bluuebunny/crossref_metadata_2025 huggingface dataset:
Carneades: The One and Only
Authors: Fleischer Kilian
Published: September 2019

The Academic scholarch Carneades of Cyrene withdrew from active lecturing several years before his death. He handed the Academy over – either formally or informally – to a successor, who remained in charge for six years (137/6–131/0 BC) and passed away in Carneades’ own lifetime. Philodemus reports this episode three times in the Index Academicorum. Since 1869 scholars have never questioned the notion that Carneades’ lifetime-successor was a namesake: Carneades, son of Polemarchus (also called Carneades the younger). Now, new readings of several lines in all three passages reveal that the name of Carneades’ successor was actually Polemarchus of Nicomedia – a man skilled in dialectical methods. There never was a second Academic named Carneades.
Evaluation of the ‘Unforgettable’ art programme by people with dementia and their care-givers
Authors: Hendriks Iris , Meiland Franka J. M. , Gerritsen Debby L. , Dröes Rose-Marie
Published: September 2019

Art programmes have been shown to contribute to the quality of life of people with dementia. To understand how people with dementia benefit from art programmes it is important to evaluate them. ‘Unforgettable’ is an interactive museum programme for people with dementia and their care-givers in the Netherlands. This study examined how it is experienced and appreciated by its users. It also investigated whether the user experience and appreciation are linked to their specific background characteristics. In a single-group design, we used a ‘take-home’ survey to collect the participants’ background characteristics and their experience and appreciation of the programme. A before and after intervention measurement took place, using a smiley face scale, to measure the change in mood of participants. Participants evaluated the programme very positively. Social interaction proved a key factor in their appreciation. The mood of the persons with dementia (N = 95) and care-givers (N = 104) improved after participation in the ‘Unforgettable’ programme. The results of this evaluation may contribute to the quality of art programmes in museums.
Gifts as governance: Church Welfare and the Samaritan's dilemma
Authors: Goodman Nathan P. , Herzberg Roberta Q.
Published: September 2019

How do gifts relate to formal and informal institutions? Giving gifts, especially in the form of anti-poverty aid, opens the givers to a serious social dilemma: the Samaritan's dilemma. We explain how the Church of Jesus Christ of Latter-day Saints uses a mixture of formal and informal governance to provide sustainable social welfare programs that avoid this dilemma. These institutions not only govern aid arrangements, but also provide governance across the entire Church community, encouraging religious adherence and broad-based participation.
Genetically engineered T cells for cancer immunotherapy
Authors: Li Dan , Li Xue , Zhou Wei-Lin , Huang Yong , Liang Xiao , Jiang Lin , Yang Xiao , Sun Jie , Li Zonghai , Han Wei-Dong , Wang Wei
Published: September 2019

T cells in the immune system protect the human body from infection by pathogens and clear mutant cells through specific recognition by T cell receptors (TCRs). Cancer immunotherapy, by relying on this basic recognition method, boosts the antitumor efficacy of T cells by unleashing the inhibition of immune checkpoints and expands adaptive immunity by facilitating the adoptive transfer of genetically engineered T cells. T cells genetically equipped with chimeric antigen receptors (CARs) or TCRs have shown remarkable effectiveness in treating some hematological malignancies, although the efficacy of engineered T cells in treating solid tumors is far from satisfactory. In this review, we summarize the development of genetically engineered T cells, outline the most recent studies investigating genetically engineered T cells for cancer immunotherapy, and discuss strategies for improving the performance of these T cells in fighting cancers.
The emerging interface of mass spectrometry with materials
Authors: Chakraborty Papri , Pradeep Thalappil
Published: September 2019

Mass spectrometry (MS), a hundred-year-old subject, has been a technique of profound importance to molecular science. Its impact in solid-state materials science has not been evident, although many materials of modern science, such as fullerenes, have their origins in MS. Of late, mass spectrometric interface with materials is increasingly strengthened with advances in atomically precise clusters of noble metals. Advances in instrumentation along with recent developments in synthetic approaches have expanded the chemistry of clusters, and new insights into matter at the nanoscale are emerging. High-resolution MS coupled with soft ionization techniques enable efficient characterization of atomically precise clusters. Apart from that, techniques such as ion mobility, tandem MS, etc. reveal structural details of these systems. Growth, nucleation, and reactivity of clusters are also probed by MS. Some of the recent advancements in this field include the development of new hyphenated techniques. Finer structural details may be obtained by coupling MS with spectroscopic tools, such as photoelectron spectroscopy, vacuum ultraviolet spectroscopy, etc. With such advancements in instrumentation, MS can evolve into a universal tool for the characterization of materials. The present review captures highlights of this area.
TRIM66 reads unmodified H3R2K4 and H3K56ac to respond to DNA damage in embryonic stem cells
Authors: Chen Jiajing , Wang Zikang , Guo Xudong , Li Fudong , Wei Qingtao , Chen Xuwen , Gong Deshun , Xu Yanxin , Chen Wen , Liu Yongrui , Kang Jiuhong , Shi Yunyu
Published: September 2019

Recognition of specific chromatin modifications by distinct structural domains within “reader” proteins plays a critical role in the maintenance of genomic stability. However, the specific mechanisms involved in this process remain unclear. Here we report that the PHD-Bromo tandem domain of tripartite motif-containing 66 (TRIM66) recognizes the unmodified H3R2-H3K4 and acetylated H3K56. The aberrant deletion of Trim66 results in severe DNA damage and genomic instability in embryonic stem cells (ESCs). Moreover, we find that the recognition of histone modification by TRIM66 is critical for DNA damage repair (DDR) in ESCs. TRIM66 recruits Sirt6 to deacetylate H3K56ac, negatively regulating the level of H3K56ac and facilitating the initiation of DDR. Importantly, Trim66-deficient blastocysts also exhibit higher levels of H3K56ac and DNA damage. Collectively, the present findings indicate the vital role of TRIM66 in DDR in ESCs, establishing the relationship between histone readers and maintenance of genomic stability.
Reducing greenhouse gas emissions of Amazon hydropower with strategic dam planning
Authors: Almeida Rafael M. , Shi Qinru , Gomes-Selman Jonathan M. , Wu Xiaojian , Xue Yexiang , Angarita Hector , Barros Nathan , Forsberg Bruce R. , García-Villacorta Roosevelt , Hamilton Stephen K. , Melack John M. , Montoya Mariana , Perez Guillaume , Sethi Suresh A. , Gomes Carla P. , Flecker Alexander S.
Published: September 2019

Hundreds of dams have been proposed throughout the Amazon basin, one of the world’s largest untapped hydropower frontiers. While hydropower is a potentially clean source of renewable energy, some projects produce high greenhouse gas (GHG) emissions per unit electricity generated (carbon intensity). Here we show how carbon intensities of proposed Amazon upland dams (median = 39 kg CO2eq MWh−1, 100-year horizon) are often comparable with solar and wind energy, whereas some lowland dams (median = 133 kg CO2eq MWh−1) may exceed carbon intensities of fossil-fuel power plants. Based on 158 existing and 351 proposed dams, we present a multi-objective optimization framework showing that low-carbon expansion of Amazon hydropower relies on strategic planning, which is generally linked to placing dams in higher elevations and smaller streams. Ultimately, basin-scale dam planning that considers GHG emissions along with social and ecological externalities will be decisive for sustainable energy development where new hydropower is contemplated.
Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents
Authors: Juvvadi Praveen R. , Fox David , Bobay Benjamin G. , Hoy Michael J. , Gobeil Sophie M. C. , Venters Ronald A. , Chang Zanetta , Lin Jackie J. , Averette Anna Floyd , Cole D. Christopher , Barrington Blake C. , Wheaton Joshua D. , Ciofani Maria , Trzoss Michael , Li Xiaoming , Lee Soo Chan , Chen Ying-Lien , Mutz Mitchell , Spicer Leonard D. , Schumacher Maria A. , Heitman Joseph , Steinbach William J.
Published: September 2019

Calcineurin is important for fungal virulence and a potential antifungal target, but compounds targeting calcineurin, such as FK506, are immunosuppressive. Here we report the crystal structures of calcineurin catalytic (CnA) and regulatory (CnB) subunits complexed with FK506 and the FK506-binding protein (FKBP12) from human fungal pathogens (Aspergillus fumigatus,Candida albicans,Cryptococcus neoformansandCoccidioides immitis). Fungal calcineurin complexes are similar to the mammalian complex, but comparison of fungal and human FKBP12 (hFKBP12) reveals conformational differences in the 40s and 80s loops. NMR analysis, molecular dynamic simulations, and mutations of theA. fumigatusCnA/CnB-FK506-FKBP12-complex identify a Phe88 residue, not conserved in hFKBP12, as critical for binding and inhibition of fungal calcineurin. These differences enable us to develop a less immunosuppressive FK506 analog, APX879, with an acetohydrazine substitution of the C22-carbonyl of FK506. APX879 exhibits reduced immunosuppressive activity and retains broad-spectrum antifungal activity and efficacy in a murine model of invasive fungal infection.
Genome-wide identification of DNA methylation QTLs in whole blood highlights pathways for cardiovascular disease
Authors: Huan Tianxiao , Joehanes Roby , Song Ci , Peng Fen , Guo Yichen , Mendelson Michael , Yao Chen , Liu Chunyu , Ma Jiantao , Richard Melissa , Agha Golareh , Guan Weihua , Almli Lynn M. , Conneely Karen N. , Keefe Joshua , Hwang Shih-Jen , Johnson Andrew D. , Fornage Myriam , Liang Liming , Levy Daniel
Published: September 2019

Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.
Organocatalytic atroposelective construction of axially chiral arylquinones
Authors: Zhu Shuai , Chen Ye-Hui , Wang Yong-Bin , Yu Peiyuan , Li Shao-Yu , Xiang Shao-Hua , Wang Jun-Qi , Xiao Jian , Tan Bin
Published: September 2019

Atropisomeric biaryl motifs are ubiquitous in chiral catalysts and ligands. Numerous efficient strategies have been developed for the synthesis of axially chiral biaryls. In contrast, the asymmetric construction of o-quinone-aryl atropisomers has yet to be realized. Inspired by the rapid progress of the chemistry of biaryls, here we present our initial investigations about the atroposelective construction of axially chiral arylquinones by a bifunctional chiral phosphoric acid-catalyzed asymmetric conjugate addition and central-to-axial chirality conversion. With o-naphthoquinone as both the electrophile and the oxidant, three types of arylation counterparts, namely 2-naphthylamines, 2-naphthols and indoles, are utilized to assemble a series of atropisomeric scaffolds in good yields and excellent enantioselectivities. This approach not only expands the axially chiral library but also offers a route to a class of potential, chiral biomimetic catalysts.
The N-Acetyl Phenylalanine Glucosamine Derivative Attenuates the Inflammatory/Catabolic Environment in a Chondrocyte-Synoviocyte Co-Culture System
Authors: Pagani Stefania , Minguzzi Manuela , Sicuro Laura , Veronesi Francesca , Santi Spartaco , Scotto D’Abusco Anna , Fini Milena , Borzì Rosa Maria
Published: September 2019

Osteoarthritis (OA), the most prevalent degenerative joint disease, still lacks a true disease-modifying therapy. The involvement of the NF-κB pathway and its upstream activating kinases in OA pathogenesis has been recognized for many years. The ability of the N-acetyl phenylalanine glucosamine derivative (NAPA) to increase anabolism and reduce catabolism via inhibition of IKKα kinase has been previously observed in vitro and in vivo. The present study aims to confirm the chondroprotective effects of NAPA in an in vitro model of joint OA established with primary cells, respecting both the crosstalk between chondrocytes and synoviocytes and their phenotypes. This model satisfactorily reproduces some features of the previously investigated DMM model, such as the prominent induction of ADAMTS-5 upon inflammatory stimulation. Both gene and protein expression analysis indicated the ability of NAPA to counteract key cartilage catabolic enzymes (ADAMTS-5) and effectors (MCP-1). Molecular analysis showed the ability of NAPA to reduce IKKα nuclear translocation and H3Ser10 phosphorylation, thus inhibiting IKKα transactivation of NF-κB signalling, a pivotal step in the NF-κB-dependent gene expression of some of its targets. In conclusion, our data confirm that NAPA could truly act as a disease-modifying drug in OA.
Probing the dynamic stalk region of the ribosome using solution NMR
Authors: Wang Xiaolin , Kirkpatrick John P. , Launay Hélène M. M. , de Simone Alfonso , Häussinger Daniel , Dobson Christopher M. , Vendruscolo Michele , Cabrita Lisa D. , Waudby Christopher A. , Christodoulou John
Published: September 2019

We describe an NMR approach based on the measurement of residual dipolar couplings (RDCs) to probe the structural and motional properties of the dynamic regions of the ribosome. Alignment of intact 70S ribosomes in filamentous bacteriophage enabled measurement of RDCs in the mobile C-terminal domain (CTD) of the stalk protein bL12. A structural refinement of this domain using the observed RDCs did not show large changes relative to the isolated protein in the absence of the ribosome, and we also found that alignment of the CTD was almost independent of the presence of the core ribosome particle, indicating that the inter-domain linker has significant flexibility. The nature of this linker was subsequently probed in more detail using a paramagnetic alignment strategy, which revealed partial propagation of alignment between neighbouring domains, providing direct experimental validation of a structural ensemble previously derived from SAXS and NMR relaxation measurements. Our results demonstrate the prospect of better characterising dynamical and functional regions of more challenging macromolecular machines and systems, for example ribosome–nascent chain complexes.
Central Glucagon-like Peptide-1 Receptor Signaling via Brainstem Catecholamine Neurons Counteracts Hypertension in Spontaneously Hypertensive Rats
Authors: Katsurada Kenichi , Nakata Masanori , Saito Toshinobu , Zhang Boyang , Maejima Yuko , Nandi Shyam S. , Sharma Neeru M. , Patel Kaushik P. , Kario Kazuomi , Yada Toshihiko
Published: September 2019

Glucagon-like peptide-1 receptor (GLP-1R) agonists, widely used to treat type 2 diabetes, reduce blood pressure (BP) in hypertensive patients. Whether this action involves central mechanisms is unknown. We here report that repeated lateral ventricular (LV) injection of GLP-1R agonist, liraglutide, once daily for 15 days counteracted the development of hypertension in spontaneously hypertensive rats (SHR). In parallel, it suppressed urinary norepinephrine excretion, and induced c-Fos expressions in the area postrema (AP) and nucleus tractus solitarius (NTS) of brainstem including the NTS neurons immunoreactive to dopamine beta-hydroxylase (DBH). Acute administration of liraglutide into fourth ventricle, the area with easy access to the AP and NTS, transiently decreased BP in SHR and this effect was attenuated after lesion of NTS DBH neurons with anti-DBH conjugated to saporin (anti-DBH-SAP). In anti-DBH-SAP injected SHR, the antihypertensive effect of repeated LV injection of liraglutide for 14 days was also attenuated. These findings demonstrate that the central GLP-1R signaling via NTS DBH neurons counteracts the development of hypertension in SHR, accompanied by attenuated sympathetic nerve activity.
In vitro metabolic zonation through oxygen gradient on a chip
Authors: Tonon Federica , Giobbe Giovanni Giuseppe , Zambon Alessandro , Luni Camilla , Gagliano Onelia , Floreani Annarosa , Grassi Gabriele , Elvassore Nicola
Published: September 2019

Among the multiple metabolic signals involved in the establishment of the hepatic zonation, oxygen could play a key role. Indeed, depending on hepatocyte position in the hepatic lobule, gene expression and metabolism are differently affected by the oxygen gradient present across the lobule. The aim of this study is to understand whether an oxygen gradient, generated in vitro in our developed device, is sufficient to instruct a functional metabolic zonation during the differentiation of human embryonic stem cells (hESCs) from endoderm toward terminally differentiated hepatocytes, thus mimicking the in vivo situation. For this purpose, a microfluidic device was designed for the generation of a stable oxygen gradient. The oxygen gradient was applied to differentiating hESCs at the pre-hepatoblast stage. The definitive endoderm and hepatic endoderm cells were characterized by the expression of the transcription factor SOX-17 and alpha-fetoprotein (AFP). Immature and mature hepatocytes were characterized by hepatocyte nuclear factor 4-alpha (HNF-4α) and albumin (ALB) expression and also analyzed for cytochrome P450 (CYP3A4) zonation and glycogen accumulation through PAS staining. Metabolic zonated genes expression was assessed through quantitative real time PCR. Application of the oxygen gradient during differentiation induced zonated glycogen storage, which was higher in the hepatocytes grown in high pO2 compared to those grown in low pO2. The mRNA levels of glutamine synthetase (GLUL), beta-catenin (CTNNB) and its direct target cyclin D1 (CCND1) showed significantly higher expression in the cells grown in low pO2 compared to those grown in high pO2. On the contrary, carbamoyl-phosphate synthetase 1 (CPS1), ALB, the proliferative marker ki67 (MKI67) and cyclin A (CCNA) resulted to be significantly higher expressed in cells cultured in high pO2 compared to those cultured in low pO2. These results indicate that the oxygen gradient generated in our device can instruct the establishment of a functional metabolic zonation in differentiating hESCs. The possibility to obtain differentiated hepatocytes in vitro may allow in the future to deepen our knowledge about the physiology/pathology of hepatocytes in relation to the oxygen content.
Metagenomic deep sequencing reveals association of microbiome signature with functional biases in bovine mastitis
Authors: Hoque M. Nazmul , Istiaq Arif , Clement Rebecca A. , Sultana Munawar , Crandall Keith A. , Siddiki Amam Zonaed , Hossain M. Anwar
Published: September 2019

Milk microbiomes significantly influence the pathophysiology of bovine mastitis. To assess the association between microbiome diversity and bovine mastitis, we compared the microbiome of clinical mastitis (CM, n = 14) and healthy (H, n = 7) milk samples through deep whole metagenome sequencing (WMS). A total of 483.38 million reads generated from both metagenomes were analyzed through PathoScope (PS) and MG-RAST (MR), and mapped to 380 bacterial, 56 archaeal, and 39 viral genomes. We observed distinct shifts and differences in abundance between the microbiome of CM and H milk in phyla Proteobacteria, Bacteroidetes, Firmicutes and Actinobacteria with an inclusion of 68.04% previously unreported and/or opportunistic strains in CM milk. PS identified 363 and 146 bacterial strains in CM and H milk samples respectively, and MR detected 356 and 251 bacterial genera respectively. Of the identified taxa, 29.51% of strains and 63.80% of genera were shared between both metagenomes. Additionally, 14 archaeal and 14 viral genera were found to be solely associated with CM. Functional annotation of metagenomic sequences identified several metabolic pathways related to bacterial colonization, proliferation, chemotaxis and invasion, immune-diseases, oxidative stress, regulation and cell signaling, phage and prophases, antibiotic and heavy metal resistance that might be associated with CM. Our WMS study provides conclusive data on milk microbiome diversity associated with bovine CM and its role in udder health.
Evaluating the taxa that provide shared pollination services across multiple crops and regions
Authors: Willcox Bryony K. , Howlett Brad G. , Robson Andrew J. , Cutting Brian , Evans Lisa , Jesson Linley , Kirkland Lindsey , Jean-Meyzonnier Malou , Potdevin Victoria , Saunders Manu E. , Rader Romina
Published: September 2019

Many pollinator species visit multiple crops in multiple regions, yet we know little about their pollination service provisioning at local and regional scales. We investigated the floral visitors (n = 13,200), their effectiveness (n = 1718 single visits) and response to landscape composition across three crops avocado, mango and macadamia within a single growing region (1 year), a single crop (3 years) and across different growing regions in multiple years. In total, eight wild visitor groups were shared across all three crops. The network was dominated by three pollinators, two bees (Apis mellifera and Tetragonula spp.) and a fly, Stomorhina discolor. The visitation network for the three crops was relatively generalised but with the addition of pollen deposition data, specialisation increased. Sixteen managed and wild taxa were consistently present across three years in avocado, yet their contribution to annual network structure varied. Node specialisation (d’) analyses indicated many individual orchard sites across each of the networks were significantly more specialised compared to that predicted by null models, suggesting the presence of site-specific factors driving these patterns. Identifying the taxa shared across multiple crops, regions and years will facilitate the development of specific pollinator management strategies to optimize crop pollination services in horticultural systems.
Production of adeno-associated virus vectors for in vitro and in vivo applications
Authors: Kimura Toyokazu , Ferran Beatriz , Tsukahara Yuko , Shang Qifan , Desai Suveer , Fedoce Alessandra , Pimentel David Richard , Luptak Ivan , Adachi Takeshi , Ido Yasuo , Matsui Reiko , Bachschmid Markus Michael
Published: September 2019

Delivering and expressing a gene of interest in cells or living animals has become a pivotal technique in biomedical research and gene therapy. Among viral delivery systems, adeno-associated viruses (AAVs) are relatively safe and demonstrate high gene transfer efficiency, low immunogenicity, stable long-term expression, and selective tissue tropism. Combined with modern gene technologies, such as cell-specific promoters, the Cre/lox system, and genome editing, AAVs represent a practical, rapid, and economical alternative to conditional knockout and transgenic mouse models. However, major obstacles remain for widespread AAV utilization, such as impractical purification strategies and low viral quantities. Here, we report an improved protocol to produce serotype-independent purified AAVs economically. Using a helper-free AAV system, we purified AAVs from HEK293T cell lysates and medium by polyethylene glycol precipitation with subsequent aqueous two-phase partitioning. Furthermore, we then implemented an iodixanol gradient purification, which resulted in preparations with purities adequate for in vivo use. Of note, we achieved titers of 1010–1011 viral genome copies per µl with a typical production volume of up to 1 ml while requiring five times less than the usual number of HEK293T cells used in standard protocols. For proof of concept, we verified in vivo transduction via Western blot, qPCR, luminescence, and immunohistochemistry. AAVs coding for glutaredoxin-1 (Glrx) shRNA successfully inhibited Glrx expression by ~66% in the liver and skeletal muscle. Our study provides an improved protocol for a more economical and efficient purified AAV preparation.
Evaluation of in vitro and in vivo antibiotic efficacy against a novel bioluminescent Shigella flexneri
Authors: McCloskey Molly C. , Shaheen Shareef , Rabago Lesley , Hulverson Matthew A. , Choi Ryan , Barrett Lynn K. , Arnold Samuel L. M.
Published: September 2019

Shigella spp., the bacteria responsible for shigellosis, are one of the leading causes of diarrheal morbidity and mortality amongst children. There is a pressing need for the development of novel therapeutics, as resistance of Shigella to many currently used antibiotics is rapidly emerging. This paper describes the development of robust in vitro and in vivo tools to study antibiotic efficacy against Shigella flexneri. A novel bioluminescent S. flexneri strain (S. flexneri lux1) was generated, which can be used in a mammalian epithelial cell co-culture assay to evaluate antibiotic intracellular and extracellular efficacy. In addition, the S. flexneri lux1 strain was used with an intraperitoneal (IP) murine model of shigellosis to test the efficacy of ciprofloxacin and ampicillin. Both antibiotics significantly reduced the observed radiance from the gastrointestinal tissue of infected mice compared to vehicle control. Furthermore, plated gastrointestinal tissue homogenate confirmed antibiotic treatment significantly reduced the S. flexneri infection. However, in contrast to the results generated with tissue homogenate, the radiance data was not able to distinguish between the efficacy of ampicillin and ciprofloxacin. Compared to traditional methods, these models can be utilized for efficient screening of novel antibiotics aiding in the discovery of new treatments against shigellosis.
Enzymatic liver function measured by LiMAx – a reliable diagnostic and prognostic tool in chronic liver disease
Authors: Buechter Matthias , Kersting Sarah , Gerken Guido , Kahraman Alisan
Published: September 2019

Chronic liver disease (CLD) is a major cause of morbidity and mortality worldwide. Non-invasive assessment of hepatic disease severity represents a relevant issue to further improve clinical management and therapeutic treatment. We retrospectively compared the diagnostic and prognostic performance of different non-invasive tools (LiMAx, transient elastography (TE), and biomarkers) in detecting different severity stages during the course of CLD. Patients were divided into four groups based on clinical parameters: (1) patients without CLD (control group), (2) patients suffering from CLD without having cirrhosis, (3) patients with CLD and compensated cirrhosis, and finally, (4) patients with CLD and decompensated cirrhosis. Patients with acute liver failure were excluded from the analysis. A total of 464 patients who underwent LiMAx measurement at the University Clinic of Essen between 10/2016 and 11/2017 were included in this study. Distribution of the different groups were n = 72 patients for group 1, n = 134 patients for group 2, n = 160 patients for group 3, and n = 98 patients for group 4, respectively. Median LiMAx values significantly declined with respect to increasing degree of CLD: (1) 510 µg/h/kg, (2) 390 µg/h/kg, (3) 264 µg/h/kg, and (4) 151 µg/h/kg (p < 0.001). When comparing the diagnostic accuracy of the LiMAx test in detecting patients with presence of cirrhosis (groups 1 and 2 vs. groups 3 and 4), an AUROC of 0.942 was found (cut-off 322 µg/h/kg, sensitivity 86.1%, specificity 91.3%, p < 0.0001). LiMAx was superior to TE and serum biomarkers in predicting patients’ outcome by 90-day mortality (AUROC 0.811, p < 0.001). Enzymatic liver function measured by LiMAx was closely associated with different severity stages of CLD and was a reliable diagnostic and prognostic tool with an accuracy comparable to current standard methods.
Ratiometric Impedance Sensing of Fingers for Robust Identity Authentication
Authors: Noh Hyung Wook , Ahn Chang-Geun , Kong Hyoun-Joong , Sim Joo Yong
Published: September 2019

We present a novel biometric authentication system enabled by ratiometric analysis of impedance of fingers. In comparison to the traditional biometrics that relies on acquired images of structural information of physiological characteristics, our biological impedance approach not only eliminates any practical means of making fake copies of the relevant physiological traits but also provides reliable features of biometrics using the ratiometric impedance of fingers. This study shows that the ratiometric features of the impedance of fingers in 10 different pairs using 5 electrodes at the fingertips can reduce the variation due to undesirable factors such as temperature and day-to-day physiological variations. By calculating the ratio of impedances, the difference between individual subjects was amplified and the spectral patterns were diversified. Overall, our ratiometric analysis of impedance improved the classification accuracy of 41 subjects and reduced the error rate of classification from 29.32% to 5.86% (by a factor of 5).
Evidence of a Causal Association Between Cancer and Alzheimer’s Disease: a Mendelian Randomization Analysis
Authors: Seddighi Sahba , Houck Alexander L. , Rowe James B. , Pharoah Paul D. P.
Published: September 2019

While limited observational evidence suggests that cancer survivors have a decreased risk of developing Alzheimer’s disease (AD), and vice versa, it is not clear whether this relationship is causal. Using a Mendelian randomization approach that provides evidence of causality, we found that genetically predicted lung cancer (OR 0.91, 95% CI 0.84–0.99, p = 0.019), leukemia (OR 0.98, 95% CI 0.96–0.995, p = 0.012), and breast cancer (OR 0.94, 95% CI 0.89–0.99, p = 0.028) were associated with 9.0%, 2.4%, and 5.9% lower odds of AD, respectively, per 1-unit higher log odds of cancer. When genetic predictors of all cancers were pooled, cancer was associated with 2.5% lower odds of AD (OR 0.98, 95% CI 0.96–0.988, p = 0.00027) per 1-unit higher log odds of cancer. Finally, genetically predicted smoking-related cancers showed a more robust inverse association with AD than non-smoking related cancers (OR 0.95, 95% CI 0.92–0.98, p = 0.0026, vs. OR 0.98, 95% CI 0.97–0.995, p = 0.0091).
Maternal cadmium exposure in the mouse leads to increased heart weight at birth and programs susceptibility to hypertension in adulthood
Authors: Hudson Kathleen M. , Belcher Scott M. , Cowley Michael
Published: September 2019

Cadmium (Cd) is a toxic heavy metal ubiquitous in the environment. Maternal exposure to Cd is associated with fetal growth restriction, trace element deficiencies, and congenital malformations. Cd exposure during adulthood is associated with cardiovascular disease (CVD); however, the effects of maternal Cd exposure on offspring cardiovascular development and disease are not well-understood. Utilizing a mouse model of maternal Cd exposure, we show that offspring born to Cd-exposed mothers have increased heart weights at birth and susceptibility to hypertension during adulthood. Despite inefficient maternal-fetal transfer of Cd, maternal Cd alters fetal levels of essential trace elements including a deficiency in iron, which is required for cardiovascular system development, oxygen homeostasis, and cellular metabolism. RNA-seq on newborn hearts identifies differentially expressed genes associated with maternal Cd exposure that are enriched for functions in CVD, hypertension, enlarged hearts, cellular energy, and hypoxic stress. We propose that a maternal Cd exposure-induced iron deficiency leads to altered cellular metabolic pathways and hypoxic conditions during fetal development; this stress may contribute to increased heart weight at birth and the programming of susceptibility to hypertension in adulthood. These studies will give insights into potential mechanisms through which maternal Cd exposure impacts cardiovascular development and disease.
Active acoustic illusions for stealth and subterfuge
Authors: Eggler Daniel , Kessissoglou Nicole
Published: September 2019

Acoustic illusion devices present a novel approach for defeating detection systems such as sonar by misrepresenting information about the target. These devices are currently designed for a predetermined illusion using metamaterials. We present the first active acoustic illusion utilizing monopole control sources and error sensors arranged circumferentially around a rigid object to generate the desired illusion in the global acoustic field. We also utilize control sources and error sensors in a line array to generate an illusion in the forward-scatter region of the object. Multiple types of illusions are achieved for a given control configuration.
Genomic diversity, linkage disequilibrium and selection signatures in European local pig breeds assessed with a high density SNP chip
Authors: Muñoz M. , Bozzi R. , García-Casco J. , Núñez Y. , Ribani A. , Franci O. , García F. , Škrlep M. , Schiavo G. , Bovo S. , Utzeri V. J. , Charneca R. , Martins J. M. , Quintanilla R. , Tibau J. , Margeta V. , Djurkin-Kušec I. , Mercat M. J. , Riquet J. , Estellé J. , Zimmer C. , Razmaite V. , Araujo J. P. , Radović Č. , Savić R. , Karolyi D. , Gallo M. , Čandek-Potokar M. , Fernández A. I. , Fontanesi L. , Óvilo C.
Published: September 2019

Genetic characterization of local breeds is essential to preserve their genomic variability, to advance conservation policies and to contribute to their promotion and sustainability. Genomic diversity of twenty European local pig breeds and a small sample of Spanish wild pigs was assessed using high density SNP chips. A total of 992 DNA samples were analyzed with the GeneSeek Genomic Profiler (GGP) 70 K HD porcine genotyping chip. Genotype data was employed to compute genetic diversity, population differentiation and structure, genetic distances, linkage disequilibrium and effective population size. Our results point out several breeds, such as Turopolje, Apulo Calabrese, Casertana, Mora Romagnola and Lithuanian indigenous wattle, having the lowest genetic diversity, supported by low heterozygosity and very small effective population size, demonstrating the need of enhanced conservation strategies. Principal components analysis showed the clustering of the individuals of the same breed, with few breeds being clearly isolated from the rest. Several breeds were partially overlapped, suggesting genetic closeness, which was particularly marked in the case of Iberian and Alentejana breeds. Spanish wild boar was also narrowly related to other western populations, in agreement with recurrent admixture between wild and domestic animals. We also searched across the genome for loci under diversifying selection based on FSToutlier tests. Candidate genes that may underlie differences in adaptation to specific environments and productive systems and phenotypic traits were detected in potentially selected genomic regions.
Atroposelective antibodies as a designed protein scaffold for artificial metalloenzymes
Authors: Adachi Takuma , Harada Akira , Yamaguchi Hiroyasu
Published: September 2019

Design and engineering of protein scaffolds are crucial to create artificial metalloenzymes. Herein we report the first example of C-C bond formation catalyzed by artificial metalloenzymes, which consist of monoclonal antibodies (mAbs) and C2 symmetric metal catalysts. Prepared as a tailored protein scaffold for a binaphthyl derivative (BN), mAbs bind metal catalysts bearing a 1,1′-bi-isoquinoline (BIQ) ligand to yield artificial metalloenzymes. These artificial metalloenzymes catalyze the Friedel-Crafts alkylation reaction. In the presence of mAb R44E1, the reaction proceeds with 88% ee. The reaction catalyzed by Cu-catalyst incorporated into the binding site of mAb R44E1 is found to show excellent enantioselectivity with 99% ee. The protein environment also enables the use of BIQ-based catalysts as asymmetric catalysts for the first time.
Targeted multiplex proteomics for molecular prescreening and biomarker discovery in metastatic colorectal cancer
Authors: Serna Garazi , Ruiz-Pace Fiorella , Cecchi Fabiola , Fasani Roberta , Jimenez Jose , Thyparambil Sheeno , Landolfi Stefania , Elez Elena , Vivancos Ana , Hembrough Todd , Tabernero Josep , Dienstmann Rodrigo , Nuciforo Paolo
Published: September 2019

Protein biomarkers are widely used in cancer diagnosis, prognosis, and prediction of treatment response. Here we introduce the use of targeted multiplex proteomics (TMP) as a tool to simultaneously measure a panel of 54 proteins involved in oncogenic, tumour suppression, drug metabolism and resistance, in patients with metastatic colorectal cancer (mCRC). TMP provided valuable diagnostic information by unmasking an occult neuroendocrine differentiation and identifying a misclassified case based on abnormal proteins phenotype. No significant differences in protein levels between unpaired primary and metastatic samples were observed. Four proteins were found differentially expressed in KRAS-mutant as compared to wild-type tumours (overexpressed in mutant: KRAS, EGFR; overexpressed in wild-type: TOPO1, TOP2A). Survival analyses revealed the association between mesothelin expression and poor overall survival, whereas lack of PTEN protein expression associated with lower progression-free survival with anti-EGFR-based therapy in the first-line setting for patients with RAS wild-type tumour. Finally, outlier analysis identified putative targetable proteins in 65% of patients lacking a targetable genomic alteration. Our data show that TMP constitutes a promising, novel molecular prescreening tool in mCRC to identify protein expression alterations that may impact on patient outcomes and more precisely guide patient eligibility to clinical trials with novel targeted experimental therapies.
Analyzing expression and phosphorylation of the EGF receptor in HNSCC
Authors: Kriegs Malte , Clauditz Till Sebastian , Hoffer Konstantin , Bartels Joanna , Buhs Sophia , Gerull Helwe , Zech Henrike Barbara , Bußmann Lara , Struve Nina , Rieckmann Thorsten , Petersen Cordula , Betz Christian Stephan , Rothkamm Kai , Nollau Peter , Münscher Adrian
Published: September 2019

Overexpression of the epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinomas (HNSCC) is considered to cause increased EGFR activity, which adds to tumorigenicity and therapy resistance. Since it is still unclear, whether EGFR expression is indeed associated with increased activity in HNSCC, we analyzed the relationship between EGFR expression and auto-phosphorylation as a surrogate marker for activity. We used a tissue micro array, fresh frozen HNSCC tumor and corresponding normal tissue samples and a large panel of HNSCC cell lines. While we observed substantial overexpression only in approximately 20% of HNSCC, we also observed strong discrepancies between EGFR protein expression and auto-phosphorylation in HNSCC cell lines as well as in tumor specimens using Western blot and SH2-profiling; for the majority of HNSCC EGFR expression therefore seems not to be correlated with EGFR auto-phosphorylation. Blocking of EGFR activity by cetuximab and erlotinib points to increased EGFR activity in samples with increased basal auto-phosphorylation. However, we could also identify cells with low basal phosphorylation but relevant EGFR activity. In summary, our data demonstrate that EGFR expression and activity are not well correlated. Therefore EGFR positivity is no reliable surrogate marker for EGFR activity, arguing the need for alternative biomarkers or functional predictive tests.
Structural Brain Correlates of Loneliness among Older Adults
Authors: Düzel Sandra , Drewelies Johanna , Gerstorf Denis , Demuth Ilja , Steinhagen-Thiessen Elisabeth , Lindenberger Ulman , Kühn Simone
Published: September 2019

Ample evidence indicates that loneliness in old age is associated with poor bodily and mental health. However, little is known about structural cerebral correlates of loneliness in healthy older adults. We examined such correlates in a magnetic resonance imaging (MRI) subsample of 319 older adults aged 61 to 82 years drawn from the Berlin Aging Study II. Using voxel-based morphometry (VBM) and structural equation modeling (SEM), latent hierarchical regression analyses were performed to examine associations of (i) loneliness, (ii) a range of covariates, and (iii) loneliness by covariate interactions with latent brain volume estimates of brain structures known to be involved in processing, expressing, and regulating emotions. Results from whole-brain VBM analyses showed that individuals with higher loneliness scores tended to have smaller gray matter volumes in three clusters comprising (i) the left amygdala/anterior hippocampus, (ii) the left posterior parahippocampus and (iii) the left cerebellum. Significant associations and interactions between loneliness and latent factors for the amygdala and the hippocampus were confirmed with a region-of-interest (ROI)-based approach. These findings suggest that individual differences in loneliness among older adults are correlated with individual differences in the volumes of brain regions that are central to cognitive processing and emotional regulation, also after correcting for confounders such as social network size. We discuss possible mechanisms underlying these associations and their implications.
One Step Fabrication of Highly Absorptive and Surface Enhanced Raman Scattering (SERS) Silver Nano-trees on Silicon Substrate
Authors: Razek Sara Abdel , Ayoub Ahmed B. , Swillam Mohamed A.
Published: September 2019

Silver Nano-trees (AgNTs) were synthesized by one-step electroless method with different densities via water or ethylene glycol (EG) on silicon substrate in one minute. The density of AgNTs is controlled by changing the concentration of silver nitrate in etchant solution. The absorption of NTs fabricated via EG is higher than absorption of NTs without EG. The AgNTs are employed as substrates for surface-enhanced Raman scattering (SERS) and exhibit high sensitivity. The silver Nano-trees fabricated via ethylene glycol (AgNTs-EG) enhances the Raman spectrum of pyridine (Py) with higher enhancement factor. Moreover, the SERS-active substrates prepared by using EG were able to detect Pyridine with concentration as low as 0.005 mM, the ones fabricated by water could only detect Pyridine at concentration of 0.2 mM.
IgA-deficient humans exhibit gut microbiota dysbiosis despite secretion of compensatory IgM
Authors: Catanzaro Jason R. , Strauss Juliet D. , Bielecka Agata , Porto Anthony F. , Lobo Francis M. , Urban Andrea , Schofield Whitman B. , Palm Noah W.
Published: September 2019

Immunoglobulin A is the dominant antibody isotype found in mucosal secretions and enforces host-microbiota symbiosis in mice, yet selective IgA-deficiency (sIgAd) in humans is often described as asymptomatic. Here, we determined the effects of IgA deficiency on human gut microbiota composition and evaluated the possibility that mucosal secretion of IgM can compensate for a lack of secretory IgA. We used 16S rRNA gene sequencing and bacterial cell sorting to evaluate gut microbiota composition and taxa-specific antibody coating of the gut microbiota in 15 sIgAd subjects and matched controls. Despite the secretion of compensatory IgM into the gut lumen, sIgAd subjects displayed an altered gut microbiota composition as compared to healthy controls. These alterations were characterized by a trend towards decreased overall microbial diversity as well as significant shifts in the relative abundances of specific microbial taxa. While secretory IgA in healthy controls targeted a defined subset of the microbiota via high-level coating, compensatory IgM in sIgAd subjects showed less specificity than IgA and bound a broader subset of the microbiota. We conclude that IgA plays a critical and non-redundant role in controlling gut microbiota composition in humans and that secretory IgA has evolved to maintain a diverse and stable gut microbial community.
Resiliency of Mutualistic Supplier-Manufacturer Networks
Authors: Xu Mengkai , Radhakrishnan Srinivasan , Kamarthi Sagar , Jin Xiaoning
Published: September 2019

Current Supplier-Manufacturer (SM) networks are highly complex and susceptible to local and global disruptions, due to connectivity and interdependency among suppliers and manufacturers. Resiliency of supply chains is critical for organizations to remain operational in the face of disruptive events. Existing quantitative analyses oversimplify the mutualistic nature of SM networks, in which failure of individual entities affects not only the directly connected entities but also those connected indirectly. In this work we investigate resiliency of SM networks using the quantitative methods employed to study mutualistic ecological systems. Much like in ecological systems, catastrophic failures of SM networks are difficult to predict due to high dimensionality of their interactive space. To address this, first we create a bipartite representation and generate a multidimensional nonlinear model that captures the dynamics of a SM network. We transform the multidimensional model into a two-dimensional model without sacrificing the model’s ability to predict the point of collapse. We extensively validate the model using real-world global automotive SM networks. We observe that the resiliency of a SM network depends on both the network structure and parameters. The current work offers a means for designing resilient supply chains that can remain robust to local and global perturbations.
Bulk superconductivity in a four-layer-type Bi-based compound La2O2Bi3Ag0.6Sn0.4S5.7Se0.3
Authors: Jha Rajveer , Goto Yosuke , Matsuda Tatsuma D. , Aoki Yuji , Nagao Masanori , Tanaka Isao , Mizuguchi Yoshikazu
Published: September 2019

Recently, we reported the observation of superconductivity at ~0.5 K in a La2O2M4S6-type (M: metal) layered compound La2O2Bi3AgS6, which is a layered system related to the BiS2-based superconductor system but possesses a thicker Bi3AgS6-type conducting layer. In this study, we have developed the La2O2Bi3AgS6-type materials by element substitutions to increase the transition temperature (Tc) and to induce bulk nature of superconductivity. A resistivity anomaly observed at 180 K in La2O2Bi3AgS6 was systematically suppressed by Sn substitution for the Ag site. By the Sn substitution, Tc increased, and the shielding volume fraction estimated from magnetization measurements also increased. The highest Tc (=2.3 K) and the highest shielding volume fraction (~20%) was observed for La2O2Bi3Ag0.6Sn0.4S6. The superconducting properties were further improved by Se substitutions for the S site. By the combinational substitutions of Sn and Se, bulk-superconducting phase of La2O2Bi3Ag0.6Sn0.4S5.7Se0.3 with a Tc of 3.0 K (Tconset = 3.6 K) was obtained.