bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death
Authors: Houl Jerry H. , Ye Zu , Brosey Chris A. , Balapiti-Modarage Lakshitha P. F. , Namjoshi Sarita , Bacolla Albino , Laverty Daniel , Walker Brian L. , Pourfarjam Yasin , Warden Leslie S. , Babu Chinnam Naga , Moiani Davide , Stegeman Roderick A. , Chen Mei-Kuang , Hung Mien-Chie , Nagel Zachary D. , Ellenberger Tom , Kim In-Kwon , Jones Darin E. , Ahmed Zamal , Tainer John A.
Published: December 2019

Poly(ADP-ribose)ylation (PARylation) by PAR polymerase 1 (PARP1) and PARylation removal by poly(ADP-ribose) glycohydrolase (PARG) critically regulate DNA damage responses; yet, conflicting reports obscure PARG biology and its impact on cancer cell resistance to PARP1 inhibitors. Here, we found that PARG expression is upregulated in many cancers. We employed chemical library screening to identify and optimize methylxanthine derivatives as selective bioavailable PARG inhibitors. Multiple crystal structures reveal how substituent positions on the methylxanthine core dictate binding modes and inducible-complementarity with a PARG-specific tyrosine clasp and arginine switch, supporting inhibitor specificity and a competitive inhibition mechanism. Cell-based assays show selective PARG inhibition and PARP1 hyperPARylation. Moreover, our PARG inhibitor sensitizes cells to radiation-induced DNA damage, suppresses replication fork progression and impedes cancer cell survival. In PARP inhibitor-resistant A172 glioblastoma cells, our PARG inhibitor shows comparable killing to Nedaplatin, providing further proof-of-concept that selectively inhibiting PARG can impair cancer cell survival.
DNA methylation directs microRNA biogenesis in mammalian cells
Authors: Glaich Ohad , Parikh Shivang , Bell Rachel E. , Mekahel Keren , Donyo Maya , Leader Yodfat , Shayevitch Ronna , Sheinboim Danna , Yannai Sivan , Hollander Dror , Melamed Ze’ev , Lev-Maor Galit , Ast Gil , Levy Carmit
Published: December 2019

MicroRNA (miRNA) biogenesis initiates co-transcriptionally, but how the Microprocessor machinery pinpoints the locations of short precursor miRNA sequences within long flanking regions of the transcript is not known. Here we show that miRNA biogenesis depends on DNA methylation. When the regions flanking the miRNA coding sequence are highly methylated, the miRNAs are more highly expressed, have greater sequence conservation, and are more likely to drive cancer-related phenotypes than miRNAs encoded by unmethylated loci. We show that the removal of DNA methylation from miRNA loci leads to their downregulation. Further, we found that MeCP2 binding to methylated miRNA loci halts RNA polymerase II elongation, leading to enhanced processing of the primary miRNA by Drosha. Taken together, our data reveal that DNA methylation directly affects miRNA biogenesis.
BRCA1 intronic Alu elements drive gene rearrangements and PARP inhibitor resistance
Authors: Wang Yifan , Bernhardy Andrea J. , Nacson Joseph , Krais John J. , Tan Yin-Fei , Nicolas Emmanuelle , Radke Marc R. , Handorf Elizabeth , Llop-Guevara Alba , Balmaña Judith , Swisher Elizabeth M. , Serra Violeta , Peri Suraj , Johnson Neil
Published: December 2019

BRCA1 mutant carcinomas are sensitive to PARP inhibitor (PARPi) therapy; however, resistance arises. BRCA1 BRCT domain mutant proteins do not fold correctly and are subject to proteasomal degradation, resulting in PARPi sensitivity. In this study, we show that cell lines and patient-derived tumors, with highly disruptive BRCT domain mutations, have readily detectable BRCA1 protein expression, and are able to proliferate in the presence of PARPi. Peptide analyses reveal that chemo-resistant cancers contain residues encoded by BRCA1 intron 15. Mechanistically, cancers with BRCT domain mutations harbor BRCA1 gene breakpoints within or adjacent to Alu elements in intron 15; producing partial gene duplications, inversions and translocations, and terminating transcription prior to the mutation-containing BRCT domain. BRCA1 BRCT domain-deficient protein isoforms avoid mutation-induced proteasomal degradation, support homology-dependent DNA repair, and promote PARPi resistance. Taken together, Alu-mediated BRCA1 gene rearrangements are responsible for generating hypomorphic proteins, and may represent a biomarker of PARPi resistance.
The autophagy receptor p62/SQST-1 promotes proteostasis and longevity in C. elegans by inducing autophagy
Authors: Kumsta Caroline , Chang Jessica T. , Lee Reina , Tan Ee Phie , Yang Yongzhi , Loureiro Rute , Choy Elizabeth H. , Lim Shaun H. Y. , Saez Isabel , Springhorn Alexander , Hoppe Thorsten , Vilchez David , Hansen Malene
Published: December 2019

Autophagy can degrade cargos with the help of selective autophagy receptors such as p62/SQSTM1, which facilitates the degradation of ubiquitinated cargo. While the process of autophagy has been linked to aging, the impact of selective autophagy in lifespan regulation remains unclear. We have recently shown in Caenorhabditis elegans that transcript levels of sqst-1/p62 increase upon a hormetic heat shock, suggesting a role of SQST-1/p62 in stress response and aging. Here, we find that sqst-1/p62 is required for hormetic benefits of heat shock, including longevity, improved neuronal proteostasis, and autophagy induction. Furthermore, overexpression of SQST-1/p62 is sufficient to induce autophagy in distinct tissues, extend lifespan, and improve the fitness of mutants with defects in proteostasis in an autophagy-dependent manner. Collectively, these findings illustrate that increased expression of a selective autophagy receptor is sufficient to induce autophagy, enhance proteostasis and extend longevity, and demonstrate an important role for sqst-1/p62 in proteotoxic stress responses.
Ensemble representations reveal distinct neural coding of visual working memory
Authors: Oh Byung-Il , Kim Yee-Joon , Kang Min-Suk
Published: December 2019

We characterized the population-level neural coding of ensemble representations in visual working memory from human electroencephalography. Ensemble representations provide a unique opportunity to investigate structured representations of working memory because the visual system encodes high-order summary statistics as well as noisy sensory inputs in a hierarchical manner. Here, we consistently observe stable coding of simple features as well as the ensemble mean in frontocentral electrodes, which even correlated with behavioral indices of the ensemble across individuals. In occipitoparietal electrodes, however, we find that remembered features are dynamically coded over time, whereas neural coding of the ensemble mean is absent in the old/new judgment task. In contrast, both dynamic and stable coding are found in the continuous estimation task. Our findings suggest that the prefrontal cortex holds behaviorally relevant abstract representations while visual representations in posterior and visual areas are modulated by the task demands.
Extracellular matrix hydrogel derived from decellularized tissues enables endodermal organoid culture
Authors: Giobbe Giovanni Giuseppe , Crowley Claire , Luni Camilla , Campinoti Sara , Khedr Moustafa , Kretzschmar Kai , De Santis Martina Maria , Zambaiti Elisa , Michielin Federica , Meran Laween , Hu Qianjiang , van Son Gijs , Urbani Luca , Manfredi Anna , Giomo Monica , Eaton Simon , Cacchiarelli Davide , Li Vivian S. W. , Clevers Hans , Bonfanti Paola , Elvassore Nicola , De Coppi Paolo
Published: December 2019

Organoids have extensive therapeutic potential and are increasingly opening up new avenues within regenerative medicine. However, their clinical application is greatly limited by the lack of effective GMP-compliant systems for organoid expansion in culture. Here, we envisage that the use of extracellular matrix (ECM) hydrogels derived from decellularized tissues (DT) can provide an environment capable of directing cell growth. These gels possess the biochemical signature of tissue-specific ECM and have the potential for clinical translation. Gels from decellularized porcine small intestine (SI) mucosa/submucosa enable formation and growth of endoderm-derived human organoids, such as gastric, hepatic, pancreatic, and SI. ECM gels can be used as a tool for direct human organoid derivation, for cell growth with a stable transcriptomic signature, and for in vivo organoid delivery. The development of these ECM-derived hydrogels opens up the potential for human organoids to be used clinically.
Acyl radical to rhodacycle addition and cyclization relay to access butterfly flavylium fluorophores
Authors: Yin Jiangliang , Zhang Yuming , Li Jian , Zhu Lei , Lan Yu , You Jingsong
Published: December 2019

Transition metal-catalyzed C–H activation and radical reactions are two versatile strategies to construct diverse organic skeletons. Here we show the construction of a class of flavylium fluorophores via the merge of radical chemistry and C–H activation starting from (hetero)aryl ketones and alkynes. This protocol is not only applicable to aryl ketones but also to heteroaryl ketones such as thiophene, benzothiophene and benzofuran, thus leading to structural diversity. Mechanism studies, including control experiments, intermediate separation, radical trapping, EPR and ESI-HRMS experiments, demonstrate that the key step lies in the addition of the acyl radical generated by the copper-catalyzed C–C bond cleavage of aryl ketone to the rhodacycle formed via the C–H activation of aryl ketone. The flavylium fluorophores feature butterfly symmetrical configuration, nearly planar skeleton and delocalized positive charge, and exhibit intriguing photophysical properties, such as tunable absorption and emission wavelengths and high quantum yields.
Trained immunity modulates inflammation-induced fibrosis
Authors: Jeljeli Mohamed , Riccio Luiza Gama Coelho , Doridot Ludivine , Chêne Charlotte , Nicco Carole , Chouzenoux Sandrine , Deletang Quentin , Allanore Yannick , Kavian Niloufar , Batteux Frédéric
Published: December 2019

Chronic inflammation and fibrosis can result from inappropriately activated immune responses that are mediated by macrophages. Macrophages can acquire memory-like characteristics in response to antigen exposure. Here, we show the effect of BCG or low-dose LPS stimulation on macrophage phenotype, cytokine production, chromatin and metabolic modifications. Low-dose LPS training alleviates fibrosis and inflammation in a mouse model of systemic sclerosis (SSc), whereas BCG-training exacerbates disease in this model. Adoptive transfer of low-dose LPS-trained or BCG-trained macrophages also has beneficial or harmful effects, respectively. Furthermore, coculture with low-dose LPS trained macrophages reduces the fibro-inflammatory profile of fibroblasts from mice and patients with SSc, indicating that trained immunity might be a phenomenon that can be targeted to treat SSc and other autoimmune and inflammatory fibrotic disorders.
Report from a multidisciplinary meeting on anxiety as a non-motor manifestation of Parkinson’s disease
Authors: Pontone Gregory M. , Dissanayaka Nadeeka , Apostolova Liana , Brown Richard G. , Dobkin Roseanne , Dujardin Kathy , Friedman Joseph H. , Leentjens Albert F. G. , Lenze Eric J. , Marsh Laura , Mari Lynda , Monchi Oury , Richard Irene H. , Schrag Anette , Strafella Antonio P. , Vernaleo Beth , Weintraub Daniel , Mari Zoltan
Published: December 2019

Anxiety is a severe problem for at least one-third of people living with Parkinson’s disease (PD). Anxiety appears to have a greater adverse impact on quality of life than motor impairment. Despite its high prevalence and impact on daily life, anxiety is often undiagnosed and untreated. To better address anxiety in PD, future research must improve knowledge about the mechanism of anxiety in PD and address the lack of empirical evidence from clinical trials. In response to these challenges, the Parkinson’s Foundation sponsored an expert meeting on anxiety on June 13th and 14th 2018. This paper summarizes the findings from that meeting informed by a review of the existing literature and discussions among patients, caregivers, and an international, clinician-scientist, expert panel working group. The goal is to provide recommendations to improve our understanding and treatment of anxiety in PD.
Activity of M3814, an Oral DNA-PK Inhibitor, In Combination with Topoisomerase II Inhibitors in Ovarian Cancer Models
Authors: Wise Hannah C. , Iyer Gopakumar V. , Moore Kathleen , Temkin Sarah M. , Gordon Sarah , Aghajanian Carol , Grisham Rachel N.
Published: December 2019

DNA-dependent protein kinase (DNA-PK) has been shown to play a crucial role in repair of DNA double-strand breaks, facilitating nonhomologous end-joining. DNA-PK inhibitors have the potential to block DNA repair and therefore enhance DNA-damaging agents. M3814 is a DNA-PK inhibitor that has shown preclinical activity in combination with DNA-damaging agents, including radiotherapy and topoisomerase II inhibitors. Here we evaluated the activity of M3814 in combination with multiple topoisomerase II inhibitors, doxorubicin, etoposide, and pegylated liposomal doxorubicin (PLD) in vivo, utilizing ovarian cancer xenografts. Using cell lines representative of P53 wild-type ovarian cancer (A2780), and P53 mutant ovarian cancer (SKOV3), cells were implanted in the flank of athymic nude female mice. Mice were treated with vehicle, M3814 alone, topoisomerase II inhibitor alone, and M3814 in combination with topoisomerase II inhibitor, and change in tumor volume over time was documented. The addition of M3814 was well tolerated. We demonstrated that M3814 shows limited efficacy as a single agent in ovarian cancer models. The combination of M3814 with PLD showed enhanced activity over PLD as a single agent. Further study of this combination is warranted.
Pregnancy vulnerability in urban areas: a pragmatic approach combining behavioral, medico-obstetrical, socio-economic and environmental factors
Authors: Brembilla Alice , Bernard Nadine , Pujol Sophie , Parmentier Anne-Laure , Eckman Astrid , Mariet Anne-Sophie , Houot Hélène , Tenailleau Quentin , Thiriez Gérard , Riethmuller Didier , Barba-Vasseur Marie , Mauny Frédéric
Published: December 2019

Multiple risk factors are associated with adverse pregnancy outcomes (APO), but how all these different factors combine and accumulate remains unknown. The objective of this observational retrospective study was to describe the accumulation of multiple vulnerability markers in pregnant women living in an urban area. Women living in Besançon (France) who delivered between 2005 and 2009 were included. Individual data were collected from the obstetrical records while environmental exposures were collected using environmental prediction models. The accumulation of 15 vulnerability markers, grouped into six dimensions (maternal age, smoking, body mass index (BMI), socio-economic, medico-obstetrical and environmental vulnerabilities) was described and analyzed in comparison with four APO. Among the 3686 included women, 20.8% were aged under 20 or over 34 and 21.9% had an extreme pre-pregnancy BMI. 18.8% declared smoking during pregnancy. Women exposed to socio-economic, medico-obstetrical or environmental vulnerability were 14.2%, 31.6% and 42.4% respectively. While 20.6% were not exposed to any marker, 18.8% accumulated three or more dimensions. The risk of APO increased significantly with the cumulative number of vulnerabilities. Define and validate a vulnerability score could be useful to identify vulnerable women, adapt their pregnancy monitoring and help policy makers to implement appropriate education or health promotion programs.
Birdlike growth and mixed-age flocks in avimimids (Theropoda, Oviraptorosauria)
Authors: Funston G. F. , Currie P. J. , Ryan M. J. , Dong Z.-M.
Published: December 2019

Avimimids were unusual, birdlike oviraptorosaurs from the Late Cretaceous of Asia. Initially enigmatic, new information has ameliorated the understanding of their anatomy, phylogenetic position, and behaviour. A monodominant bonebed from the Nemegt Formation of Mongolia showed that some avimimids were gregarious, but the site is unusual in the apparent absence of juveniles. Here, a second monodominant avimimid bonebed is described from the Iren Dabasu Formation of northern China. Elements recovered include numerous vertebrae and portions of the forelimbs and hindlimbs, representing a minimum of six individuals. Histological sampling of two tibiotarsi from the bonebed reveals rapid growth early in ontogeny followed by unexpectedly early onset of fusion and limited subsequent growth. This indicates that avimimids grew rapidly to adult size, like most extant birds but contrasting other small theropod dinosaurs. The combination of adults and juveniles in the Iren Dabasu bonebed assemblage provides evidence of mixed-age flocking in avimimids and the onset of fusion in young individuals suggests that some of the individuals in the Nemegt Formation bonebed may have been juveniles. Regardless, these individuals were likely functionally analogous to adults, and this probably facilitated mixed-age flocking by reducing ontogenetic niche shift in avimimids.
Hollow PdAg-CeO2 heterodimer nanocrystals as highly structured heterogeneous catalysts
Authors: Patarroyo Javier , Delgado Jorge A. , Merkoçi Florind , Genç Aziz , Sauthier Guillaume , Llorca Jordi , Arbiol Jordi , Bastus Neus G. , Godard Cyril , Claver Carmen , Puntes Victor
Published: December 2019

In the present work, hollow PdAg-CeO2 heterodimer nanocrystals (NCs) were prepared and tested as catalysts for the selective hydrogenation of alkynes. These nanostructures combine for the first time the beneficial effect of alloying Pd with Ag in a single NC hollow domain with the formation of active sites at the interface with the CeO2 counterpart in an additive manner. The PdAg-CeO2 NCs display excellent alkene selectivity for aliphatic alkynes. For the specific case of hydrogenation of internal alkynes such as 4-octyne, very low over-hydrogenation and isomerization products were observed over a full conversion regime, even after prolonged reaction times. These catalytic properties were remarkably superior in comparison to standard catalysts. The promotion of Ag on the moderation of the reactivity of the Pd phase, in combination with the creation of interfacial sites with the CeO2 moiety in the same nanostructure, is pointed as the responsible of such a remarkable catalytic performance.
Systemic inhibition of tissue-nonspecific alkaline phosphatase alters the brain-immune axis in experimental sepsis
Authors: Brichacek Allison L. , Benkovic Stanley A. , Chakraborty Sreeparna , Nwafor Divine C. , Wang Wei , Jun Sujung , Dakhlallah Duaa , Geldenhuys Werner J. , Pinkerton Anthony B. , Millán José Luis , Brown Candice M.
Published: December 2019

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitous enzyme present in many cells and tissues, including the central nervous system. Yet its functions at the brain-immune axis remain unclear. The goal of this study was to use a novel small molecular inhibitor of TNAP, SBI-425, to interrogate the function of TNAP in neuroimmune disorders. Following intraperitoneal (IP) administration of SBI-425, mass spectrometry analysis revealed that the SBI-425 does not cross the blood-brain barrier (BBB) in healthy mice. To elucidate the role of TNAP at the brain-immune axis, mice were subjected to experimental sepsis and received either vehicle or SBI-425 (25 mg/kg, IP) daily for 7 days. While SBI-425 administration did not affect clinical severity outcomes, we found that SBI-425 administration suppressed CD4 + Foxp3+ CD25− and CD8 + Foxp3+ CD25− splenocyte T-cell populations compared to controls. Further evaluation of SBI-425’s effects in the brain revealed that TNAP activity was suppressed in the brain parenchyma of SBI-425-treated mice compared to controls. When primary brain endothelial cells were treated with a proinflammatory stimulus the addition of SBI-425 treatment potentiated the loss of barrier function in BBB endothelial cells. To further demonstrate a protective role for TNAP at endothelial barriers within this axis, transgenic mice with a conditional overexpression of TNAP were subjected to experimental sepsis and found to have increased survival and decreased clinical severity scores compared to controls. Taken together, these results demonstrate a novel role for TNAP activity in shaping the dynamic interactions within the brain-immune axis.
Uppermost Triassic phosphorites from Williston Lake, Canada: link to fluctuating euxinic-anoxic conditions in northeastern Panthalassa before the end-Triassic mass extinction
Authors: Larina Ekaterina , Bottjer David J. , Corsetti Frank A. , Zonneveld John-Paul , Celestian Aaron J. , Bailey Jake V.
Published: December 2019

The end-Triassic mass extinction (ETE) is associated with a rise in CO2 due to eruptions of the Central Atlantic Magmatic Province (CAMP), and had a particularly dramatic effect on the Modern Fauna, so an understanding of the conditions that led to the ETE has relevance to current rising CO2 levels. Here, we report multiple phosphorite deposits in strata that immediately precede the ETE at Williston Lake, Canada, which allow the paleoenvironmental conditions leading up to the mass extinction to be investigated. The predominance of phosphatic coated grains within phoshorites indicates reworking in shallow water environments. Raman spectroscopy reveals that the phosphorites contain organic carbon, and petrographic and scanning electron microscopic analyses reveal that the phosphorites contain putative microfossils, potentially suggesting microbial involvement in a direct or indirect way. Thus, we favor a mechanism of phosphogenesis that involves microbial polyphosphate metabolism in which phosphatic deposits typically form at the interface of euxinic/anoxic and oxic conditions. When combined with data from deeper water deposits (Kennecott Point) far to the southwest, it would appear a very broad area of northeastern Panthalassa experienced anoxic to euxinic bottom water conditions in the direct lead up to the end-Triassic mass extinction. Such a scenario implies expansion and shallowing of the oxygen minimum zone across a very broad area of northeastern Panthalassa, which potentially created a stressful environment for benthic metazoan communities. Studies of the pre-extinction interval from different sites across the globe are required to resolve the chronology and spatial distribution of processes that governed before the major environmental collapse that caused the ETE. Results from this study demonstrate that fluctuating anoxic and euxinic conditions could have been potentially responsible for reduced ecosystem stability before the onset of CAMP volcanism, at least at the regional scale.
Equivalent circuit parameters of planar transmission lines with spoof surface plasmon polaritons and its application in high density circuits
Authors: Wu Chia Ho , Shen Linfang , Zhang Hang , Yan Jinhua , Hou Da Jun , Zhou Guobing , Wu Yu Lin
Published: December 2019

In this paper, the characteristics of a class of transmission lines which support spoof surface plasmon polaritons are investigated both numerically and experimentally. In order to provide the characteristic impedance of spoof surface plasmon polaritons for PCB designers, the equivalent circuit parameters of the microstrip line periodically structured on subwavelength scale are extracted with the numerical method. It is found that the equivalent circuit parameters significantly vary with frequency when the subwavelength periodic structure is introduced into the edge of the conventional microstrip line. The results of time-domain measurements show that spoof surface plasmon polaritons have remarkable advantage over conventional microstrip lines and can be directly used in actual high-speed circuits, which is helpful for eliminating the doubts whether the metamaterials can be directly used in actual circuits.
MAP2K1 is a potential therapeutic target in erlotinib resistant head and neck squamous cell carcinoma
Authors: Jain Ankit P. , Patel Krishna , Pinto Sneha , Radhakrishnan Aneesha , Nanjappa Vishalakshi , Kumar Manish , Raja Remya , Patil Arun H. , Kumari Anjali , Manoharan Malini , Karunakaran Coral , Murugan Saktivel , Keshava Prasad T. S. , Chang Xiaofei , Mathur Premendu Prakash , Kumar Prashant , Gupta Ravi , Gupta Rohit , Khanna-Gupta Arati , Sidransky David , Chatterjee Aditi , Gowda Harsha
Published: December 2019

Epidermal growth factor receptor (EGFR) targeted therapies have shown limited efficacy in head and neck squamous cell carcinoma (HNSCC) patients despite its overexpression. Identifying molecular mechanisms associated with acquired resistance to EGFR-TKIs such as erlotinib remains an unmet need and a therapeutic challenge. In this study, we employed an integrated multi-omics approach to delineate mechanisms associated with acquired resistance to erlotinib by carrying out whole exome sequencing, quantitative proteomic and phosphoproteomic profiling. We observed amplification of several genes including AXL kinase and transcription factor YAP1 resulting in protein overexpression. We also observed expression of constitutively active mutant MAP2K1 (p.K57E) in erlotinib resistant SCC-R cells. An integrated analysis of genomic, proteomic and phosphoproteomic data revealed alterations in MAPK pathway and its downstream targets in SCC-R cells. We demonstrate that erlotinib-resistant cells are sensitive to MAPK pathway inhibition. This study revealed multiple genetic, proteomic and phosphoproteomic alterations associated with erlotinib resistant SCC-R cells. Our data indicates that therapeutic targeting of MAPK pathway is an effective strategy for treating erlotinib-resistant HNSCC tumors.
Multiphoton NAD(P)H FLIM reveals metabolic changes in individual cell types of the intact cochlea upon sensorineural hearing loss
Authors: Majumder Paromita , Blacker Thomas S. , Nolan Lisa S. , Duchen Michael R. , Gale Jonathan E.
Published: December 2019

An increasing volume of data suggests that changes in cellular metabolism have a major impact on the health of tissues and organs, including in the auditory system where metabolic alterations are implicated in both age-related and noise-induced hearing loss. However, the difficulty of access and the complex cyto-architecture of the organ of Corti has made interrogating the individual metabolic states of the diverse cell types present a major challenge. Multiphoton fluorescence lifetime imaging microscopy (FLIM) allows label-free measurements of the biochemical status of the intrinsically fluorescent metabolic cofactors NADH and NADPH with subcellular spatial resolution. However, the interpretation of NAD(P)H FLIM measurements in terms of the metabolic state of the sample are not completely understood. We have used this technique to explore changes in metabolism associated with hearing onset and with acquired (age-related and noise-induced) hearing loss. We show that these conditions are associated with altered NAD(P)H fluorescence lifetimes, use a simple cell model to confirm an inverse relationship between τbound and oxidative stress, and propose such changes as a potential index of oxidative stress applicable to all mammalian cell types.
Monitoring type 2 diabetes from volatile faecal metabolome in Cushing’s syndrome and single Afmid mouse models via a longitudinal study
Authors: Lourenço Célia , Kelly Darren , Cantillon Jack , Cauchi Michael , Yon Marianne A. , Bentley Liz , Cox Roger D. , Turner Claire
Published: December 2019

The analysis of volatile organic compounds (VOCs) as a non-invasive method for disease monitoring, such as type 2 diabetes (T2D) has shown potential over the years although not yet set in clinical practice. Longitudinal studies to date are limited and the understanding of the underlying VOC emission over the age is poorly understood. This study investigated longitudinal changes in VOCs present in faecal headspace in two mouse models of T2D – Cushing’s syndrome and single Afmid knockout mice. Longitudinal changes in bodyweight, blood glucose levels and plasma insulin concentration were also reported. Faecal headspace analysis was carried out using selected ion flow tube mass spectrometry (SIFT-MS) and thermal desorption coupled to gas chromatography-mass spectrometry (TD-GC-MS). Multivariate data analysis of the VOC profile showed differences mainly in acetic acid and butyric acid able to discriminate the groups Afmid and Cushing’s mice. Moreover, multivariate data analysis revealed statistically significant differences in VOCs between Cushing’s mice/wild-type (WT) littermates, mainly short-chain fatty acids (SCFAs), ketones, and alcohols, and longitudinal differences mainly attributed to methanol, ethanol and acetone. Afmid mice did not present statistically significant differences in their volatile faecal metabolome when compared to their respective WT littermates. The findings suggested that mice developed a diabetic phenotype and that the altered VOC profile may imply a related change in gut microbiota, particularly in Cushing’s mice. Furthermore, this study provided major evidence of age-related changes on the volatile profile of diabetic mice.
West Asian sources of the Eurasian component in Ethiopians: a reassessment
Authors: Molinaro Ludovica , Montinaro Francesco , Yelmen Burak , Marnetto Davide , Behar Doron M. , Kivisild Toomas , Pagani Luca
Published: December 2019

The presence of genomic signatures of Eurasian origin in contemporary Ethiopians has been reported by several authors and estimated to have arrived in the area from 3000 years ago. Several studies reported plausible source populations for such a signature, using haplotype based methods on modern data or single-site methods on modern or ancient data. These studies did not reach a consensus and suggested an Anatolian or Sardinia-like proxy, broadly Levantine or Neolithic Levantine as possible sources. We demonstrate, however, that the deeply divergent, autochthonous African component which accounts for ~50% of most contemporary Ethiopian genomes, affects the overall allele frequency spectrum to an extent that makes it hard to control for it and, at once, to discern between subtly different, yet important, Eurasian sources (such as Anatolian or Levant Neolithic ones). Here we re-assess pattern of allele sharing between the Eurasian component of Ethiopians (here called “NAF” for Non African) and ancient and modern proxies. Our results unveil a genomic legacy that may connect the Eurasian genetic component of contemporary Ethiopians with Sea People and with population movements that affected the Mediterranean area and the Levant after the fall of the Minoan civilization.
Suprahyoid Muscle Activity in Patients with Chagasic Megaesophagus
Authors: El Gharib Aretuza Zaupa Gasparim , Berretin-Felix Giédre , Dantas Roberto Oliveira , Rossoni Diogo Francisco , de Ornelas Toledo Max Jean
Published: December 2019

The objective of this investigation was to evaluate the activity of the suprahyoid musculature during swallowing and to correlate the findings with the degree of megaesophagus, oral and pharyngeal videofluoroscopy and esophageal manometry in patients with achalasia caused by Chagas’ disease. Twenty-nine patients with positive serology for Trypanosoma cruzi and dysphagia (Chagas’ disease group) and 29 individuals matched by sex and age (control group) participated in the study. Surface electromyography of the suprahyoid musculature and videofluoroscopy during swallowing of paste and liquid consistencies were performed. Canonical correlation analysis of the MANOVA test results showed that the Chagas’ disease group had lower electromyographic activity when compared with controls. Overlapping circles of radiological findings were found for megaesophagus. The Spearman test showed a positive correlation between the electromyographic activity in the maximum voluntary isometric contraction and the time of pharyngeal transit for both liquid (p = 0.014) and paste (p = 0.047). The logistic regression test showed no association between electromyographic activity of the suprahyoid muscles and esophageal manometry results (p > 0.05). In conclusion, individuals with chagasic megaesophagus have reduced electromyographic activity of the suprahyoid muscles during swallowing, in addition to a greater recruitment of the suprahyoid musculature with increased pharyngeal transit time.
Bioinformatic analysis of peripheral blood RNA-sequencing sensitively detects the cause of late graft loss following overt hyperglycemia in pig-to-nonhuman primate islet xenotransplantation
Authors: Kim Hyun-Je , Moon Ji Hwan , Chung Hyunwoo , Shin Jun-Seop , Kim Bongi , Kim Jong-Min , Kim Jung-Sik , Yoon Il-Hee , Min Byoung-Hoon , Kang Seong-Jun , Kim Yong-Hee , Jo Kyuri , Choi Joungmin , Chae Heejoon , Lee Won-Woo , Kim Sun , Park Chung-Gyu
Published: December 2019

Clinical islet transplantation has recently been a promising treatment option for intractable type 1 diabetes patients. Although early graft loss has been well studied and controlled, the mechanisms of late graft loss largely remains obscure. Since long-term islet graft survival had not been achieved in islet xenotransplantation, it has been impossible to explore the mechanism of late islet graft loss. Fortunately, recent advances where consistent long-term survival (≥6 months) of adult porcine islet grafts was achieved in five independent, diabetic nonhuman primates (NHPs) enabled us to investigate on the late graft loss. Regardless of the conventional immune monitoring methods applied in the post-transplant period, the initiation of late graft loss could rarely be detected before the overt graft loss observed via uncontrolled blood glucose level. Thus, we retrospectively analyzed the gene expression profiles in 2 rhesus monkey recipients using peripheral blood RNA-sequencing (RNA-seq) data to find out the potential cause(s) of late graft loss. Bioinformatic analyses showed that highly relevant immunological pathways were activated in the animal which experienced late graft failure. Further connectivity analyses revealed that the activation of T cell signaling pathways was the most prominent, suggesting that T cell-mediated graft rejection could be the cause of the late-phase islet loss. Indeed, the porcine islets in the biopsied monkey liver samples were heavily infiltrated with CD3+ T cells. Furthermore, hypothesis test using a computational experiment reinforced our conclusion. Taken together, we suggest that bioinformatics analyses with peripheral blood RNA-seq could unveil the cause of insidious late islet graft loss.
Mental rotation of sequentially presented 3D figures: sex and sex hormones related differences in behavioural and ERP measures
Authors: Griksiene Ramune , Arnatkeviciute Aurina , Monciunskaite Rasa , Koenig Thomas , Ruksenas Osvaldas
Published: December 2019

Mental rotation of 3D objects demonstrates one of the largest sex differences. We investigated sex and sex hormones-related differences in behaviour and event related potentials (ERP) using a modified Shepard and Metzler task composed of sequentially presented 3D figures in 29 men and 32 women. We demonstrated a significant increase in response time and decrease in both accuracy and positivity of the parietal ERP with increasing angular disparity between the figures. Higher angular disparity evoked an increase of global field power (GFP) from 270 to 460 ms and different activation topographies from 470 to 583 ms with lower parietal, but higher left frontal positivity. Flatter slopes in higher angular disparity condition suggest distinct strategies being implemented depending on the difficulty of the rotation. Men performed the task more accurately than women. Performance accuracy in women tended to be negatively related to estradiol while the response time tended to increase with increasing progesterone. There were no associations with testosterone. Women demonstrated higher GFP and an increased positivity over the parietal scalp area, while men showed higher activation in the left frontal cortex. Together these findings indicate dynamic angular disparity- and sex-related differences in brain activity during mental rotation of 3D figures.
QuantSeq. 3′ Sequencing combined with Salmon provides a fast, reliable approach for high throughput RNA expression analysis
Authors: Corley Susan M. , Troy Niamh M. , Bosco Anthony , Wilkins Marc R.
Published: December 2019

RNA-Seq is increasingly used for the diagnosis of patients, targeting of therapies and for single cell transcriptomics. These applications require cost effective, fast and reliable ways of capturing and analyzing gene expression data. Here we compared Lexogen’s QuantSeq which captures only the 3′ end of RNA transcripts and Illumina’s TruSeq, using both Tophat2 and Salmon for gene quantification. We also compared these results to microarray. This analysis was performed on peripheral blood mononuclear cells stimulated with Poly (I:C), a viral mimic that induces innate antiviral responses. This provides a well-established model to determine if RNA-Seq and QuantSeq identify the same biological signatures. Gene expression levels in QuantSeq and RNA-Seq were strongly correlated (Spearman’s rho ~0.8), Salmon and Tophat2 (Spearman’s rho > 0.9). There was high consistency in protein coding genes, non-concordant genes had a high proportion of shorter, non-coding features. RNA-Seq identified more differentially expressed genes than QuantSeq, both methods outperformed microarray. The same key biological signals emerged in each of these approaches. We conclude that QuantSeq, coupled with a fast quantification method such as Salmon, should provide a viable alternative to traditional RNA-Seq in many applications and may be of particular value in the study of the 3′UTR region of mRNA.
Assessment of Local Climate Zone Classification Maps of Cities in China and Feasible Refinements
Authors: Ren Chao , Cai Meng , Li Xinwei , Zhang Lei , Wang Ran , Xu Yong , Ng Edward
Published: December 2019

Local climate zone (LCZ) maps that describe the urban surface structure and cover with consistency and comparability across cities are gaining applications in studies of urban heat waves, sustainable urbanization and urban energy balance. Following the standard World Urban Database and Access Portal Tools (WUDAPT) method, we generated LCZ maps for over 20 individual cities and 3 major economic regions in China. Based on the confusion matrices constructed by manual comparison between the predicted classes and ground truths, we highlight the following: (1) notable variation in overall accuracies (i.e., 60%–89%) among cities were observed, which was mainly due to class incompleteness and distinct proportions of natural landscapes; (2) building classes in selected cities were poorly classified in general, with a mean accuracy of 48%; (3) the sparsely built class (i.e., LCZ 9), which is rare in the selected Chinese cities, had the lowest classification accuracy (32% on average), and the class of low plants had the widest accuracy range. The findings indicate that the standard WUDAPT method alone is insufficient for generating LCZ products that demonstrate practical value, especially for built-up areas in China, and the misclassification is largely caused by the lack of building height data. This result is confirmed by a refinement test, in which the urban DEM retrieved from Sentinel-1 data with radar interferometry technique was used. The study shows a detailed and comprehensive assessment of applying the WUDAPT method in China and a feasible refinement strategy to improve the classification accuracy, especially for the built-up types of LCZ. The study could serve as a useful reference for generating quality-ensured LCZ maps. This study also examines and explores the relationship between socio-economic status and LCZ products, which is essential for further implementations.
Machine-learning based patient classification using Hepatitis B virus full-length genome quasispecies from Asian and European cohorts
Authors: Mueller-Breckenridge Alan J. , Garcia-Alcalde Fernando , Wildum Steffen , Smits Saskia L. , de Man Robert A. , van Campenhout Margo J. H. , Brouwer Willem P. , Niu Jianjun , Young John A. T. , Najera Isabel , Zhu Lina , Wu Daitze , Racek Tomas , Hundie Gadissa Bedada , Lin Yong , Boucher Charles A. , van de Vijver David , Haagmans Bart L.
Published: December 2019

Chronic infection with Hepatitis B virus (HBV) is a major risk factor for the development of advanced liver disease including fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The relative contribution of virological factors to disease progression has not been fully defined and tools aiding the deconvolution of complex patient virus profiles is an unmet clinical need. Variable viral mutant signatures develop within individual patients due to the low-fidelity replication of the viral polymerase creating ‘quasispecies’ populations. Here we present the first comprehensive survey of the diversity of HBV quasispecies through ultra-deep sequencing of the complete HBV genome across two distinct European and Asian patient populations. Seroconversion to the HBV e antigen (HBeAg) represents a critical clinical waymark in infected individuals. Using a machine learning approach, a model was developed to determine the viral variants that accurately classify HBeAg status. Serial surveys of patient quasispecies populations and advanced analytics will facilitate clinical decision support for chronic HBV infection and direct therapeutic strategies through improved patient stratification.
Clinical Implications of Sub-grouping HER2 Positive Tumors by Amplicon Structure and Co-amplified Genes
Authors: Maoz Myriam , Devir Michal , Inbar Michal , Inbar-Daniel Ziva , Sherill-Rofe Dana , Bloch Idit , Meir Karen , Edelman David , Azzam Salah , Nechushtan Hovav , Maimon Ofra , Uziely Beatrice , Kadouri Luna , Sonnenblick Amir , Eden Amir , Peretz Tamar , Zick Aviad
Published: December 2019

ERBB2 amplification is a prognostic marker for aggressive tumors and a predictive marker for prolonged survival following treatment with HER2 inhibitors. We attempt to sub-group HER2+ tumors based on amplicon structures and co-amplified genes. We examined five HER2+ cell lines, three HER2+ xenographs and 57 HER2+ tumor tissues. ERBB2 amplification was analyzed using digital droplet PCR and low coverage whole genome sequencing. In some HER2+ tumors PPM1D, that encodes WIP1, is co-amplified. Cell lines were treated with HER2 and WIP1 inhibitors. We find that inverted duplication is the amplicon structure in the majority of HER2+ tumors. In patients suffering from an early stage disease the ERBB2 amplicon is composed of a single segment while in patients suffering from advanced cancer the amplicon is composed of several different segments. We find robust WIP1 inhibition in some HER2+ PPM1D amplified cell lines. Sub-grouping HER2+ tumors using low coverage whole genome sequencing identifies inverted duplications as the main amplicon structure and based on the number of segments, differentiates between local and advanced tumors. In addition, we found that we could determine if a tumor is a recurrent tumor or second primary tumor and identify co-amplified oncogenes that may serve as targets for therapy.
Silver vacancy concentration engineering leading to the ultralow lattice thermal conductivity and improved thermoelectric performance of Ag1-xInTe2
Authors: Zhong Yaqiong , Luo Yong , Li Xie , Cui Jiaolin
Published: December 2019

AgInTe2 compound has not received enough recognition in thermoelectrics, possibly due to the fact that the presence of Te vacancy (VTe) and antisite defect of In at Ag site (InAg) degrades its electrical conductivity. In this work, we prepared the Ag1-xInTe2 compounds with substoichiometric amounts of Ag and observed an ultralow lattice thermal conductivity (κL = 0.1 Wm−1K−1) for the sample at x = 0.15 and 814 K. This leads to more than 2-fold enhancement in the ZT value (ZT = 0.62) compared to the pristine AgInTe2. In addition, we have traced the origin of the untralow κL using the Callaway model. The results attained in this work suggest that the engineering of the silver vacancy (VAg) concentration is still an effective way to manipulate the thermoelectric performance of AgInTe2, realized by the increased point defects and modified crystal structure distortion as the VAg concentration increases.
Author Correction: Graphene-assisted biosensing based on terahertz nanoslot antennas
Authors: Choi Geunchang , Hong Sung Ju , Bahk Young-Mi
Published: December 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Sputum and salivary protein biomarkers and point-of-care biosensors for the management of COPD
Authors: Dong Tao , Santos Simão , Yang Zhaochu , Yang Shuai , Kirkhus Niels E.
Published: December 2019

Chronic obstructive pulmonary disease (COPD) has become one of the most fatal diseases of the century considering mortality and morbidity levels worldwide.
Advanced sodium storage properties of a porous nitrogen-doped carbon with a NiO/Cu/Cu2O hetero-interface derived from bimetal–organic frameworks
Authors: Zhang Yan , Ullah Sana , Zheng Guang-Ping , Zheng Xiu-Cheng , Li Dan
Published: December 2019

The hetero-interfaces within NiO/Cu/Cu2O endow the porous N-doped carbon with fast Na+ diffusion, high electrical conductivity, and improved sodium storage.
A biomimetic MOF nanoreactor enables synergistic suppression of intracellular defense systems for augmented tumor ablation
Authors: Gao Peng , Shi Mingwan , Wei Ruyue , Pan Wei , Liu Xiaohan , Li Na , Tang Bo
Published: December 2019

A homotypic cancer cell membrane camouflaged MOF-based nanoreactor with the photothermal–starvation effect has been developed for synergistic suppression of intracellular defensive systems for enhanced cancer treatment.
cis alkenes stabilized by intramolecular sulphur⋯π interactions
Authors: Zhao Xiaolei , Zheng Wei , Zhang Yi , Huang Wei
Published: December 2019

A series of alkenes with bistable isomers were obtained containing a thiophene/azoheteroaryl backbone.
Off-stoichiometry effects on the thermoelectric properties of Cu2+δSe (−0.1 ≤δ≤ 0.05) compounds synthesized by a high-pressure and high-temperature method
Authors: Xue Lisha , Shen Weixia , Zhang Zhuangfei , Shen Manjie , Ji Wenting , Fang Chao , Zhang Yuewen , Jia Xiaopeng
Published: December 2019

The chemical composition can directly tune the transport properties of Cu2Se liquid-like materials, including the carrier concentration, carrier mobility and superionic feature.
Automatic classification of single-molecule charge transport data with an unsupervised machine-learning algorithm
Authors: Huang Feifei , Li Ruihao , Wang Gan , Zheng Jueting , Tang Yongxiang , Liu Junyang , Yang Yang , Yao Yuan , Shi Jia , Hong Wenjing
Published: December 2019

Based on unsupervised deep learning algorithms, an automatic data analysis method for single-molecule charge transport data is developed, which offers an opportunity to reveal more physical and chemical phenomena at the single-molecule level.
Two-dimensional bimolecular recombination in amorphous organic semiconductors
Authors: Novikov Sergey
Published: December 2019

Two-dimensional recombination in the spatially correlated random landscape demonstrates rich behavior depending on the disorder parameters and charge carrier density.
Molecular dynamics simulation of imidazolium CnMIM-BF4 ionic liquids using a coarse grained force-field
Authors: Fajardo Oscar Y. , Di Lecce Silvia , Bresme Fernando
Published: December 2019

A Coarse Grained (CG) model to investigate the structure, dynamics and interfacial properties of the [C2–8MIM][BF4] family of ionic liquids is proposed.
Advances of 2D bismuth in energy sciences
Authors: Liu Xuhai , Zhang Shengli , Guo Shiying , Cai Bo , Yang Shengyuan A. , Shan Fukai , Pumera Martin , Zeng Haibo
Published: December 2019

This review explores the fundamentals of 2D bismuth, its improved fabrication methods, and its theoretical–experimental achievements in energy-related applications.
Hydrogenation of substituted nitroaromatics on non-noble metal catalysts: mechanistic insights to improve selectivity
Authors: Millán Reisel , Boronat Mercedes
Published: December 2019

An alternative reaction mechanism combined with preferential perpendicular adsorption make non-noble metals chemoselective catalysts for nitroarene hydrogenation.