma patterning of carbon MEMS electrodes with oxygen functionalities. In microplasma direct writing, a high-voltage source generates a microplasma discharge between a microelectrode tip and a target surface held at atmospheric pressure. In our setup, water vapor acts as an ionic precursor for the carboxylation and hydroxylation of carbon surface atoms. Plasma direct writing increases the oxygen content of an SU-8-derived pyrolytic carbon surface from ~3 to 27% while reducing the carbon-to-oxygen ratio from 35 to 2.75. Specifically, a microplasma treatment increases the number of carbonyl, carboxylic, and hydroxyl functional groups with the largest increase observed for carboxylic functionalities. Furthermore, water microplasma direct writing improves the hydrophilicity and the electrochemical performance of carbon electrodes with a contact-angle change from ~90° to ~20°, a reduction in the anodic peak to cathodic peak separation from 0.5 V to 0.17 V, and a 5-fold increase in specific capacitance from 8.82 mF∙cm−2 to 46.64 mF∙cm−2. The plasma direct-writing technology provides an efficient and easy-to-implement method for the selective surface functionalization of carbon MEMS electrodes for electrochemical and biosensor applications.
MicroRNA mediators of early life stress vulnerability to depression and suicidal behavior
Authors: Allen Lauren , Dwivedi Yogesh
Published: November 2019

Childhood environment can have a profound impact on brain structure and function. Epigenetic mechanisms have been shown to play a critical role in adaptive and maladaptive processes by regulating gene expression without changing the genome. Over the past few years, early life stress (ELS) has been established as a major risk factor for major depression and suicidal behavior along with other psychiatric illnesses in adulthood. In recent years, the emergence of small noncoding RNAs as a mega controller of gene expression has gained attention for their role in various disease processes. Among various noncoding RNAs, microRNAs (miRNAs) are the most studied and well characterized and have emerged as a major regulator of neural plasticity and higher brain functioning. More recently, although limited in number, studies are focusing on how miRNAs can play a role in the maladaptive processes associated with ELS both at adolescent and adult age and whether these processes are critical in developing depression and suicidal behavior. In this review, we critically evaluate how postnatal ELS relates to abnormalities in miRNA expression and functions from both animal and human literature and draw connections from these findings to depression and suicidal behavior later in life.
A regulatory variant of CHRM3 is associated with cannabis-induced hallucinations in European Americans
Authors: Cheng Zhongshan , Phokaew Chureerat , Chou Yi-Ling , Lai Dongbing , Meyers Jacquelyn L. , Agrawal Arpana , Farrer Lindsay A. , Kranzler Henry R. , Gelernter Joel
Published: November 2019

Cannabis, the most widely used illicit drug, can induce hallucinations. Our understanding of the biology of cannabis-induced hallucinations (Ca-HL) is limited. We used the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA) to identify cannabis-induced hallucinations (Ca-HL) among long-term cannabis users (used cannabis ≥1 year and ≥100 times). A genome-wide association study (GWAS) was conducted by analyzing European Americans (EAs) and African Americans (AAs) in Yale-Penn 1 and 2 cohorts individually, then meta-analyzing the two cohorts within population. In the meta-analysis of Yale-Penn EAs (n = 1917), one genome-wide significant (GWS) signal emerged at the CHRM3 locus, represented by rs115455482 (P = 1.66 × 10−10), rs74722579 (P = 2.81 × 10−9), and rs1938228 (P = 1.57 × 10−8); signals were GWS in Yale-Penn 1 EAs (n = 1092) and nominally significant in Yale-Penn 2 EAs (n = 825). Two SNPs, rs115455482 and rs74722579, were available from the Collaborative Study on the Genetics of Alcoholism data (COGA; 3630 long-term cannabis users). The signals did not replicate, but when meta-analyzing Yale-Penn and COGA EAs, the two SNPs’ association signals were increased (meta-P-values 1.32 × 10−10 and 2.60 × 10−9, respectively; n = 4291). There were no significant findings in AAs, but in the AA meta-analysis (n = 3624), nominal significance was seen for rs74722579. The rs115455482*T risk allele was associated with lower CHRM3 expression in the thalamus. CHRM3 was co-expressed with three psychosis risk genes (GABAG2, CHRNA4, and HRH3) in the thalamus and other human brain tissues and mouse GABAergic neurons. This work provides strong evidence for the association of CHRM3 with Ca-HL and provides insight into the potential involvement of thalamus for this trait.
Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics
Authors: Ruso-Julve Fulgencio , Pombero Ana , Pilar-Cuéllar Fuencisla , García-Díaz Nuria , Garcia-Lopez Raquel , Juncal-Ruiz María , Castro Elena , Díaz Álvaro , Vazquez-Bourgón Javier , García-Blanco Agustín , Garro-Martinez Emilio , Pisonero Helena , Estirado Alicia , Ayesa-Arriola Rosa , López-Giménez Juan , Mayor Federico , Valdizán Elsa , Meana Javier , Gonzalez-Maeso Javier , Martínez Salvador , Vaqué José Pedro , Crespo-Facorro Benedicto
Published: November 2019

A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.
Modulation of autophagy by RTN-1C: role in autophagosome biogenesis
Authors: D’ Eletto Manuela , Risuglia Anna , Oliverio Serafina , Mehdawy Bisan , Nardacci Roberta , Bordi Matteo , Di Sano Federica
Published: November 2019

The endoplasmic reticulum (ER) is a key organelle fundamental for the maintenance of cellular homeostasis and to determine the cell’s fate under stress conditions. Among the known proteins that regulate ER structure and function there is Reticulon-1C (RTN-1C), a member of the reticulon family localized primarily on the ER membrane. We previously demonstrated that RTN-1C expression affects ER function and stress condition. ER is an essential site for the regulation of apoptotic pathways and it has also been recently recognized as an important component of autophagic signaling. Based on these evidences, we have investigated the impact of RTN-1C modulation on autophagy induction. Interestingly we found that reticulon overexpression is able to activate autophagic machinery and its silencing results in a significative inhibition of both basal and induced autophagic response. Using different experimental approaches we demonstrated that RTN-1C colocalizes with ATG16L and LC3II on the autophagosomes. Considering the key role of reticulon proteins in the control of ER membrane shaping and homeostasis, our data suggest the participation of RTN-1C in the autophagic vesicle biogenesis at the level of the ER compartment. Our data indicate a new mechanism by which this structural ER protein modulates cellular stress, that is at the basis of different autophagy-related pathologies.
Neurons can upregulate Cav-1 to increase intake of endothelial cells-derived extracellular vesicles that attenuate apoptosis via miR-1290
Authors: Yue Kang-Yi , Zhang Pei-Ran , Zheng Min-Hua , Cao Xiu-Li , Cao Yuan , Zhang Yi-Zhe , Zhang Yu-Fei , Wu Hai-Ning , Lu Zhi-Hong , Liang Liang , Jiang Xiao-Fan , Han Hua
Published: November 2019

Extracellular vesicles (EVs) including exosomes can serve as mediators of cell–cell communication under physiological and pathological conditions. However, cargo molecules carried by EVs to exert their functions, as well as mechanisms for their regulated release and intake, have been poorly understood. In this study, we examined the effects of endothelial cells-derived EVs on neurons suffering from oxygen-glucose deprivation (OGD), which mimics neuronal ischemia-reperfusion injury in human diseases. In a human umbilical endothelial cell (HUVEC)–neuron coculture assay, we found that HUVECs reduced apoptosis of neurons under OGD, and this effect was compromised by GW4869, a blocker of exosome release. Purified EVs could be internalized by neurons and alleviate neuronal apoptosis under OGD. A miRNA, miR-1290, was highly enriched in HUVECs-derived EVs and was responsible for EV-mediated neuronal protection under OGD. Interestingly, we found that OGD enhanced intake of EVs by neurons cultured in vitro. We examined the expression of several potential receptors for EV intake and found that caveolin-1 (Cav-1) was upregulated in OGD-treated neurons and mice suffering from middle cerebral artery occlusion (MCAO). Knock-down of Cav-1 in neurons reduced EV intake, and canceled EV-mediated neuronal protection under OGD. HUVEC-derived EVs alleviated MCAO-induced neuronal apoptosis in vivo. These findings suggested that ischemia likely upregulates Cav-1 expression in neurons to increase EV intake, which protects neurons by attenuating apoptosis via miR-1290.
Browning of white adipose tissue after a burn injury promotes hepatic steatosis and dysfunction
Authors: Abdullahi Abdikarim , Samadi Osai , Auger Christopher , Kanagalingam Tharsan , Boehning Darren , Bi Sheng , Jeschke Marc G.
Published: November 2019

Burn patients experiencing hypermetabolism develop hepatic steatosis, which is associated with liver failure and poor outcomes after the injury. These same patients also undergo white adipose tissue (WAT) browning, which has been implicated in mediating post-burn cachexia and sustained hypermetabolism. Despite the clinical presentation of hepatic steatosis and WAT browning in burns, whether or not these two pathological responses are linked remains poorly understood. Here, we show that the burn-induced WAT browning and its associated increased lipolysis leads to the accelerated development of hepatic steatosis in mice. Deletion of interleukin 6 (IL-6) and the uncoupling protein 1 (UCP1), regulators of burn-induced WAT browning completely protected mice from hepatic steatosis after the injury. Treatment of post-burn mice with propranolol or IL-6 receptor blocker attenuated burn-induced WAT browning and its associated hepatic steatosis pathology. Lipidomic profiling in the plasma of post-burn mice and burn patients revealed elevated levels of damage-inducing lipids (palmitic and stearic acids), which induced hepatic endoplasmic reticulum (ER) stress and compromised hepatic fat oxidation. Mechanistically, we show that hepatic ER stress after a burn injury leads to a greater ER-mitochondria interaction, hepatocyte apoptosis, oxidative stress, and impaired fat oxidation. Collectively, our findings uncover an adverse “cross-talk” between the adipose and liver tissue in the context of burn injury, which is critically mediated by WAT browning.
Hyperactivity of Mek in TNS1 knockouts leads to potential treatments for cystic kidney diseases
Authors: Wu Zong-Ye , Chiu Chun-Lung , Lo Ethan , Lee Yuh-Ru Julie , Yamada Soichiro , Lo Su Hao
Published: November 2019

Cystic kidney disease is the progressive development of multiple fluid-filled cysts that may severely compromise kidney functions and lead to renal failure. TNS1 (tensin-1) knockout mice develop cystic kidneys and die from renal failure. Here, we have established TNS1-knockout MDCK cells and applied 3D culture system to investigate the mechanism leading to cyst formation. Unlike wild-type MDCK cells, which form cysts with a single lumen, TNS1-knockout cysts contain multiple lumens and upregulated Mek/Erk activities. The multiple lumen phenotype and Mek/Erk hyperactivities are rescued by re-expression of wild-type TNS1 but not the TNS1 mutant lacking a fragment essential for its cell–cell junction localization. Furthermore, Mek inhibitor treatments restore the multiple lumens back to single lumen cysts. Mek/Erk hyperactivities are also detected in TNS1-knockout mouse kidneys. Treatment with the Mek inhibitor trametinib significantly reduces the levels of interstitial infiltrates, fibrosis and dilated tubules in TNS1-knockout kidneys. These studies establish a critical role of subcellular localization of TNS1 in suppressing Mek/Erk signaling and maintaining lumenogenesis, and provide potential therapeutic strategies by targeting the Mek/Erk pathway for cystic kidney diseases.
Quorum sensing modulates the formation of virulent Legionella persisters within infected cells
Authors: Personnic Nicolas , Striednig Bianca , Lezan Emmanuelle , Manske Christian , Welin Amanda , Schmidt Alexander , Hilbi Hubert
Published: November 2019

The facultative intracellular bacterium Legionella pneumophila replicates in environmental amoebae and in lung macrophages, and causes Legionnaires’ disease. Here we show that L. pneumophila reversibly forms replicating and nonreplicating subpopulations of similar size within amoebae. The nonreplicating bacteria are viable and metabolically active, display increased antibiotic tolerance and a distinct proteome, and show high virulence as well as the capacity to form a degradation-resistant compartment. Upon infection of naïve or interferon-γ-activated macrophages, the nonreplicating subpopulation comprises ca. 10% or 50%, respectively, of the total intracellular bacteria; hence, the nonreplicating subpopulation is of similar size in amoebae and activated macrophages. The numbers of nonreplicating bacteria within amoebae are reduced in the absence of the autoinducer synthase LqsA or other components of the Lqs quorum-sensing system. Our results indicate that virulent, antibiotic-tolerant subpopulations of L. pneumophila are formed during infection of evolutionarily distant phagocytes, in a process controlled by the Lqs system.
Effect of microgravity on the solidification of aluminum–bismuth–tin immiscible alloys
Authors: Jiang Hongxiang , Li Shixin , Zhang Lili , He Jie , Zhao Jiuzhou
Published: November 2019

Directional solidification experiment was carried out with Al-Bi-Sn immiscible alloy under microgravity environment onboard the Tiangong 2 space laboratory of China. Sample with a well-dispersed microstructure was obtained by properly designing the experimental scheme, the matrix shows equiaxed morphology, and there is no visible gas cavity or pinhole in the sample. In contrast, the reference samples solidified on earth show phase-segregated structure and contain some gas cavities or pinholes. The grain morphology of the terrestrial sample depends on the solidification direction, it is equiaxed when the sample ampoule was withdrawn against the gravity direction, while it is columnar when the sample ampoule was withdrawn along the gravity direction. The solidification process and affecting mechanisms of microgravity on the microstructure formation are discussed. The results indicate that the microgravity conditions can effectively diminish the convective flow of the melt and the Stokes motions of the minority phase droplets and gas bubbles, which are helpful for suppressing the occurrence of macro-segregation and preventing the formation of porosity. The results also demonstrate that the microgravity conditions favor the detachment between the melt and the wall of crucible, thus increasing the nucleation undercooling of α-Al nuclei and promoting the formation of equiaxed grain.
Gut bacteria of Cuora amboinensis (turtle) produce broad-spectrum antibacterial molecules
Authors: Akbar Noor , Khan Naveed Ahmed , Sagathevan K. , Iqbal Mazhar , Tawab Abdul , Siddiqui Ruqaiyyah
Published: November 2019

Antimicrobial resistance is a major threat to human health, hence there is an urgent need to discover antibacterial molecule(s). Previously, we hypothesized that microbial gut flora of animals are a potential source of antibacterial molecules. Among various animals, Cuora amboinensis (turtle) represents an important reptile species living in diverse ecological environments and feed on organic waste and terrestrial organisms and have been used in folk medicine. The purpose of this study was to mine turtle’s gut bacteria for potential antibacterial molecule(s). Several bacteria were isolated from the turtle gut and their conditioned media were prepared. Conditioned media showed potent antibacterial activity against several Gram-positive (Bacillus cereus, Streptococcus pyogenes and methicillin-resistant Staphylococcus aureus) and Gram-negative (neuropathogenic Escherichia coli K1, Serratia marcescens, Pseudomonas aeruginosa, Salmonella enterica and Klebsiella pneumoniae) pathogenic bacteria. Conditioned media-mediated bactericidal activity was heat-resistant when treated at 95°C for 10 min. By measuring Lactate dehydrogenase release, the results showed that conditioned media had no effect on human cell viability. Tandem Mass Spectrometric analysis revealed the presence of various secondary metabolites, i.e., a series of known as well as novel N-acyl-homoserine lactones, several homologues of 4-hydroxy-2-alkylquinolines, and rhamnolipids, which are the signature metabolites of Pseudomonas species. These findings are significant and provide the basis for rational development of therapeutic interventions against bacterial infections.
Time-Course Changes in Urine Metabolic Profiles of Rats Following 90-Day Exposure to Propoxur
Authors: Liang Yu-Jie , Wang Pan , Wang Hui-Ping , Long Ding-Xin , Sun Ying-Jian , Wu Yi-Jun
Published: November 2019

As a major kind of carbamate insecticide, propoxur plays an important role in agriculture, veterinary medicine, and public health. The acute toxicity of propoxur is mainly neurotoxicity due to the inhibition of cholinesterase. However, little is known regarding the toxicity of propoxur upon long-term exposure at low dose. In this study, Wistar rats were orally administrated with low dose (4.25 mg/kg body weight/day) for consecutive 90 days. And the urine samples in rats treated with propoxur for 30, 60, and 90 days were collected and analyzed by employing 1H NMR-based metabolomics approach. We found that propoxur caused significant changes in the urine metabolites, including taurine, creatinine, citrate, succinate, dimethylamine, and trimethylamine-N-oxide. And the alteration of the metabolites was getting more difference compared with that of the control as the exposure time extending. The present study not only indicated that the changed metabolites could be used as biomarkers of propoxur-induced toxicity but also suggested that the time-course alteration of the urine metabolomic profiles could reflect the progressive development of the toxicity following propoxur exposure.
Pauli-limit upper critical field of high-temperature superconductor La1.84Sr0.16CuO4
Authors: Nakamura Daisuke , Adachi Tadashi , Omori Keisuke , Koike Yoji , Takeyama Shojiro
Published: November 2019

The upper critical field of a cuprate high-temperature superconductor, La1.84Sr0.16CuO4, was investigated by high-frequency self-resonant contactless electrical conductivity measurements in magnetic fields up to 102 T. An irreversible transition was observed at 85 T (T = 4.2 K), defined as the upper critical field. The temperature-dependent upper critical field was argued on the basis of the Werthamer-Helfand-Hohenberg theory. The Pauli-limiting pair-breaking process with a small contribution of the spin-orbit coupling explained the first-order phase transition exhibiting a hysteresis observed at low temperatures.
An efficient protein production system via gene amplification on a human artificial chromosome and the chromosome transfer to CHO cells
Authors: Ohira Takahito , Miyauchi Koichi , Uno Narumi , Shimizu Noriaki , Kazuki Yasuhiro , Oshimura Mitsuo , Kugoh Hiroyuki
Published: November 2019

Gene amplification methods play a crucial role in establishment of cells that produce high levels of recombinant protein. However, the stability of such cell lines and the level of recombinant protein produced continue to be suboptimal. Here, we used a combination of a human artificial chromosome (HAC) vector and initiation region (IR)/matrix attachment region (MAR) gene amplification method to establish stable cells that produce high levels of recombinant protein. Amplification of Enhanced green fluorescent protein (EGFP) was induced on a HAC carrying EGFP gene and IR/MAR sequences (EGFP MAR-HAC) in CHO DG44 cells. The expression level of EGFP increased approximately 6-fold compared to the original HAC without IR/MAR sequences. Additionally, anti-vascular endothelial growth factor (VEGF) antibody on a HAC (VEGF MAR-HAC) was also amplified by utilization of this IR/MAR-HAC system, and anti-VEGF antibody levels were approximately 2-fold higher compared with levels in control cells without IR/MAR. Furthermore, the expression of anti-VEGF antibody with VEGF MAR-HAC in CHO-K1 cells increased 2.3-fold compared with that of CHO DG44 cells. Taken together, the IR/MAR-HAC system facilitated amplification of a gene of interest on the HAC vector, and could be used to establish a novel cell line that stably produced protein from mammalian cells.
Plasticity of fruit and oil traits in olive among different environments
Authors: Mousavi Soraya , de la Rosa Raul , Moukhli Abdelmajid , El Riachy Milad , Mariotti Roberto , Torres Mariela , Pierantozzi Pierluigi , Stanzione Vitale , Mastio Valerio , Zaher Hayat , El Antari Abderraouf , Ayoub Salam , Dandachi Faten , Youssef Hiyam , Aggelou Nikolas , Contreras Cibeles , Maestri Damián , Belaj Angjelina , Bufacchi Marina , Baldoni Luciana , Leon Lorenzo
Published: November 2019

Olive is a long-living perennial species with a wide geographical distribution, showing a large genetic and phenotypic variation in its growing area. There is an urgent need to uncover how olive phenotypic traits and plasticity can change regardless of the genetic background. A two-year study was conducted, based on the analysis of fruit and oil traits of 113 cultivars from five germplasm collections established in Mediterranean Basin countries and Argentina. Fruit and oil traits plasticity, broad‐sense heritability and genotype by environment interaction were estimated. From variance and heritability analyses, it was shown that fruit fresh weight was mainly under genetic control, whereas oleic/(palmitic + linoleic) acids ratio was regulated by the environment and genotype by environment interaction had the major effect on oil content. Among the studied cultivars, different level of stability was observed, which allowed ranking the cultivars based on their plasticity for oil traits. High thermal amplitude, the difference of low and high year values of temperature, negatively affected the oil content and the oleic acid percentage. Information derived from this work will help to direct the selection of cultivars with the highest global fitness averaged over the environments rather than the highest fitness in each environment separately.
Insight into the dimer dissociation process of the Chromobacterium violaceum (S)-selective amine transaminase
Authors: Ruggieri Federica , Campillo-Brocal Jonatan C. , Chen Shan , Humble Maria S. , Walse Björn , Logan Derek T. , Berglund Per
Published: November 2019

One of the main factors hampering the implementation in industry of transaminase-based processes for the synthesis of enantiopure amines is their often low storage and operational stability. Our still limited understanding of the inactivation processes undermining the stability of wild-type transaminases represents an obstacle to improving their stability through enzyme engineering. In this paper we present a model describing the inactivation process of the well-characterized (S)-selective amine transaminase from Chromobacterium violaceum. The cornerstone of the model, supported by structural, computational, mutagenesis and biophysical data, is the central role of the catalytic lysine as a conformational switch. Upon breakage of the lysine-PLP Schiff base, the strain associated with the catalytically active lysine conformation is dissipated in a slow relaxation process capable of triggering the known structural rearrangements occurring in the holo-to-apo transition and ultimately promoting dimer dissociation. Due to the occurrence in the literature of similar PLP-dependent inactivation models valid for other non-transaminase enzymes belonging to the same fold-class, the role of the catalytic lysine as conformational switch might extend beyond the transaminase enzyme group and offer new insight to drive future non-trivial engineering strategies.
Metabolic Effects of Fasting and Animal Source Food Avoidance in an Ethiopian Adult Cohort
Authors: Sinaga Makeda , Teshome Melese Sinaga , Kidane Radiet , Yemane Tilahun , Tegene Elsah , Lindstrom David , Belachew Tefera
Published: November 2019

Fasting is a religious practice to which the faithful comply strictly. The longest period of fasting in Orthodox religion is the lent (in Ethiopia known as “Hudade”). According to the doctrine of Ethiopian Orthodox Christianity, fasters should strictly avoid all animal source foods (ASF) and skip breakfast at least up to lunch time. This can be taken as a well-controlled natural experiment to evaluate the effect of breakfast skipping and avoidance of ASF for 55 days. However, there is no study that evaluated the effect of ASF fasting (avoidance of animal source foods  and breakfast skipping) on lipid profiles, fasting blood sugar and body composition in Ethiopian set up. A retrospective cohort study was carried out among 704 employees of Jimma University (253 fasters and 451 non-fasters) from February 2015 to April 2015. Data on socio-demographic, anthropometry, blood pressure and blood samples were collected according to WHO STEPS procedure. Descriptive statistics and multivariable linear regression models were used to compare the effect of fasting on outcome variables. There was a significant difference in the body fat percent (mean ± sd) between non-fasters (32.35 ± 11.12) and fasters (30.59 ± 11.22, P = 0.045). Similarly, the mean ± sd waist circumference was higher among non-fasters (84.96 ± 11.43 cm) compared to fasters (83.04 ± 11.43 cm, P < 0.033). High density lipoprotein was significantly (P = 0.001) high among fasters (68.29 mg/dl) compared to non-fasters (57.24 mg/dl). Total cholesterol (T.chol) was also higher among non- fasters (181.01 mg/dl) than fasters (173.80 mg/dl, P = 0.035). The mean Triglyceride level was significantly (P = 0.035) high among non-fasters (142.76 mg/dl) compared to fasters (129.39 mg/dl). Similarly, fasting blood sugar was high among non-fasters (100.14 mg/dl) compared to fasters (95.11 mg/dl), P = 0.009. On multivariable linear regression analyses after adjusting for different variables, fasters had a significantly high mean HDL and lower mean T.chol, Triglycerides, FBS and LDL levels. Similarly, fasters had a significantly low mean waist circumference and low mean body fat percent (P < 0.05). In conclusion, animal source food avoidanceand breakfast skipping has a significant desirable health effects on lipid profiles, fasting blood sugar and body composition. The findings imply the need for considering such a dietary practice as a basis for public health promotion. Future research should investigate the effect of ASF fasting and breakfast skipping on micronutrient intake and determine the minimum number of days of fasting required to generate clinically significant effects.
Quality evaluation based on color grading: quality discrimination of the Chinese medicine Corni Fructus by an E-eye
Authors: YongXia Cui , RuiXin Liu , ZhaoZhou Lin , PengJu Chen , LiLi Wang , YanLi Wang , SuiQing Chen
Published: November 2019

‘Quality evaluation based on color grading’ is one of the features used in Chinese medicine discrimination. In order to assess the feasibility of electronic eye (E-eye) in implementing ‘quality evaluation based on color grading’, the present study applied an IRIS VA400 E-eye to test 58 batches of Corni Fructus samples. Their optical data were acquired and combined with their corresponding classes. A total of four quality discrimination models were produced according to discrimination analysis (DA), least squares support vector machine (LS-SVM), partial least squares-discrimination analysis (PLS-DA), and principal component analysis-discrimination analysis (PCA-DA). The accuracy rate of the aforementioned 4 cross evaluation models were 86.21%, 89.66%, 81.03% and 91.38%, respectively. Therefore, the PCA-DA method was used to build the final discrimination model for classifying Corni Fructus or discriminating its quality.
In vivo Labeling of Bone Microdamage in an Animal Model of Type 1 Diabetes Mellitus
Authors: Mohsin Sahar , Kaimala Suneesh , AlTamimi Eman Khamis Yousef , Tariq Saeed , Adeghate Ernest
Published: November 2019

Type 1 diabetes mellitus (DM1) is linked to a decrease in bone strength. Bone strength entails both bone mineral density and bone quality. Limited data are available regarding diabetes-induced microdamage, which can severely influence bone quality. This study has investigated bone microdamage as a measure of bone quality in an animal model of DM1. Microdamage in the neck of the femur was labelled in vivo using multiple fluorochromes at 4, 12 and 24 weeks after the onset of DM1. Microcracks were quantified and their morphology analyzed using microscopy techniques. The mean length of microcracks at 24 weeks, and crack numerical and surface densities were significantly higher (p < 0.05) 4 weeks after the onset of DM1 when compared with control. Diffuse damage density was highest at 12 weeks after the onset of DM1. The arrangement of the collagen fibrils became progressively more irregular from 4 to 24 weeks of DM. This is the first study to analyze microdamage in vivo at different time points of DM1. DM1is associated with microcracks from the early stage, however bone microstructure shows toughening mechanisms that arrest their growth but disease progression further deteriorates bone quality resulting in longer microcracks which may increase fracture risk.
Integration of TGF-β-induced Smad signaling in the insulin-induced transcriptional response in endothelial cells
Authors: Budi Erine H. , Hoffman Steven , Gao Shaojian , Zhang Ying E. , Derynck Rik
Published: November 2019

Insulin signaling governs many processes including glucose homeostasis and metabolism, and is therapeutically used to treat hyperglycemia in diabetes. We demonstrated that insulin-induced Akt activation enhances the sensitivity to TGF-β by directing an increase in cell surface TGF-β receptors from a pool of intracellular TGF-β receptors. Consequently, increased autocrine TGF-β signaling in response to insulin participates in insulin-induced angiogenic responses of endothelial cells. With TGF-β signaling controlling many cell responses, including differentiation and extracellular matrix deposition, and pathologically promoting fibrosis and cancer cell dissemination, we addressed to which extent autocrine TGF-β signaling participates in insulin-induced gene responses of human endothelial cells. Transcriptome analyses of the insulin response, in the absence or presence of a TGF-β receptor kinase inhibitor, revealed substantial positive and negative contributions of autocrine TGF-β signaling in insulin-responsive gene responses. Furthermore, insulin-induced responses of many genes depended on or resulted from autocrine TGF-β signaling. Our analyses also highlight extensive contributions of autocrine TGF-β signaling to basal gene expression in the absence of insulin, and identified many novel TGF-β-responsive genes. This data resource may aid in the appreciation of the roles of autocrine TGF-β signaling in normal physiological responses to insulin, and implications of therapeutic insulin usage.
Mucin CYS domain stiffens the mucus gel hindering bacteria and spermatozoa
Authors: Demouveaux Bastien , Gouyer Valérie , Robbe-Masselot Catherine , Gottrand Frédéric , Narita Tetsuharu , Desseyn Jean-Luc
Published: November 2019

Mucus is the first biological barrier encountered by particles and pathogenic bacteria at the surface of secretory epithelia. The viscoelasticity of mucus is governed in part by low energy interactions that are difficult to assess. The CYS domain is a good candidate to support low energy interactions between GFMs and/or mucus constituents. Our aim was to stiffen the mucus from HT29-MTX cell cocultures and the colon of mice through the delivery of a recombinant protein made of hydrophobic CYS domains and found in multiple copies in polymeric mucins. The ability of the delivery of a poly-CYS molecule to stiffen mucus gels was assessed by probing cellular motility and particle diffusion. We demonstrated that poly-CYS enrichment decreases mucus permeability and hinders displacement of pathogenic flagellated bacteria and spermatozoa. Particle tracking microrheology showed a decrease of mucus diffusivity. The empirical obstruction scaling model evidenced a decrease of mesh size for mouse mucus enriched with poly-CYS molecules. Our data bring evidence that enrichment with a protein made of CYS domains stiffens the mucin network to provide a more impermeable and protective mucus barrier than mucus without such enrichment.
The Prognostic Significance of PDE7B in Cytogenetically Normal Acute Myeloid Leukemia
Authors: Cao Ling , Zhang Weilong , Liu Xiaoni , Yang Ping , Wang Jing , Hu Kai , Zhang Xiuru , Liu Weiyou , He Xue , Jing Hongmei , Yuan Xiaoliang
Published: November 2019

Acute myeloid leukemia (AML) is a malignant hematological disease in which nearly half have normal cytogenetics. We have tried to find some significant molecular markers for this part of the cytogenetic normal AML, which hopes to provide a benefit for the diagnosis, molecular typing and prognosis prediction of AML patients. In the present study, we calculated and compared the gene expression profiles of cytogenetically normal acute myeloid leukemia (CN-AML) patients in database of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and dataset Vizome (a total of 632 CN-AML samples), and we have demonstrated a correlation between PDE7B gene and CN-AML. Then we proceeded to a survival analysis and prognostic risk analysis between the expression levels of PDE7B gene and CN-AML patients. The result showed that the event-free survival (EFS) and overall survival (OS) were significantly shorter in CN-AML patients with high PDE7B levels in each dataset. And we detected a significantly higher expression level of PDE7B in the leukemia stem cell (LSC) positive group. The Cox proportional hazards regression model showed that PDE7B is an independent risk predictor for CN-AML. All results indicate that PDE7B is an unfavorable prognostic factor for CN-AML.
Neutrophil-lymphocyte ratio in metastatic breast cancer is not an independent predictor of survival, but depends on other variables
Authors: Ivars Rubio Alejandra , Yufera Juan Carlos , de la Morena Pilar , Fernández Sánchez Ana , Navarro Manzano Esther , García Garre Elisa , García Martinez Elena , Marín Zafra Gema , Sánchez Cánovas Manuel , García Torralba Esmeralda , Ayala de la Peña Francisco
Published: November 2019

The prognostic impact of neutrophil-lymphocyte ratio (NLR) in metastatic breast cancer (MBC) has been previously evaluated in early and metastatic mixed breast cancer cohorts or without considering other relevant prognostic factors. Our aim was to determine whether NLR prognostic and predictive value in MBC was dependent on other clinical variables. We studied a consecutive retrospective cohort of patients with MBC from a single centre, with any type of first line systemic treatment. The association of NLR at diagnosis of metastasis with progression free survival (PFS) and overall survival (OS) was evaluated using Cox univariate and multivariate proportional hazard models. In the full cohort, that included 263 MBC patients, a higher than the median (>2.32) NLR was significantly associated with OS in the univariate analysis (HR 1.36, 95% CI 1.00–1.83), but the association was non-significant (HR 1.12, 95% CI 0.80–1.56) when other clinical covariates (performance status, stage at diagnosis, CNS involvement, visceral disease and visceral crisis) were included in the multivariate analysis. No significant association was observed for PFS. In conclusion, MBC patients with higher baseline NLR had worse overall survival, but the prognostic impact of NLR is likely derived from its association with other relevant clinical prognostic factors.