bluuebunny/crossref_metadata_2025 huggingface dataset:
Likelihood of Infectious Outcomes Following Infectious Risk Moments During Patient Care—An International Expert Consensus Study and Quantitative Risk Index
Authors: Clack Lauren , Passerini Simone , Manser Tanja , Sax Hugo
Published: March 2018

OBJECTIVE

To elicit expert consensus on the likelihood of infectious outcomes (patient colonization or infection) following a broad range of infectious risk moments (IRMs) from observations in acute care.

DESIGN

Expert consensus study using modified Delphi technique.

PARTICIPANTS

Panel of 40 international experts including nurses, physicians and microbiologists specialized in infectious diseases and infection prevention and control (IPC).

METHODS

The modified Delphi process consisted of 3 online survey rounds, with feedback of mean ratings and expert comments between rounds. The Delphi survey comprised 52 care scenarios representing observed IRMs organized into 6 sections: hands, gloves, medical devices, mobile objects, invasive procedures, and additional moments. For each scenario, experts indicated the likelihood of both patient colonization and infection on a scale from 0 to 5 (high). Expert ratings were plotted against frequencies of IRMs observed during actual patient care resulting in a risk index.

RESULTS

Following 3 rounds, consensus was achieved for 92 of 104 items (88.5%). The mean ratings across all scenarios for likelihood of colonization and infection were 2.68 and 2.02, respectively. The likelihood of colonization was rated higher than infection for 48 of 52 scenarios. Ratings were significantly higher for colonization (P=.001) and infection (P<.0005) when the scenario involved transfer of pathogens to critical patient sites.

CONCLUSIONS

The design of effective IPC strategies requires the selection of behaviors according to their impact on patient outcomes. The IRM index reported here provides a basis for standardizing and prioritizing targets for quality improvement initiatives, training, and future research in acute health care.

Infect Control Hosp Epidemiol 2018;39:280–289
Environmental enteric dysfunction and systemic inflammation predict reduced weight but not length gain in rural Bangladeshi children
Authors: Campbell Rebecca K. , Schulze Kerry J. , Shaikh Saijuddin , Raqib Rubhana , Wu Lee S. F. , Ali Hasmot , Mehra Sucheta , West Keith P. , Christian Parul
Published: March 2018

Environmental enteric dysfunction (EED) and systemic inflammation (SI) are common in developing countries and may cause stunting. In Bangladesh, >40 % of preschool children are stunted, but EED and SI contributions are unknown. We aimed to determine the impact of EED and SI (assessed with multiple indicators) on growth in children (n 539) enrolled in a community-based randomised food supplementation trial in rural Bangladesh. EED was defined with faecal myeloperoxidase, α-1 antitrypsin and neopterin and serum endotoxin core antibody and glucagon-like peptide-2, consolidated into gut inflammation (GI) and permeability (GP) scores, and urinary lactulose:mannitol α-1 acid glycoprotein (AGP) characterised SI. Biomarker associations with anthropometry (15-, 18- and 24-month length-for-age (LAZ), weight-for-length (WLZ) and weight-for-age (WAZ) z scores) were examined in pairwise correlations and adjusted mixed-effects regressions. Stunting, wasting and underweight prevalence at 18 months were 45, 15 and 37 %, respectively, with elevated EED and SI markers common. EED and SI were not associated with 15–24-month length trajectory. Elevated (worse) GI and GP scores predicted reduced 18–24-month WLZ change (β −0·01 (se 0·00) z score/month for both). Elevated GP was also associated with reduced 15–18-month WLZ change (β −0·03 (se 0·01) z score/month) and greater 15-month WLZ (β 0·16 (se 0·05)). Higher AGP was associated with reduced prior and increased subsequent WLZ change (β −0·04 (se 0·01) and β 0·02 (se 0·00) z score/month for 15–18 and 18–24 months). The hypothesised link from EED to stunting was not observed in this sample of Bangladeshi 18-month-olds, but the effects of EED on constrained weight gain may have consequences for later linear growth or for other health and development outcomes.
Mother–child dietary behaviours and their observed associations with socio-demographic factors: findings from the Healthy Beginnings Trial
Authors: Kunaratnam Kanita , Halaki Mark , Wen Li Ming , Baur Louise A. , Flood Victoria M.
Published: March 2018

Few studies have investigated the effect of maternal factors on child eating practices. Our study aimed to explore mother–child dietary behaviours and their associations with socio-demographic factors. A cross-sectional analysis was conducted using data from control participants (n243) in the Healthy Beginnings Trial, which involved first-time mothers and their 2-year-old children. Mother–child dietary behaviours were assessed using short dietary questions (short FFQ) and their associations with socio-demographic factors were examined using binary logistic regression. The dietary intake of 2-year-old children was characterised by low vegetable consumption and high discretionary food intake. In multivariate analysis, lower-income mothers (<Australian $40 000 per annum) reported their child was more likely to consume less fruit (<1 serve/d) (adjusted OR (AOR): 5·83; 95 % CI 1·49, 22·80) and ate hot chips more frequently (≥2 times/week) (AOR: 4·80; 95 % CI 1·28, 18·04), compared with higher-income mothers (≥Australian $40 000 per annum). Younger mothers (<25 years) reported their child consumed more sugary drinks and soft drink (>0·5 cups/d) AOR 2·93 (95 % CI 1·03, 8·35), compared with older mothers (≥25 years). Non-Australian-born mothers reported their child consumed more fruit juice (>0·5 cups/d) AOR 2·04 (95 % CI 1·02, 4·05), sweet snacks AOR 1·96 (95 % CI 1·02, 3·76) and fast food (≥2 times/week) AOR 3·67 (95 % CI 1·29, 10·43) compared with Australian-born mothers. Significant positive correlations between maternal and child dietary intake were observed for all dietary variables except milk, with the largest association for fast foods (Pearson’sr0·52,P<0·001). This study shows that maternal factors are associated with child dietary behaviours. Targeting young mothers (<25 years) of potential disadvantage, before commencement of early feeding practices, has the potential to improve children’s diets.
Effect of increased calcium consumption from fat-free milk in an energy-restricted diet on the metabolic syndrome and cardiometabolic outcomes in adults with type 2 diabetes mellitus: a randomised cross-over clinical trial
Authors: Gomes Junia M. G. , Costa Jorge d. A. , Alfenas Rita C. G.
Published: March 2018

We investigated the effects of high-Ca fat-free milk phase (MD) (prescription of approximately 1500 mg of Ca/d) v. low-Ca phase (CD) (prescription of approximately 800 mg of Ca/d) in an energy-restricted diet on the metabolic syndrome (MetS) and cardiometabolic measures in individuals with type 2 diabetes mellitus (T2DM) and low habitual Ca consumption (<600 mg/d). In this randomised cross-over design, fourteen adults with T2DM (49·5 (sd 8·6) years, BMI 29·4 (sd 4·5) kg/m2) consumed either MD or CD for 12 weeks, with a washout of 18 weeks between phases. A breakfast shake containing 700 mg (MD) or 6·4 mg (CD) of Ca was consumed in the laboratory. In addition, energy-restricted diets were prescribed (800 mg of dietary Ca/d). Waist circumference (WC), fasting glucose, fasting TAG, systolic (SBP) and diastolic blood pressure (DBP), fasting total cholesterol, fasting LDL-cholesterol, fasting HDL-cholesterol, HDL:LDL ratio, HDL:TAG ratio and lipid accumulation product (LAP) index were assessed at baseline and after each phase. Ca consumption during the study was equivalent to 1200 mg/d during MD and 525 mg/d during CD. There was a greater reduction in WC, SBP, DBP and LAP index after MD compared with CD. HDL:LDL ratio increased and total cholesterol, LDL-cholesterol, SBP, DBP and LAP index decreased only in MD. The consumption of approximately 1200 mg of Ca/d (700 mg from fat-free milk+500mg from other dietary sources) associated with an energy-restricted diet decreased some of the MetS components and cardiometabolic measures in adults with T2DM.
Diyanet as a Turkish Foreign Policy Tool: Evidence from the Netherlands and Bulgaria
Authors: Öztürk Ahmet Erdi , Sözeri Semiha
Published: March 2018

How does Turkey's Presidency of Religious Affairs (Diyanet) act as an instrument of foreign policy (FP)? What are the factors that allow such an instrumentalization of Islam in Turkish FP? In addressing these questions, this paper uses semi-structured expert interviews from Bulgaria and the Netherlands. Although both countries host a sizeable Muslim minority, these populations differ in their characteristics and historical ties with Turkey. ComparingDiyanet’s role in the Netherlands with its recent Turkish-Muslim diaspora, and in Bulgaria with its centuries-old Muslim minority allows us to reveal variation in the practical engagement strategies that Diyanet adopts in different country contexts. Thus, this paper advances two main claims; first,Diyanetserves as a primary FP tool of Turkey in countries with a significant Turkish-Muslim minority. Secondly, this instrumentalization destabilizes secularization projects both at home and abroad.
Simultaneous induction and blockade of autophagy by a single agent
Authors: Kucharewicz Karolina , Dudkowska Magdalena , Zawadzka Anna , Ogrodnik Mikolaj , Szczepankiewicz Andrzej A. , Czarnocki Zbigniew , Sikora Ewa
Published: March 2018

Besides cell death, autophagy and cell senescence are the main outcomes of anticancer treatment. We demonstrate that tacrine-melatonin heterodimer C10, a potent anti-Alzheimer’s disease drug, has an antiproliferative effect on MCF-7 breast cancer cells. The main cell response to a 24 h-treatment with C10 was autophagy enhancement accompanied by inhibition of mTOR and AKT pathways. Significantly increased autophagy markers, such as LC3B- and ATG16L-positive vesicles, confirmed autophagy induction by C10. However, analysis of autophagic flux using mCherry-GFP-LC3B construct revealed inhibition of autophagy by C10 at the late-stage. Moreover, electron microscopy and analysis of colocalization of LC3B and LAMP-1 proteins provided evidence of autophagosome-lysosome fusion with concomitant inhibition of autolysosomal degradation function. After transient treatment with IC50 dose of C10 followed by cell culture without the drug, 20% of MCF-7 cells displayed markers of senescence. On the other hand, permanent cell treatment with C10 resulted in massive cell death on the 5th or 6th day. Recently, an approach whereby autophagy is induced by one compound and simultaneously blocked by the use of another one has been proposed as a novel anticancer strategy. We demonstrate that the same effect may be achieved using a single agent, C10. Our findings offer a new, promising strategy for anticancer treatment.
The role of osteopontin in the progression of solid organ tumour
Authors: Zhao Hailin , Chen Qian , Alam Azeem , Cui Jiang , Suen Ka Chun , Soo Aurelie Pac , Eguchi Shiori , Gu Jianteng , Ma Daqing
Published: March 2018

Osteopontin (OPN) is a bone sialoprotein involved in osteoclast attachment to mineralised bone matrix, as well as being a bone matrix protein, OPN is also a versatile protein that acts on various receptors which are associated with different signalling pathways implicated in cancer. OPN mediates various biological events involving the immune system and the vascular system; the protein plays a role in processes such as immune response, cell adhesion and migration, and tumorigenesis. This review discusses the potential role of OPN in tumour cell proliferation, angiogenesis and metastasis, as well as the molecular mechanisms involved in these processes in different cancers, including brain, lung, kidney, liver, bladder, breast, oesophageal, gastric, colon, pancreatic, prostate and ovarian cancers. The understanding of OPN’s role in tumour development and progression could potentially influence cancer therapy and contribute to the development of novel anti-tumour treatments.
2-Aminoethoxydiphenylborane sensitizes anti-tumor effect of bortezomib via suppression of calcium-mediated autophagy
Authors: Qu Yuan Qing , Gordillo-Martinez Flora , Law Betty Yuen Kwan , Han Yu , Wu Anguo , Zeng Wu , Lam Wai Kei , Ho Charles , Mok Simon Wing Fai , He Hu Qiang , Wong Vincent Kam Wai , Wang Renxiao
Published: March 2018

Non-small-cell lung cancer (NSCLC) accounts for most lung cancer cases. Therapeutic interventions integrating the use of different agents that focus on different targets are needed to overcome this set of diseases. The proteasome system has been demonstrated clinically as a potent therapeutic target for haematological cancers. However, promising preclinical data in solid tumors are yet to be confirmed in clinics. Herein, the combinational use of Bortezomib (BZM) and 2-aminoethoxydiphenylborane (2-APB) toward NSCLC cells was studied. We confirmed that BZM-triggered cytoprotective autophagy that may counteract with the cytotoxic effects of the drug per se. 2-APB was selected from screening of a commercial natural compounds library, which potentiated BZM-induced cytotoxicity. Such an enhancement effect was associated with 2-APB-mediated autophagy inhibition. In addition, we revealed that 2-APB suppressed calcium-induced autophagy in H1975 and A549 NSCLC cells. Interestingly, BZM [0.3 mg/kg/3 days] combined with 2-APB [2 mg/kg/day] significantly inhibited both primary (around 47% tumor growth) and metastatic Lewis lung carcinoma after a 20-day treatment. Our results suggested that BZM and 2-APB combination therapy can potentially be developed as a novel formulation for lung cancer treatment.
A proteomic landscape of diffuse-type gastric cancer
Authors: Ge Sai , Xia Xia , Ding Chen , Zhen Bei , Zhou Quan , Feng Jinwen , Yuan Jiajia , Chen Rui , Li Yumei , Ge Zhongqi , Ji Jiafu , Zhang Lianhai , Wang Jiayuan , Li Zhongwu , Lai Yumei , Hu Ying , Li Yanyan , Li Yilin , Gao Jing , Chen Lin , Xu Jianming , Zhang Chunchao , Jung Sung Yun , Choi Jong Min , Jain Antrix , Liu Mingwei , Song Lei , Liu Wanlin , Guo Gaigai , Gong Tongqing , Huang Yin , Qiu Yang , Huang Wenwen , Shi Tieliu , Zhu Weimin , Wang Yi , He Fuchu , Shen Lin , Qin Jun
Published: March 2018

The diffuse-type gastric cancer (DGC) is a subtype of gastric cancer with the worst prognosis and few treatment options. Here we present a dataset from 84 DGC patients, composed of a proteome of 11,340 gene products and mutation information of 274 cancer driver genes covering paired tumor and nearby tissue. DGC can be classified into three subtypes (PX1–3) based on the altered proteome alone. PX1 and PX2 exhibit dysregulation in the cell cycle and PX2 features an additional EMT process; PX3 is enriched in immune response proteins, has the worst survival, and is insensitive to chemotherapy. Data analysis revealed four major vulnerabilities in DGC that may be targeted for treatment, and allowed the nomination of potential immunotherapy targets for DGC patients, particularly for those in PX3. This dataset provides a rich resource for information and knowledge mining toward altered signaling pathways in DGC and demonstrates the benefit of proteomic analysis in cancer molecular subtyping.
Oscillating modes of driven colloids in overdamped systems
Authors: Berner Johannes , Müller Boris , Gomez-Solano Juan Ruben , Krüger Matthias , Bechinger Clemens
Published: March 2018

Microscopic colloidal particles suspended in liquids are a prominent example of an overdamped system where viscous forces dominate over inertial effects. Frequently, colloids are used as sensitive probes, e.g., in biophysical applications from which molecular forces are inferred. The interpretation of such experiments rests on the assumption that, even when the particles are driven, the liquid remains in equilibrium. Here we experimentally demonstrate that this is not valid for particles in viscoelastic fluids. Even at small driving forces, we observe particle oscillations with several tens of seconds. They are attributed to non-equilibrium fluctuations of the fluid being excited by the particle’s motion. The oscillatory dynamics is in quantitative agreement with an overdamped Langevin equation with negative friction-memory term being equivalent to a stochastically driven underdamped oscillator. Such oscillatory modes are expected to widen the use of colloids as model systems but must also be considered in colloidal probe experiments.
Phosphorylation of conserved phosphoinositide binding pocket regulates sorting nexin membrane targeting
Authors: Lenoir Marc , Ustunel Cansel , Rajesh Sandya , Kaur Jaswant , Moreau Dimitri , Gruenberg Jean , Overduin Michael
Published: March 2018

Sorting nexins anchor trafficking machines to membranes by binding phospholipids. The paradigm of the superfamily is sorting nexin 3 (SNX3), which localizes to early endosomes by recognizing phosphatidylinositol 3-phosphate (PI3P) to initiate retromer-mediated segregation of cargoes to the trans-Golgi network (TGN). Here we report the solution structure of full length human SNX3, and show that PI3P recognition is accompanied by bilayer insertion of a proximal loop in its extended Phox homology (PX) domain. Phosphoinositide (PIP) binding is completely blocked by cancer-linked phosphorylation of a conserved serine beside the stereospecific PI3P pocket. This “PIP-stop” releases endosomal SNX3 to the cytosol, and reveals how protein kinases control membrane assemblies. It constitutes a widespread regulatory element found across the PX superfamily and throughout evolution including of fungi and plants. This illuminates the mechanism of a biological switch whereby structured PIP sites are phosphorylated to liberate protein machines from organelle surfaces.
Nanoscale kinetics of asymmetrical corrosion in core-shell nanoparticles
Authors: Shan Hao , Gao Wenpei , Xiong Yalin , Shi Fenglei , Yan Yucong , Ma Yanling , Shang Wen , Tao Peng , Song Chengyi , Deng Tao , Zhang Hui , Yang Deren , Pan Xiaoqing , Wu Jianbo
Published: March 2018

Designing new materials and structure to sustain the corrosion during operation requires better understanding on the corrosion dynamics. Observation on how the corrosion proceeds in atomic scale is thus critical. Here, using a liquid cell, we studied the real-time corrosion process of palladium@platinum (Pd@Pt) core-shell nanocubes via transmission electron microscopy (TEM). The results revealed that multiple etching pathways operatively contribute to the morphology evolution during corrosion, including galvanic etching on non-defected sites with slow kinetics and halogen-induced etching at defected sites at faster rates. Corners are the preferential corrosion sites; both etching pathways are mutually restricted during corrosion. Those insights on the interaction of nanostructures with reactive liquid environments can help better engineer the surface structure to improve the stability of electrocatalysts as well as design a new porous structure that may provide more active sites for catalysis.
Cation vacancy stabilization of single-atomic-site Pt1/Ni(OH)x catalyst for diboration of alkynes and alkenes
Authors: Zhang Jian , Wu Xi , Cheong Weng-Chon , Chen Wenxing , Lin Rui , Li Jia , Zheng Lirong , Yan Wensheng , Gu Lin , Chen Chen , Peng Qing , Wang Dingsheng , Li Yadong
Published: March 2018

Development of single-atomic-site catalysts with high metal loading is highly desirable but proved to be very challenging. Although utilizing defects on supports to stabilize independent metal atoms has become a powerful method to fabricate single-atomic-site catalysts, little attention has been devoted to cation vacancy defects. Here we report a nickel hydroxide nanoboard with abundant Ni2+ vacancy defects serving as the practical support to achieve a single-atomic-site Pt catalyst (Pt1/Ni(OH)x) containing Pt up to 2.3 wt% just by a simple wet impregnation method. The Ni2+ vacancies are found to have strong stabilizing effect of single-atomic Pt species, which is determined by X-ray absorption spectrometry analyses and density functional theory calculations. This Pt1/Ni(OH)x catalyst shows a high catalytic efficiency in diboration of a variety of alkynes and alkenes, yielding an overall turnover frequency value upon reaction completion for phenylacetylene of ~3000 h−1, which is much higher than other reported heterogeneous catalysts.
Design and validation of a foldable and photovoltaic wide-field epiretinal prosthesis
Authors: Ferlauto Laura , Airaghi Leccardi Marta Jole Ildelfonsa , Chenais Naïg Aurelia Ludmilla , Gilliéron Samuel Charles Antoine , Vagni Paola , Bevilacqua Michele , Wolfensberger Thomas J. , Sivula Kevin , Ghezzi Diego
Published: March 2018

Retinal prostheses have been developed to fight blindness in people affected by outer retinal layer dystrophies. To date, few hundred patients have received a retinal implant. Inspired by intraocular lenses, we have designed a foldable and photovoltaic wide-field epiretinal prosthesis (named POLYRETINA) capable of stimulating wireless retinal ganglion cells. Here we show that within a visual angle of 46.3 degrees, POLYRETINA embeds 2215 stimulating pixels, of which 967 are in the central area of 5 mm, it is foldable to allow implantation through a small scleral incision, and it has a hemispherical shape to match the curvature of the eye. We demonstrate that it is not cytotoxic and respects optical and thermal safety standards; accelerated ageing shows a lifetime of at least 2 years. POLYRETINA represents significant progress towards the improvement of both visual acuity and visual field with the same device, a current challenging issue in the field.
An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm
Authors: Lino Cardenas Christian L. , Kessinger Chase W. , Cheng Yisha , MacDonald Carolyn , MacGillivray Thomas , Ghoshhajra Brian , Huleihel Luai , Nuri Saifar , Yeri Ashish S. , Jaffer Farouc A. , Kaminski Naftali , Ellinor Patrick , Weintraub Neal L. , Malhotra Rajeev , Isselbacher Eric M. , Lindsay Mark E.
Published: March 2018

Thoracic aortic aneurysm (TAA) has been associated with mutations affecting members of the TGF-β signaling pathway, or components and regulators of the vascular smooth muscle cell (VSMC) actomyosin cytoskeleton. Although both clinical groups present similar phenotypes, the existence of potential common mechanisms of pathogenesis remain obscure. Here we show that mutations affecting TGF-β signaling and VSMC cytoskeleton both lead to the formation of a ternary complex comprising the histone deacetylase HDAC9, the chromatin-remodeling enzyme BRG1, and the long noncoding RNA MALAT1. The HDAC9–MALAT1–BRG1 complex binds chromatin and represses contractile protein gene expression in association with gain of histone H3-lysine 27 trimethylation modifications. Disruption of Malat1 or Hdac9 restores contractile protein expression, improves aortic mural architecture, and inhibits experimental aneurysm growth. Thus, we highlight a shared epigenetic pathway responsible for VSMC dysfunction in both forms of TAA, with potential therapeutic implication for other known HDAC9-associated vascular diseases.
An accurate and robust imputation method scImpute for single-cell RNA-seq data
Authors: Li Wei Vivian , Li Jingyi Jessica
Published: March 2018

The emerging single-cell RNA sequencing (scRNA-seq) technologies enable the investigation of transcriptomic landscapes at the single-cell resolution. ScRNA-seq data analysis is complicated by excess zero counts, the so-called dropouts due to low amounts of mRNA sequenced within individual cells. We introduce scImpute, a statistical method to accurately and robustly impute the dropouts in scRNA-seq data. scImpute automatically identifies likely dropouts, and only perform imputation on these values without introducing new biases to the rest data. scImpute also detects outlier cells and excludes them from imputation. Evaluation based on both simulated and real human and mouse scRNA-seq data suggests that scImpute is an effective tool to recover transcriptome dynamics masked by dropouts. scImpute is shown to identify likely dropouts, enhance the clustering of cell subpopulations, improve the accuracy of differential expression analysis, and aid the study of gene expression dynamics.
Expansion of functional personalized cells with specific transgene combinations
Authors: Lipps Christoph , Klein Franziska , Wahlicht Tom , Seiffert Virginia , Butueva Milada , Zauers Jeannette , Truschel Theresa , Luckner Martin , Köster Mario , MacLeod Roderick , Pezoldt Jörn , Hühn Jochen , Yuan Qinggong , Müller Peter Paul , Kempf Henning , Zweigerdt Robert , Dittrich-Breiholz Oliver , Pufe Thomas , Beckmann Rainer , Drescher Wolf , Riancho Jose , Sañudo Carolina , Korff Thomas , Opalka Bertram , Rebmann Vera , Göthert Joachim R. , Alves Paula M. , Ott Michael , Schucht Roland , Hauser Hansjörg , Wirth Dagmar , May Tobias
Published: March 2018

Fundamental research and drug development for personalized medicine necessitates cell cultures from defined genetic backgrounds. However, providing sufficient numbers of authentic cells from individuals poses a challenge. Here, we present a new strategy for rapid cell expansion that overcomes current limitations. Using a small gene library, we expanded primary cells from different tissues, donors, and species. Cell-type-specific regimens that allow the reproducible creation of cell lines were identified. In depth characterization of a series of endothelial and hepatocytic cell lines confirmed phenotypic stability and functionality. Applying this technology enables rapid, efficient, and reliable production of unlimited numbers of personalized cells. As such, these cell systems support mechanistic studies, epidemiological research, and tailored drug development.
The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages
Authors: Chu Lan H. , Indramohan Mohanalaxmi , Ratsimandresy Rojo A. , Gangopadhyay Anu , Morris Emily P. , Monack Denise M. , Dorfleutner Andrea , Stehlik Christian
Published: March 2018

Lipopolysaccharide (LPS) of Gram-negative bacteria can elicit a strong immune response. Although extracellular LPS is sensed by TLR4 at the cell surface and triggers a transcriptional response, cytosolic LPS binds and activates non-canonical inflammasome caspases, resulting in pyroptotic cell death, as well as canonical NLRP3 inflammasome-dependent cytokine release. Contrary to the highly regulated multiprotein platform required for caspase-1 activation in the canonical inflammasomes, the non-canonical mouse caspase-11 and the orthologous human caspase-4 function simultaneously as innate sensors and effectors, and their regulation is unclear. Here we show that the oxidized phospholipid 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC) inhibits the non-canonical inflammasome in macrophages, but not in dendritic cells. Aside from a TLR4 antagonistic role, oxPAPC binds directly to caspase-4 and caspase-11, competes with LPS binding, and consequently inhibits LPS-induced pyroptosis, IL-1β release and septic shock. Therefore, oxPAPC and its derivatives might provide a basis for therapies that target non-canonical inflammasomes during Gram-negative bacterial sepsis.
Mutual potentiation drives synergy between trimethoprim and sulfamethoxazole
Authors: Minato Yusuke , Dawadi Surendra , Kordus Shannon L. , Sivanandam Abiram , Aldrich Courtney C. , Baughn Anthony D.
Published: March 2018

Trimethoprim (TMP)-sulfamethoxazole (SMX) is a widely used synergistic antimicrobial combination to treat a variety of bacterial and certain fungal infections. These drugs act by targeting sequential steps in the biosynthetic pathway for tetrahydrofolate (THF), where SMX inhibits production of the THF precursor dihydropteroate, and TMP inhibits conversion of dihydrofolate (DHF) to THF. Consequently, SMX potentiates TMP by limiting de novo DHF production and this mono-potentiation mechanism is the current explanation for their synergistic action. Here, we demonstrate that this model is insufficient to explain the potent synergy of TMP-SMX. Using genetic and biochemical approaches, we characterize a metabolic feedback loop in which THF is critical for production of the folate precursor dihydropterin pyrophosphate (DHPPP). We reveal that TMP potentiates SMX activity through inhibition of DHPPP synthesis. Our study demonstrates that the TMP-SMX synergy is driven by mutual potentiation of the action of each drug on the other.
Sedimentary noise and sea levels linked to land–ocean water exchange and obliquity forcing
Authors: Li Mingsong , Hinnov Linda A. , Huang Chunju , Ogg James G.
Published: March 2018

In ancient hothouses lacking ice sheets, the origins of large, million-year (myr)-scale sea-level oscillations remain a mystery, challenging current models of sea-level change. To address this mystery, we develop a sedimentary noise model for sea-level changes that simultaneously estimates geologic time and sea level from astronomically forced marginal marine stratigraphy. The noise model involves two complementary approaches: dynamic noise after orbital tuning (DYNOT) and lag-1 autocorrelation coefficient (ρ1). Noise modeling of Lower Triassic marine slope stratigraphy in South China reveal evidence for global sea-level variations in the Early Triassic hothouse that are anti-phased with continental water storage variations in the Germanic Basin. This supports the hypothesis that long-period (1-2 myr) astronomically forced water mass exchange between land and ocean reservoirs is a missing link for reconciling geological records and models for sea-level change during non-glacial periods.
Aberrant GlyRS-HDAC6 interaction linked to axonal transport deficits in Charcot-Marie-Tooth neuropathy
Authors: Mo Zhongying , Zhao Xiaobei , Liu Huaqing , Hu Qinghua , Chen Xu-Qiao , Pham Jessica , Wei Na , Liu Ze , Zhou Jiadong , Burgess Robert W. , Pfaff Samuel L. , Caskey C. Thomas , Wu Chengbiao , Bai Ge , Yang Xiang-Lei
Published: March 2018

Dominant mutations in glycyl-tRNA synthetase (GlyRS) cause a subtype of Charcot-Marie-Tooth neuropathy (CMT2D). Although previous studies have shown that GlyRS mutants aberrantly interact with Nrp1, giving insight into the disease’s specific effects on motor neurons, these cannot explain length-dependent axonal degeneration. Here, we report that GlyRS mutants interact aberrantly with HDAC6 and stimulate its deacetylase activity on α-tubulin. A decrease in α-tubulin acetylation and deficits in axonal transport are observed in mice peripheral nerves prior to disease onset. An HDAC6 inhibitor used to restore α-tubulin acetylation rescues axonal transport deficits and improves motor functions of CMT2D mice. These results link the aberrant GlyRS-HDAC6 interaction to CMT2D pathology and suggest HDAC6 as an effective therapeutic target. Moreover, the HDAC6 interaction differs from Nrp1 interaction among GlyRS mutants and correlates with divergent clinical presentations, indicating the existence of multiple and different mechanisms in CMT2D.
Genomics of habitat choice and adaptive evolution in a deep-sea fish
Authors: Gaither Michelle R. , Gkafas Georgios A. , de Jong Menno , Sarigol Fatih , Neat Francis , Regnier Thomas , Moore Daniel , Grӧcke Darren R. , Hall Neil , Liu Xuan , Kenny John , Lucaci Anita , Hughes Margaret , Haldenby Sam , Hoelzel A. Rus
Published: March 2018

Intraspecific diversity promotes evolutionary change, and when partitioned among geographic regions or habitats can form the basis for speciation. Marine species live in an environment that can provide as much scope for diversification in the vertical as in the horizontal dimension. Understanding the relevant mechanisms will contribute significantly to our understanding of eco-evolutionary processes and effective biodiversity conservation. Here, we provide an annotated genome assembly for the deep-sea fishCoryphaenoides rupestrisand re-sequencing data to show that differentiation at non-synonymous sites in functional loci distinguishes individuals living at different depths, independent of horizontal spatial distance. Our data indicate disruptive selection at these loci; however, we find no clear evidence for differentiation at neutral loci that may indicate assortative mating. We propose that individuals with distinct genotypes at relevant loci segregate by depth as they mature (supported by survey data), which may be associated with ecotype differentiation linked to distinct phenotypic requirements at different depths.
Mechanical dyssynchrony and diastolic dysfunction are common in LVH: a pilot correlation study using Doppler echocardiography and CZT gated-SPECT MPI
Authors: Tsai Szu-Ying , Wang Shan-Ying , Shiau Yu-Chien , Wu Yen-Wen
Published: March 2018

Hypertrophic cardiomyopathy (HCM) is an often under-diagnosed cause of left ventricular hypertrophy (LVH). It affects 1/500 of the population, is the most commonly inherited cardiovascular disorder, and can present in apical, concentric, or septal forms. Although most patients are asymptomatic, sudden cardiac death can be the initial presentation of HCM. By retrospectively enrolling patients suspected of having three different types of HCM in the absence of epicardial coronary stenosis, we aimed to examine systolic and diastolic dysfunction and perfusion abnormalities using both Doppler echocardiography and state-of-the-art gated single-photon emission computerized tomography (SPECT) myocardial perfusion imaging (MPI) with a cadmium-zinc-telluride camera and thallium-201. Both regional perfusion and gated SPECT parameters were collected in addition to diastolic parameters from Doppler echocardiography. The results showed that mild ischemia was common in patients suspected of having HCM, with a mean summed stress score of 4.7 ± 4.9 (score 0–4 in 17-segment model). The patients with HCM were associated with discernible left ventricular mechanical dyssynchrony, especially those with the apical form. In addition, diastolic dysfunction was prevalent and early to late ventricular filling velocity ratios were significantly different between groups. By combining gated-MPI and Doppler data, the trivial functional changes in HCM may be identified.
Modulating the water channel AQP4 alters miRNA expression, astrocyte connectivity and water diffusion in the rodent brain
Authors: Jullienne Amandine , Fukuda Andrew M. , Ichkova Aleksandra , Nishiyama Nina , Aussudre Justine , Obenaus André , Badaut Jérôme
Published: March 2018

Aquaporins (AQPs) facilitate water diffusion through the plasma membrane. Brain aquaporin-4 (AQP4) is present in astrocytes and has critical roles in normal and disease physiology. We previously showed that a 24.9% decrease in AQP4 expression after in vivo silencing resulted in a 45.8% decrease in tissue water mobility as interpreted from magnetic resonance imaging apparent diffusion coefficients (ADC). Similar to previous in vitro studies we show decreased expression of the gap junction protein connexin 43 (Cx43) in vivo after intracortical injection of siAQP4 in the rat. Moreover, siAQP4 induced a loss of dye-coupling between astrocytes in vitro, further demonstrating its effect on gap junctions. In contrast, silencing of Cx43 did not alter the level of AQP4 or water mobility (ADC) in the brain. We hypothesized that siAQP4 has off-target effects on Cx43 expression via modification of miRNA expression. The decreased expression of Cx43 in siAQP4-treated animals was associated with up-regulation of miR224, which is known to target AQP4 and Cx43 expression. This could be one potential molecular mechanism responsible for the effect of siAQP4 on Cx43 expression, and the resultant decrease in astrocyte connectivity and dramatic effects on ADC values and water mobility.
Genetic and metabolic regulation of Mycobacterium tuberculosis acid growth arrest
Authors: Baker Jacob J. , Abramovitch Robert B.
Published: March 2018

Mycobacterium tuberculosis (Mtb) senses and adapts to acidic environments during the course of infection. Acidic pH-dependent adaptations include the induction of metabolic genes associated with anaplerosis and growth arrest on specific carbon sources. Here we report that deletion of isocitrate lyase or phosphoenolpyruvate carboxykinase results in reduced growth at acidic pH and altered metabolite profiles, supporting that remodeling of anaplerotic metabolism is required for pH-dependent adaptation. Mtb cultured at pH 5.7 in minimal medium containing glycerol as a single carbon source exhibits an acid growth arrest phenotype, where the bacterium is non-replicating but viable and metabolically active. The bacterium assimilates and metabolizes glycerol and maintains ATP pools during acid growth arrest and becomes tolerant to detergent stress and the antibiotics isoniazid and rifampin. A forward genetic screen identified mutants that do not arrest their growth at acidic pH, including four enhanced acid growth (eag) mutants with three distinct mutations in the proline-proline-glutamate (PPE) gene MT3221 (also named ppe51). Overexpression of the MT3221(S211R) variant protein in wild type Mtb results in enhanced acid growth and reduced drug tolerance. These findings support that acid growth arrest is a genetically controlled, adaptive process and not simply a physiological limitation associated with acidic pH.
Metaboloptics: Visualization of the tumor functional landscape via metabolic and vascular imaging
Authors: Martinez Amy F. , McCachren Samuel S. , Lee Marianne , Murphy Helen A. , Zhu Caigang , Crouch Brian T. , Martin Hannah L. , Erkanli Alaattin , Rajaram Narasimhan , Ashcraft Kathleen A. , Fontanella Andrew N. , Dewhirst Mark W. , Ramanujam Nirmala
Published: March 2018

Many cancers adeptly modulate metabolism to thrive in fluctuating oxygen conditions; however, current tools fail to image metabolic and vascular endpoints at spatial resolutions needed to visualize these adaptations in vivo. We demonstrate a high-resolution intravital microscopy technique to quantify glucose uptake, mitochondrial membrane potential (MMP), and SO2 to characterize the in vivo phentoypes of three distinct murine breast cancer lines. Tetramethyl rhodamine, ethyl ester (TMRE) was thoroughly validated to report on MMP in normal and tumor-bearing mice. Imaging MMP or glucose uptake together with vascular endpoints revealed that metastatic 4T1 tumors maintained increased glucose uptake across all SO2 (“Warburg effect”), and also showed increased MMP relative to normal tissue. Non-metastatic 67NR and 4T07 tumor lines both displayed increased MMP, but comparable glucose uptake, relative to normal tissue. The 4T1 peritumoral areas also showed a significant glycolytic shift relative to the tumor regions. During a hypoxic stress test, 4T1 tumors showed significant increases in MMP with corresponding significant drops in SO2, indicative of intensified mitochondrial metabolism. Conversely, 4T07 and 67NR tumors shifted toward glycolysis during hypoxia. Our findings underscore the importance of imaging metabolic endpoints within the context of a living microenvironment to gain insight into a tumor’s adaptive behavior.
Spatiotemporal Airy Ince–Gaussian wave packets in strongly nonlocal nonlinear media
Authors: Peng Xi , Zhuang Jingli , Peng Yulian , Li DongDong , Zhang Liping , Chen Xingyu , Zhao Fang , Deng Dongmei
Published: March 2018

The self-accelerating Airy Ince–Gaussian (AiIG) and Airy helical Ince–Gaussian (AihIG) wave packets in strongly nonlocal nonlinear media (SNNM) are obtained by solving the strongly nonlocal nonlinear Schrödinger equation. For the first time, the propagation properties of three dimensional localized AiIG and AihIG breathers and solitons in the SNNM are demonstrated, these spatiotemporal wave packets maintain the self-accelerating and approximately non-dispersion properties in temporal dimension, periodically oscillating (breather state) or steady (soliton state) in spatial dimension. In particular, their numerical experiments of spatial intensity distribution, numerical simulations of spatiotemporal distribution, as well as the transverse energy flow and the angular momentum in SNNM are presented. Typical examples of the obtained solutions are based on the ratio between the input power and the critical power, the ellipticity and the strong nonlocality parameter. The comparisons of analytical solutions with numerical simulations and numerical experiments of the AiIG and AihIG optical solitons show that the numerical results agree well with the analytical solutions in the case of strong nonlocality.
Design of broadband graphene-metamaterial absorbers for permittivity sensing at mid-infrared regions
Authors: Huang Hailong , Xia Hui , Xie Wenke , Guo Zhibo , Li Hongjian , Xie Ding
Published: March 2018

In this paper, a tunable broadband metamaterial absorber (MA) based on graphene is investigated theoretically and numerically at mid-infrared regions. Compared with the previously reported multiband graphene-based MAs, a broad bandwidth of 11.7 THz with the absorption over 90% is obtained in the proposed MA, which is composed of a Jerusalem cross (JC) metal encrusting into the slot graphene layer in the top layer. The results show that the origin of broadband absorption is caused by coupling effect between metal and graphene, and this effect is explained by the two-mode waveguide coupling theory. The tunability of MA is achieved via changing the external gate voltage to modify the Fermi energy of graphene. Further results show that the proposed MA can be used as the permittivity sensor with a high absorption. This work indicates that the proposed MA has the potential applications with respect to sensors and infrared absorbers.
Volcanic ash as a driver of enhanced organic carbon burial in the Cretaceous
Authors: Lee Cin-Ty A. , Jiang Hehe , Ronay Elli , Minisini Daniel , Stiles Jackson , Neal Matthew
Published: March 2018

On greater than million year timescales, carbon in the ocean-atmosphere-biosphere system is controlled by geologic inputs of CO2 through volcanic and metamorphic degassing. High atmospheric CO2 and warm climates in the Cretaceous have been attributed to enhanced volcanic emissions of CO2 through more rapid spreading at mid-ocean ridges and, in particular, to a global flare-up in continental arc volcanism. Here, we show that global flare-ups in continental arc magmatism also enhance the global flux of nutrients into the ocean through production of windblown ash. We show that up to 75% of Si, Fe and P is leached from windblown ash during and shortly after deposition, with soluble Si, Fe and P inputs from ash alone in the Cretaceous being higher than the combined input of dust and rivers today. Ash-derived nutrient inputs may have increased the efficiency of biological productivity and organic carbon preservation in the Cretaceous, possibly explaining why the carbon isotopic signature of Cretaceous seawater was high. Variations in volcanic activity, particularly continental arcs, have the potential of profoundly altering carbon cycling at the Earth’s surface by increasing inputs of CO2 and ash-borne nutrients, which together enhance biological productivity and burial of organic carbon, generating an abundance of hydrocarbon source rocks.
Global transcriptomic analysis suggests carbon dioxide as an environmental stressor in spaceflight: A systems biology GeneLab case study
Authors: Beheshti Afshin , Cekanaviciute Egle , Smith David J. , Costes Sylvain V.
Published: March 2018

Spaceflight introduces a combination of environmental stressors, including microgravity, ionizing radiation, changes in diet and altered atmospheric gas composition. In order to understand the impact of each environmental component on astronauts it is important to investigate potential influences in isolation. Rodent spaceflight experiments involve both standard vivarium cages and animal enclosure modules (AEMs), which are cages used to house rodents in spaceflight. Ground control AEMs are engineered to match the spaceflight environment. There are limited studies examining the biological response invariably due to the configuration of AEM and vivarium housing. To investigate the innate global transcriptomic patterns of rodents housed in spaceflight-matched AEM compared to standard vivarium cages we utilized publicly available data from the NASA GeneLab repository. Using a systems biology approach, we observed that AEM housing was associated with significant transcriptomic differences, including reduced metabolism, altered immune responses, and activation of possible tumorigenic pathways. Although we did not perform any functional studies, our findings revealed a mild hypoxic phenotype in AEM, possibly due to atmospheric carbon dioxide that was increased to match conditions in spaceflight. Our investigation illustrates the process of generating new hypotheses and informing future experimental research by repurposing multiple space-flown datasets.
HSP27 inhibitor attenuates radiation-induced pulmonary inflammation
Authors: Kim Jee-Youn , An Yong-Min , Yoo Byeong Rok , Kim Jin-Mo , Han Song Yee , Na Younghwa , Lee Yun-Sil , Cho Jaeho
Published: March 2018

Radiation therapy has been used to treat over 70% of thoracic cancer; however, the method usually causes radiation pneumonitis. In the current study, we investigated the radioprotective effects of HSP27 inhibitor (J2) on radiation-induced lung inflammation in comparison to amifostine. In gross and histological findings, J2 treatment significantly inhibited immune cell infiltration in lung tissue, revealing anti-inflammatory potential of J2. Normal lung volume, evaluated by micro-CT analysis, in J2-treated mice was higher compared to that in irradiated mice. J2-treated mice reversed radiation-induced respiratory distress. However, amifostine did not show significant radioprotective effects in comparison to that of J2. In HSP27 transgenic mice, we observed increased immune cells recruitment and decreased volume of normal lung compared to wild type mice. Increased ROS production and oxidative stress after IR were down-regulated by J2 treatment, demonstrating antioxidant property of J2. The entire data of this study collectively showed that J2 may be an effective therapeutic agent for radiation-induced lung injury.
Microscopic diffusion processes measured in living planarians
Authors: Mamontov Eugene
Published: March 2018

Living planarian flatworms were probed using quasielastic neutron scattering to measure, on the pico-to-nanosecond time scale and nanometer length scale, microscopic diffusion of water and cell constituents in the planarians. Measurable microscopic diffusivities were surprisingly well defined in such a complex system as living animals. The overall variation in the microscopic diffusivity of cell constituents was found to be far lower than the variation in the microscopic diffusivity of water in planarians in a temperature range of 284.5 to 304.1 K.