bluuebunny/crossref_metadata_2025 huggingface dataset:
A unified mechanistic model of niche, neutrality and violation of the competitive exclusion principle
Authors: Kalmykov Lev , Kalmykov Vyacheslav
Published: July 2019

The origin of species richness is one of the most widely discussed questions in ecology. The absence of unified mechanistic model of competition makes difficult our deep understanding of this subject. Here we show such a two-species competition model that unifies (i) a mechanistic niche model, (ii) a mechanistic neutral (null) model and (iii) a mechanistic violation of the competitive exclusion principle. Our model is an individual-based cellular automaton. We demonstrate how two trophically identical and aggressively propagating species can stably coexist in one stable homogeneous habitat without any trade-offs in spite of their 10% difference in fitness. Competitive exclusion occurs if the fitness difference is significant (approximately more than 30%). If the species have one and the same fitness they stably coexist and have similar numbers. We conclude that this model shows diffusion-like and half-soliton-like mechanisms of interactions of colliding population waves. The revealed mechanisms eliminate the existing contradictions between ideas of niche, neutrality and cases of violation of the competitive exclusion principle.
Fundamental Principles of Neural Organization of Cognition
Authors: Perlovsky Leonid
Published: July 2019

The manuscript advances a hypothesis that there are few fundamental principles of neural organization of cognition, which explain several wide areas of the cognitive functioning. We summarize the fundamental principles, experimental, theoretical, and modeling evidence for these principles, relate them to hypothetical neural mechanisms, and made a number of predictions. We consider cognitive functioning including concepts, emotions, drives-instincts, learning, “higher” cognitive functions of language, interaction of language and cognition, role of emotions in this interaction, the beautiful, sublime, and music. Among mechanisms of behavior we concentrate on internal actions in the brain, learning and decision making. A number of predictions are made, some of which have been previously formulated and experimentally confirmed, and a number of new predictions are made that can be experimentally tested. Is it possible to explain a significant part of workings of the mind from a few basic principles, similar to how Newton explained motions of planets? This manuscript summarizes a part of contemporary knowledge toward this goal.
Complex Systems Analysis of Arrested Neural Cell Differentiation during Development and Analogous Cell Cycling Models in Carcinogenesis
Authors: Baianu I , Prisecaru V.
Published: July 2019

A new approach to the modular, complex systems analysis of nonlinear dynamics of arrested neural cell Differentiation--induced cell proliferation during organismic development and the analogous cell cycling network transformations involved in carcinogenesis is proposed. Neural tissue arrested differentiation that induces cell proliferation during perturbed development and Carcinogenesis are complex processes that involve dynamically inter-connected biomolecules in the intercellular, membrane, cytosolic, nuclear and nucleolar compartments. Such 'dynamically inter-connected' biomolecules form numerous inter-related pathways referred to as 'molecular networks'. One such family of signaling pathways contains the cell cyclins. Cyclins are proteins that link several critical pro-apoptotic and other cell cycling/division components, including the tumor suppressor gene TP53 and its product, the Thomsen-Friedenreich antigen (T antigen), Rb, mdm2, c-Myc, p21, p27, Bax, Bad and Bcl-2, which play major roles in various neoplastic transformations of many tissues.The novel theoretical analysis presented here is based on recently published studies of arrested cell differentiation that normally leads to neural system formation during early developmental stages; the perturbed development may involve cyclin signaling and cell cycling responsible for rapidly induced cell proliferation without differentiation into neural cells in such experimental studies.
A MEMS ultrasound stimulation system for modulation of neural circuits with high spatial resolution in vitro
Authors: Lee Jungpyo , Ko Kyungmin , Shin Hyogeun , Oh Soo-Jin , Lee C. Justin , Chou Namsun , Choi Nakwon , Tack Oh Min , Chul Lee Byung , Chan Jun Seong , Cho Il-Joo
Published: July 2019

Neuromodulation by ultrasound has recently received attention due to its noninvasive stimulation capability for treating brain diseases. Although there have been several studies related to ultrasonic neuromodulation, these studies have suffered from poor spatial resolution of the ultrasound and low repeatability with a fixed condition caused by conventional and commercialized ultrasound transducers. In addition, the underlying physics and mechanisms of ultrasonic neuromodulation are still unknown. To determine these mechanisms and accurately modulate neural circuits, researchers must have a precisely controllable ultrasound transducer to conduct experiments at the cellular level. Herein, we introduce a new MEMS ultrasound stimulation system for modulating neurons or brain slices with high spatial resolution. The piezoelectric micromachined ultrasonic transducers (pMUTs) with small membranes (sub-mm membranes) generate enough power to stimulate neurons and enable precise modulation of neural circuits. We designed the ultrasound transducer as an array structure to enable localized modulation in the target region. In addition, we integrated a cell culture chamber with the system to make it compatible with conventional cell-based experiments, such as in vitro cell cultures and brain slices. In this work, we successfully demonstrated the functionality of the system by showing that the number of responding cells is proportional to the acoustic intensity of the applied ultrasound. We also demonstrated localized stimulation capability with high spatial resolution by conducting experiments in which cocultured cells responded only around a working transducer.
Development of a delayed-release nutrient for appetite control in adults with obesity and type 2 diabetes and initial clinical testing in a single dose randomized controlled trial
Authors: Beale E. , Lim E. , Yassine H. , Azen C. , Christopher C.
Published: July 2019

Background and objectives

Delivery of nutrients directly to the small intestine, either via enteral feeding tube or by gastric bypass surgery, is associated with increased levels of appetite-suppressing and glucoregulatory hormones, including GLP-1, and reduced appetite. Achieving these changes non-invasively using formulated foods may be of therapeutic benefit in individuals with obesity and related comorbidities. The aim of this pilot study was to determine the effect of a single dose of a novel delayed-release nutrient (DRN) on glucose, GLP-1, c-peptide, insulin, and appetite in adults with obesity and type 2 diabetes.

Subjects and methods

We formulated an all-natural, generally recognized as safe (‘GRAS”) DRN and conducted a randomized prospective crossover trial. Nineteen adults with obesity and type 2 diabetes underwent paired 3-h meal tolerance tests (MTT) in randomized order 1–4 weeks apart. Subjects ingested a single dose of DRN and the same nutrients as unformulated powders (UN).

Results

For DRN compared with UN, the maximal concentration (Cmax) was significantly lower for glucose, c-peptide, and insulin, and the time of maximal concentration (Tmax) was significantly delayed. While Tmax for GLP-1 was also significantly delayed following DRN compared with UN (45 min later; p = 0.26), Cmax did not differ significantly. GLP-1 rose significantly during the last 90 min of the 3-h MTT (β1 = 0.16 pg/mL/min, p = 0.025), while following UN it decreased (β1 = −0.21 pg/mL/min, p = 0.0026) (p difference = 0.0003). There were minimal differences in seven measures of appetite and adverse symptoms between DRN and UN.

Conclusions

We conclude that nutrient can be formulated using all-natural ingredients to induce a delayed rise in GLP-1. Further testing is needed to determine the amount and site of nutrient release, when maximum GLP-1 levels occur, and if modification of the formulation specifications and dose are associated with appetite and glucose control.
Clinical update on head and neck cancer: molecular biology and ongoing challenges
Authors: Alsahafi Elham , Begg Katheryn , Amelio Ivano , Raulf Nina , Lucarelli Philippe , Sauter Thomas , Tavassoli Mahvash
Published: July 2019

Head and neck squamous cell carcinomas (HNSCCs) are an aggressive, genetically complex and difficult to treat group of cancers. In lieu of truly effective targeted therapies, surgery and radiotherapy represent the primary treatment options for most patients. But these treatments are associated with significant morbidity and a reduction in quality of life. Resistance to both radiotherapy and the only available targeted therapy, and subsequent relapse are common. Research has therefore focussed on identifying biomarkers to stratify patients into clinically meaningful groups and to develop more effective targeted therapies. However, as we are now discovering, the poor response to therapy and aggressive nature of HNSCCs is not only affected by the complex alterations in intracellular signalling pathways but is also heavily influenced by the behaviour of the extracellular microenvironment. The HNSCC tumour landscape is an environment permissive of these tumours’ aggressive nature, fostered by the actions of the immune system, the response to tumour hypoxia and the influence of the microbiome. Solving these challenges now rests on expanding our knowledge of these areas, in parallel with a greater understanding of the molecular biology of HNSCC subtypes. This update aims to build on our earlier 2014 review by bringing up to date our understanding of the molecular biology of HNSCCs and provide insights into areas of ongoing research and perspectives for the future.
Association of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms
Authors: Emami Nima C. , Kachuri Linda , Meyers Travis J. , Das Rajdeep , Hoffman Joshua D. , Hoffmann Thomas J. , Hu Donglei , Shan Jun , Feng Felix Y. , Ziv Elad , Van Den Eeden Stephen K. , Witte John S.
Published: July 2019

Here we train cis-regulatory models of prostate tissue gene expression and impute expression transcriptome-wide for 233,955 European ancestry men (14,616 prostate cancer (PrCa) cases, 219,339 controls) from two large cohorts. Among 12,014 genes evaluated in the UK Biobank, we identify 38 associated with PrCa, many replicating in the Kaiser Permanente RPGEH. We report the association of elevated TMPRSS2 expression with increased PrCa risk (independent of a previously-reported risk variant) and with increased tumoral expression of the TMPRSS2:ERG fusion-oncogene in The Cancer Genome Atlas, suggesting a novel germline-somatic interaction mechanism. Three novel genes, HOXA4, KLK1, and TIMM23, additionally replicate in the RPGEH cohort. Furthermore, 4 genes, MSMB, NCOA4, PCAT1, and PPP1R14A, are associated with PrCa in a trans-ethnic meta-analysis (N = 9117). Many genes exhibit evidence for allele-specific transcriptional activation by PrCa master-regulators (including androgen receptor) in Position Weight Matrix, Chip-Seq, and Hi-C experimental data, suggesting common regulatory mechanisms for the associated genes.
Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis
Authors: Serwas Nina K. , Hoeger Birgit , Ardy Rico C. , Stulz Sigrun V. , Sui Zhenhua , Memaran Nima , Meeths Marie , Krolo Ana , Yüce Petronczki Özlem , Pfajfer Laurène , Hou Tie Z. , Halliday Neil , Santos-Valente Elisangela , Kalinichenko Artem , Kennedy Alan , Mace Emily M. , Mukherjee Malini , Tesi Bianca , Schrempf Anna , Pickl Winfried F. , Loizou Joanna I. , Kain Renate , Bidmon-Fliegenschnee Bettina , Schickel Jean-Nicolas , Glauzy Salomé , Huemer Jakob , Garncarz Wojciech , Salzer Elisabeth , Pierides Iro , Bilic Ivan , Thiel Jens , Priftakis Peter , Banerjee Pinaki P. , Förster-Waldl Elisabeth , Medgyesi David , Huber Wolf-Dietrich , Orange Jordan S. , Meffre Eric , Sansom David M. , Bryceson Yenan T. , Altman Amnon , Boztug Kaan
Published: July 2019

Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families indifferentially expressed in FDCP6 homolog (DEF6)as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated inDEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11+CTLA-4+vesicles inDEF6-mutated cells. One of the patients has been treated with CTLA-4-Ig and achieved sustained remission. Collectively, we uncover DEF6 as player in immune homeostasis ensuring availability of the checkpoint protein CTLA-4 at T-cell surface, identifying a potential target for autoimmune and/or cancer therapy.
Detection of cell-type-specific risk-CpG sites in epigenome-wide association studies
Authors: Luo Xiangyu , Yang Can , Wei Yingying
Published: July 2019

In epigenome-wide association studies, the measured signals for each sample are a mixture of methylation profiles from different cell types. Current approaches to the association detection claim whether a cytosine-phosphate-guanine (CpG) site is associated with the phenotype or not at aggregate level and can suffer from low statistical power. Here, we propose a statistical method, HIgh REsolution (HIRE), which not only improves the power of association detection at aggregate level as compared to the existing methods but also enables the detection of risk-CpG sites for individual cell types.
Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma
Authors: Mourikis Thanos P. , Benedetti Lorena , Foxall Elizabeth , Temelkovski Damjan , Nulsen Joel , Perner Juliane , Cereda Matteo , Lagergren Jesper , Howell Michael , Yau Christopher , Fitzgerald Rebecca C. , Scaffidi Paola ,   The Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, Noorani Ayesha , Edwards Paul A. W. , Elliott Rachael Fels , Grehan Nicola , Nutzinger Barbara , Hughes Caitriona , Fidziukiewicz Elwira , Bornschein Jan , MacRae Shona , Crawte Jason , Northrop Alex , Contino Gianmarco , Li Xiaodun , de la Rue Rachel , Katz-Summercorn Annalise , Abbas Sujath , Loureda Daniel , O’Donovan Maria , Miremadi Ahmad , Malhotra Shalini , Tripathi Monika , Tavaré Simon , Lynch Andy G. , Eldridge Matthew , Secrier Maria , Bower Lawrence , Devonshire Ginny , Jammula Sriganesh , Davies Jim , Crichton Charles , Carroll Nick , Safranek Peter , Hindmarsh Andrew , Sujendran Vijayendran , Hayes Stephen J. , Ang Yeng , Sharrocks Andrew , Preston Shaun R. , Oakes Sarah , Bagwan Izhar , Save Vicki , Skipworth Richard J. E. , Hupp Ted R. , Robert O’Neill J. , Tucker Olga , Beggs Andrew , Taniere Philippe , Puig Sonia , Underwood Timothy J. , Walker Robert C. , Grace Ben L. , Barr Hugh , Shepherd Neil , Old Oliver , Gossage James , Davies Andrew , Chang Fuju , Zylstra Janine , Mahadeva Ula , Goh Vicky , Sanders Grant , Berrisford Richard , Harden Catherine , Lewis Mike , Cheong Ed , Kumar Bhaskar , Parsons Simon L. , Soomro Irshad , Kaye Philip , Saunders John , Lovat Laurence , Haidry Rehan , Igali Laszlo , Scott Michael , Sothi Sharmila , Suortamo Sari , Lishman Suzy , Hanna George B. , Peters Christopher J. , Moorthy Krishna , Grabowska Anna , Turkington Richard , McManus Damian , Khoo David , Fickling Will , Ciccarelli Francesca D.
Published: July 2019

The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy.
Optogenetic control of Bacillus subtilis gene expression
Authors: Castillo-Hair Sebastian M. , Baerman Elliot A. , Fujita Masaya , Igoshin Oleg A. , Tabor Jeffrey J.
Published: July 2019

The Gram-positive bacteriumBacillus subtilisexhibits complex spatial and temporal gene expression signals. Although optogenetic tools are ideal for studying such processes, none has been engineered for this organism. Here, we port a cyanobacterial light sensor pathway comprising the green/red photoreversible two-component system CcaSR, two metabolic enzymes for production of the chromophore phycocyanobilin (PCB), and an output promoter to control transcription of a gene of interest intoB. subtilis. Following an initial non-functional design, we optimize expression of pathway genes, enhance PCB production via a translational fusion of the biosynthetic enzymes, engineer a strong chimeric output promoter, and increase dynamic range with a miniaturized photosensor kinase. Our final design exhibits over 70-fold activation and rapid response dynamics, making it well-suited to studying a wide range of gene regulatory processes. In addition, the synthetic biology methods we develop to port this pathway should makeB. subtilis easier to engineer in the future.
Landscape of transcriptomic interactions between breast cancer and its microenvironment
Authors: Fox Natalie S. , Haider Syed , Harris Adrian L. , Boutros Paul C.
Published: July 2019

Solid tumours comprise mixtures of tumour cells (TCs) and tumour-adjacent cells (TACs), and the intricate interconnections between these diverse populations shape the tumour’s microenvironment. Despite this complexity, clinical genomic profiling is typically performed from bulk samples, without distinguishing TCs from TACs. To better understand TC–TAC interactions, we computationally distinguish their transcriptomes in 1780 primary breast tumours. We show that TC and TAC mRNA abundances are divergently associated with clinical phenotypes, including tumour subtypes and patient survival. These differences reflect distinct responses of TCs and TACs to specific somatic driver mutations, particularly TP53. These data further elucidate how the molecular interplay between breast tumours and their microenvironment drives aggressive tumour phenotypes.
Laser-sculptured ultrathin transition metal carbide layers for energy storage and energy harvesting applications
Authors: Zang Xining , Jian Cuiying , Zhu Taishan , Fan Zheng , Wang Wanlin , Wei Minsong , Li Buxuan , Follmar Diaz Mateo , Ashby Paul , Lu Zhengmao , Chu Yao , Wang Zizhao , Ding Xinrui , Xie Yingxi , Chen Juhong , Hohman J. Nathan , Sanghadasa Mohan , Grossman Jeffrey C. , Lin Liwei
Published: July 2019

Ultrathin transition metal carbides with high capacity, high surface area, and high conductivity are a promising family of materials for applications from energy storage to catalysis. However, large-scale, cost-effective, and precursor-free methods to prepare ultrathin carbides are lacking. Here, we demonstrate a direct pattern method to manufacture ultrathin carbides (MoCx, WCx, and CoCx) on versatile substrates using a CO2 laser. The laser-sculptured polycrystalline carbides (macroporous, ~10–20 nm wall thickness, ~10 nm crystallinity) show high energy storage capability, hierarchical porous structure, and higher thermal resilience than MXenes and other laser-ablated carbon materials. A flexible supercapacitor made of MoCx demonstrates a wide temperature range (−50 to 300 °C). Furthermore, the sculptured microstructures endow the carbide network with enhanced visible light absorption, providing high solar energy harvesting efficiency (~72 %) for steam generation. The laser-based, scalable, resilient, and low-cost manufacturing process presents an approach for construction of carbides and their subsequent applications.
Weakly supervised classification of aortic valve malformations using unlabeled cardiac MRI sequences
Authors: Fries Jason A. , Varma Paroma , Chen Vincent S. , Xiao Ke , Tejeda Heliodoro , Saha Priyanka , Dunnmon Jared , Chubb Henry , Maskatia Shiraz , Fiterau Madalina , Delp Scott , Ashley Euan , Ré Christopher , Priest James R.
Published: July 2019

Biomedical repositories such as the UK Biobank provide increasing access to prospectively collected cardiac imaging, however these data are unlabeled, which creates barriers to their use in supervised machine learning. We develop a weakly supervised deep learning model for classification of aortic valve malformations using up to 4,000 unlabeled cardiac MRI sequences. Instead of requiring highly curated training data, weak supervision relies on noisy heuristics defined by domain experts to programmatically generate large-scale, imperfect training labels. For aortic valve classification, models trained with imperfect labels substantially outperform a supervised model trained on hand-labeled MRIs. In an orthogonal validation experiment using health outcomes data, our model identifies individuals with a 1.8-fold increase in risk of a major adverse cardiac event. This work formalizes a deep learning baseline for aortic valve classification and outlines a general strategy for using weak supervision to train machine learning models using unlabeled medical images at scale.
Fourier ring correlation simplifies image restoration in fluorescence microscopy
Authors: Koho Sami , Tortarolo Giorgio , Castello Marco , Deguchi Takahiro , Diaspro Alberto , Vicidomini Giuseppe
Published: July 2019

Fourier ring correlation (FRC) has recently gained popularity among fluorescence microscopists as a straightforward and objective method to measure the effective image resolution. While the knowledge of the numeric resolution value is helpful in e.g., interpreting imaging results, much more practical use can be made of FRC analysis—in this article we propose blind image restoration methods enabled by it. We apply FRC to perform image de-noising by frequency domain filtering. We propose novel blind linear and non-linear image deconvolution methods that use FRC to estimate the effective point-spread-function, directly from the images. We show how FRC can be used as a powerful metric to observe the progress of iterative deconvolution. We also address two important limitations in FRC that may be of more general interest: how to make FRC work with single images (within certain practical limits) and with three-dimensional images with highly anisotropic resolution.
Sticky collisions of ultracold RbCs molecules
Authors: Gregory Philip D. , Frye Matthew D. , Blackmore Jacob A. , Bridge Elizabeth M. , Sawant Rahul , Hutson Jeremy M. , Cornish Simon L.
Published: July 2019

Understanding and controlling collisions is crucial to the burgeoning field of ultracold molecules. All experiments so far have observed fast loss of molecules from the trap. However, the dominant mechanism for collisional loss is not well understood when there are no allowed 2-body loss processes. Here we experimentally investigate collisional losses of nonreactive ultracold 87Rb133Cs molecules, and compare our findings with the sticky collision hypothesis that pairs of molecules form long-lived collision complexes. We demonstrate that loss of molecules occupying their rotational and hyperfine ground state is best described by second-order rate equations, consistent with the expectation for complex-mediated collisions, but that the rate is lower than the limit of universal loss. The loss is insensitive to magnetic field but increases for excited rotational states. We demonstrate that dipolar effects lead to significantly faster loss for an incoherent mixture of rotational states.
SHB1 and CCA1 interaction desensitizes light responses and enhances thermomorphogenesis
Authors: Sun Qingbin , Wang Shulei , Xu Gang , Kang Xiaojun , Zhang Min , Ni Min
Published: July 2019

Light and temperature are two important environmental signals to plants. After dawn, photo-activated phytochromes translocate into the nucleus and interact with a family of negative basic helix-loop-helix PIF regulators. Subsequent phosphorylation and degradation of PIFs triggers a series of photomorphogenic responses. However, excess light can damage the photosynthetic apparatus and leads to photoinhibition. Plants acclimate to a balanced state of photomorphogenesis to avoid photodamage. Here, we show that upregulation of PIF4 expression by SHB1 and CCA1 under red light represents a desensitization step. After dawn, the highly expressed circadian clock protein CCA1 brings circadian signals to the regulatory region of the PIF4 signaling hub. Recruitment of SHB1 by CCA1 modulates red light-specific induction of PIF4 expression thus integrating circadian and light signals. As noon approaches and light intensity and ambient temperature tend to increase, the SHB1–CCA1 interaction sustains PIF4 expression to trigger thermomorphogenic responses to changing light and temperature conditions.
Rapid fabrication of reinforced and cell-laden vascular grafts structurally inspired by human coronary arteries
Authors: Akentjew Tamara L. , Terraza Claudia , Suazo Cristian , Maksimcuka Jekaterina , Wilkens Camila A. , Vargas Francisco , Zavala Gabriela , Ocaña Macarena , Enrione Javier , García-Herrera Claudio M. , Valenzuela Loreto M. , Blaker Jonny J. , Khoury Maroun , Acevedo Juan Pablo
Published: July 2019

Design strategies for small diameter vascular grafts are converging toward native-inspired tissue engineered grafts. A new automated technology is presented that combines a dip-spinning methodology for depositioning concentric cell-laden hydrogel layers, with an adapted solution blow spinning (SBS) device for intercalated placement of aligned reinforcement nanofibres. This additive manufacture approach allows the assembly of bio-inspired structural configurations of concentric cell patterns with fibres at specific angles and wavy arrangements. The middle and outer layers were tuned to structurally mimic the media and adventitia layers of native arteries, enabling the fabrication of small bore grafts that exhibit the J-shape mechanical response and compliance of human coronary arteries. This scalable automated system can fabricate cellularized multilayer grafts within 30 min. Grafts were evaluated by hemocompatibility studies and a preliminary in vivo carotid rabbit model. The dip-spinning-SBS technology generates constructs with native mechanical properties and cell-derived biological activities, critical for clinical bypass applications.
Reward signaling in a recurrent circuit of dopaminergic neurons and peptidergic Kenyon cells
Authors: Lyutova Radostina , Selcho Mareike , Pfeuffer Maximilian , Segebarth Dennis , Habenstein Jens , Rohwedder Astrid , Frantzmann Felix , Wegener Christian , Thum Andreas S. , Pauls Dennis
Published: July 2019

Dopaminergic neurons in the brain of the Drosophila larva play a key role in mediating reward information to the mushroom bodies during appetitive olfactory learning and memory. Using optogenetic activation of Kenyon cells we provide evidence that recurrent signaling exists between Kenyon cells and dopaminergic neurons of the primary protocerebral anterior (pPAM) cluster. Optogenetic activation of Kenyon cells paired with odor stimulation is sufficient to induce appetitive memory. Simultaneous impairment of the dopaminergic pPAM neurons abolishes appetitive memory expression. Thus, we argue that dopaminergic pPAM neurons mediate reward information to the Kenyon cells, and in turn receive feedback from Kenyon cells. We further show that this feedback signaling is dependent on short neuropeptide F, but not on acetylcholine known to be important for odor-shock memories in adult flies. Our data suggest that recurrent signaling routes within the larval mushroom body circuitry may represent a mechanism subserving memory stabilization.
Natural course of fatty liver in 36,195 South Korean adults
Authors: Sung Ki-Chul , Lee Mi-Yeon , Lee Jong-Young , Lee Sung-Ho , Kim Yong-Bum , Song Won-Jun , Huh Ji-Hye , Park Jin-Sun , Shin Jeong-Hun , Seo Mi Hae , Kim Seong-Hwan , Kim Sun H.
Published: July 2019

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease, and yet the natural course remains unclear. Study population included 36,195 individuals who participated in a health-screening program and diagnosed with fatty liver by abdominal ultrasound. Participants were provided written information regarding fatty liver and advised to make lifestyle changes. Ultrasound was repeated after at least 6 months. After a mean follow up of 4.9 years (±3.4), 19.6% resolved their fatty liver. Individuals who resolved were more likely female (22.9% vs. 12.3%), thinner (body mass index [BMI], 25.2 ± 2.7 vs. 26 ± 2.7), and with lower HOMA-IR (1.4 vs. 1.7) (P .70.001). Decrease in BMI predicted resolution of fatty liver with 42% of those in the top quartile of BMI decline resolving compared with 5.7% in the lowest quartile (odds ratio [OR] (95% confidence interval [CI]) 15.65 (14.13–17.34), P < 0.001)). Baseline HOMA-IR also predicted resolution with those in the top quartile (most insulin resistant) being least likely to resolve (12%) vs. those in the lowest quartile (25%) (OR 0.36 [0.31–0.42], P < 0.001). Fatty liver disease is persistent. Individuals with higher degree of insulin resistance are also the most likely to have persistent steatosis at follow up.
Environmentally-Controlled Near Infrared Spectroscopic Imaging of Bone Water
Authors: Ailavajhala Ramyasri , Oswald Jack , Rajapakse Chamith S. , Pleshko Nancy
Published: July 2019

We have designed an environmentally-controlled chamber for near infrared spectroscopic imaging (NIRSI) to monitor changes in cortical bone water content, an emerging biomarker related to bone quality assessment. The chamber is required to ensure repeatable spectroscopic measurements of tissues without the influence of atmospheric moisture. A calibration curve to predict gravimetric water content from human cadaveric cortical bone was created using NIRSI data obtained at six different lyophilization time points. Partial least squares (PLS) models successfully predicted bone water content that ranged from 0–10% (R = 0.96, p < 0.05, root mean square error of prediction (RMSEP) = 7.39%), as well as in the physiologic range of 4–10% of wet tissue weight (R = 0.87, p < 0.05, RMSEP = 14.5%). Similar results were obtained with univariate and bivariate regression models for prediction of water in the 0–10% range. Further, we identified two new NIR bone absorbances, at 6560 cm−1 and 6688 cm−1, associated with water and collagen respectively. Such data will be useful in pre-clinical studies that investigate changes in bone quality with disease, aging and with therapeutic use.
SDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice
Authors: Casey Ruth T. , ten Hoopen Rogier , Ochoa Eguzkine , Challis Benjamin G. , Whitworth James , Smith Philip S. , Martin Jose Ezequiel , Clark Graeme R. , Rodger Fay , Maranian Mel , Allinson Kieren , Madhu Basetti , Roberts Thomas , Campos Luis , Anstee Joanne , Park Soo-Mi , Marker Alison , Watts Colin , Bulusu Venkata R. , Giger Olivier T. , Maher Eamonn R.
Published: July 2019

The enzyme succinate dehydrogenase (SDH) functions in the citric acid cycle and loss of function predisposes to the development of phaeochromocytoma/paraganglioma (PPGL), wild type gastrointestinal stromal tumour (wtGIST) and renal cell carcinoma. SDH-deficient tumours are most commonly associated with a germline SDH subunit gene (SDHA/B/C/D) mutation but can also be associated with epigenetic silencing of the SDHC gene. However, clinical diagnostic testing for an SDHC epimutation is not widely available. The objective of this study was to investigate the indications for and the optimum diagnostic pathways for the detection of SDHC epimutations in clinical practice. SDHC promoter methylation analysis of 32 paraffin embedded tumours (including 15 GIST and 17 PPGL) was performed using a pyrosequencing technique and correlated with SDHC gene expression. SDHC promoter methylation was identified in 6 (18.7%) tumours. All 6 SDHC epimutation cases presented with SDH deficient wtGIST and 3/6 cases had multiple primary tumours. No case of constitutional SDHC promoter hypermethylation was detected. Whole genome sequencing of germline DNA from three wtGIST cases with an SDHC epimutation, did not reveal any causative sequence anomalies. Herein, we recommend a diagnostic workflow for the detection of an SDHC epimutation in a service setting.
Sperm transfer through hyper-elongated beetle penises – morphology and theoretical approaches
Authors: Matsumura Yoko , Michels Jan , Rajabi Hamed , Shimozawa Tateo , Gorb Stanislav N.
Published: July 2019

Many insects possess a hyper-elongated intromittent organ with a diameter of only a few micrometers. Using morphological and theoretical approaches, we investigated the biomechanics of sperm transfer through such organs by calculating (1) how far and how fast sperm could fill in the penis by capillary action, (2) how much capillary pressure is generated in the penis, and (3) how much pressure is needed to pump sperm out of the penis. The results enabled us to propose the following hypotheses: (1) penile filling basically occurs by capillary action, and (2) sperm transport to females occurs by contracting the sperm pump muscles or by active propulsion of spermatozoa. Potential experimental approaches to test these hypotheses are discussed.
Anti-inflammatory nutrition with high protein attenuates cardiac and skeletal muscle alterations in a pulmonary arterial hypertension model
Authors: Vinke Paulien , Bowen T. Scott , Boekschoten Mark. V. , Witkamp Renger F. , Adams Volker , van Norren Klaske
Published: July 2019

Pulmonary arterial hypertension (PAH) is characterized by remodelling of the pulmonary arteries and right ventricle (RV), which leads to functional decline of cardiac and skeletal muscle. This study investigated the effects of a multi-targeted nutritional intervention with extra protein, leucine, fish oil and oligosaccharides on cardiac and skeletal muscle in PAH. PAH was induced in female C57BL/6 mice by weekly injections of monocrotaline (MCT) for 8 weeks. Control diet (sham and MCT group) and isocaloric nutritional intervention (MCT + NI) were administered. Compared to sham, MCT mice increased heart weight by 7%, RV thickness by 13% and fibrosis by 60% (all p < 0.05) and these were attenuated in MCT + NI mice. Microarray and qRT-PCR analysis of RV confirmed effects on fibrotic pathways. Skeletal muscle fiber atrophy was induced (P < 0.05) by 22% in MCT compared to sham mice, but prevented in MCT + NI group. Our findings show that a multi-targeted nutritional intervention attenuated detrimental alterations to both cardiac and skeletal muscle in a mouse model of PAH, which provides directions for future therapeutic strategies targeting functional decline of both tissues.
Synchronization in time-varying random networks with vanishing connectivity
Authors: Faggian Marco , Ginelli Francesco , Rosas Fernando , Levnajić Zoran
Published: July 2019

A sufficiently connected topology linking the constituent units of a complex system is usually seen as a prerequisite for the emergence of collective phenomena such as synchronization. We present a random network of heterogeneous phase oscillators in which the links mediating the interactions are constantly rearranged with a characteristic timescale and, possibly, an extremely low instantaneous connectivity. We show that with strong coupling and sufficiently fast rewiring the network reaches partial synchronization even in the vanishing connectivity limit. In particular, we provide an approximate analytical argument, based on the comparison between the different characteristic timescales of our system in the low connectivity regime, which is able to predict the transition to synchronization threshold with satisfactory precision beyond the formal fast rewiring limit. We interpret our results as a qualitative mechanism for emergence of consensus in social communities. In particular, our result suggest that groups of individuals are capable of aligning their opinions under extremely sparse exchanges of views, which is reminiscent of fast communications that take place in the modern social media. Our results may also be relevant to characterize the onset of collective behavior in engineered systems of mobile units with limited wireless capabilities.
The Effect of Electronic Cigarette User Modifications and E-liquid Adulteration on the Particle Size Profile of an Aerosolized Product
Authors: Mulder Haley A. , Patterson Jesse L. , Halquist Matthew S. , Kosmider Leon , Turner Joseph B. McGee , Poklis Justin L , Poklis Alphonse , Peace Michelle R.
Published: July 2019

Electronic cigarettes (e-cigarettes) are an alternate nicotine delivery system that generate a condensation aerosol to be inhaled by the user. The size of the droplets formed in the aerosol can vary and contributes to drug deposition and ultimate bioavailability in the lung. The growing popularity of e-cigarette products has caused an increase in internet sources promoting the use of drugs other than nicotine (DOTNs) in e-cigarettes. The purpose of this study was to determine the effect of various e-cigarette and e-liquid modifications, such as coil resistance, battery voltage, and glycol and drug formulation, on the aerosol particle size. E-liquids containing 12 mg/mL nicotine prepared in glycol compositions of 100% propylene glycol (PG), 100% vegetable glycerin (VG), or 50:50 PG:VG were aerosolized at three voltages and three coil resistances. Methamphetamine and methadone e-liquids were prepared at 60 mg/mL in 50:50 PG:VG and all e-liquids were aerosolized onto a 10 stage Micro-Orifice Uniform Deposit Impactor. Glycol deposition correlated with drug deposition, and the majority of particles centered between 0.172–0.5 μm in diameter, representing pulmonary deposition. The 100% PG e-liquid produced the largest aerosol particles and the 100% VG and 50:50 PG:VG e-liquids produced ultra-fine particles <0.3 μm. The presence of ultrafine particles indicates that drugs can be aerosolized and reach the pulmonary alveolar regions, highlighting a potential for abuse and risk of overdose with DOTNs aerosolized in an e-cigarette system.
Experimental study on flow characteristics of gas transport in micro- and nanoscale pores
Authors: Shen Weijun , Song Fuquan , Hu Xiao , Zhu Genmin , Zhu Weiyao
Published: July 2019

Gas flow behavior in porous media with micro- and nanoscale pores has always been attracted great attention. Gas transport mechanism in such pores is a complex problem, which includes continuous flow, slip flow and transition flow. In this study, the microtubes of quartz microcapillary and nanopores alumina membrane were used, and the gas flow measurements through the microtubes and nanopores with the diameters ranging from 6.42 μm to 12.5 nm were conducted. The experimental results show that the gas flow characteristics are in rough agreement with the Hagen-Poiseuille (H-P) equation in microscale. However, the flux of gas flow through the nanopores is larger than the H-P equation by more than an order of magnitude, and thus the H-P equation considerably underestimates gas flux. The Knudsen diffusion and slip flow coexist in the nanoscale pores and their contributions to the gas flux increase as the diameter decreases. The slip flow increases with the decrease in diameter, and the slip length decreases with the increase in driving pressure. Furthermore, the experimental gas flow resistance is less than the theoretical value in the nanopores and the flow resistance decreases along with the decrease in diameter, which explains the phenomenon of flux increase and the occurrence of a considerable slip length in nanoscale. These results can provide insights into a better understanding of gas flow in micro- and nanoscale pores and enable us to exactly predict and actively control gas slip.
Metasurface Antennas: New Models, Applications and Realizations
Authors: Faenzi Marco , Minatti Gabriele , González-Ovejero David , Caminita Francesco , Martini Enrica , Della Giovampaola Cristian , Maci Stefano
Published: July 2019

This paper presents new designs, implementation and experiments of metasurface (MTS) antennas constituted by subwavelength elements printed on a grounded dielectric slab. These antennas exploit the interaction between a cylindrical surface wave (SW) wavefront and an anisotropic impedance boundary condition (BC) to produce an almost arbitrary aperture field. They are extremely thin and excited by a simple in-plane monopole. By tailoring the BC through the shaping of the printed elements, these antennas can be largely customized in terms of beam shape, bandwidth and polarization. In this paper, we describe new designs and their implementation and measurements. It is experimentally shown for the first time that these antennas can have aperture efficiency up to 70%, a bandwidth up to 30%, they can produce two different direction beams of high-gain and similar beams at two different frequencies, showing performances never reached before.
Phosphite binding by the HtxB periplasmic binding protein depends on the protonation state of the ligand
Authors: Adams Nathan B. P. , Robertson Angus J. , Hunter C. Neil , Hitchcock Andrew , Bisson Claudine
Published: July 2019

Phosphorus acquisition is critical for life. In low phosphate conditions, some species of bacteria have evolved mechanisms to import reduced phosphorus compounds, such as phosphite and hypophosphite, as alternative phosphorus sources. Uptake is facilitated by high-affinity periplasmic binding proteins (PBPs) that bind cargo in the periplasm and shuttle it to an ATP-binding cassette (ABC)-transporter in the bacterial inner membrane. PtxB and HtxB are the PBPs responsible for binding phosphite and hypophosphite, respectively. They recognize the P-H bond of phosphite/hypophosphite via a conserved P-H...π interaction, which confers nanomolar dissociation constants for their respective ligands. PtxB also has a low-level binding affinity for phosphate and hypophosphite, whilst HtxB can facilitate phosphite uptake in vivo. However, HtxB does not bind phosphate, thus the HtxBCDE transporter has recently been successfully exploited for biocontainment of genetically modified organisms by phosphite-dependent growth. Here we use a combination of X-ray crystallography, NMR and Microscale Thermophoresis to show that phosphite binding to HtxB depends on the protonation state of the ligand, suggesting that pH may effect the efficiency of phosphite uptake by HtxB in biotechnology applications.
Loss of Cubilin, the intrinsic factor-vitamin B12 receptor, impairs visceral endoderm endocytosis and endodermal patterning in the mouse
Authors: Perea-Gomez Aitana , Cases Olivier , Lelièvre Vincent , Pulina Maria V. , Collignon Jérôme , Hadjantonakis Anna-Katerina , Kozyraki Renata
Published: July 2019

The visceral endoderm is a polarized epithelial monolayer necessary for early embryonic development in rodents. A key feature of this epithelium is an active endocytosis and degradation of maternal nutrients, in addition to being the source of various signaling molecules or inhibitors required for the differentiation and patterning of adjacent embryonic tissues. Endocytosis across the visceral endoderm epithelium involves specific cell surface receptors and an extensive sub-membrane vesicular system with numerous apical vacuoles/lysosomes. We previously reported that Cubilin, the endocytic receptor for intrinsic factor-vitamin B12, albumin and apolipoproteinA-I/HDL allows maternal nutrient uptake by the visceral endoderm. In the present study, we show that the germline ablation of Cubilin impairs endodermal and mesodermal patterning, and results in developmental arrest at gastrulation. Notably, visceral endoderm dispersal is impeded in Cubilin null embryos. We further confirm the essential role of Cubilin in nutrient internalization by the early visceral endoderm and highlight its involvement in the formation of apical vacuoles. Our results reveal essential roles for Cubilin in early embryonic development, and suggest that in addition to its nutritive function, Cubilin sustains signaling pathways involved in embryonic differentiation and patterning.
Peripartum depression and infant care, sleep and growth
Authors: Iwata Sachiko , Kinoshita Masahiro , Fujita Fumie , Tsuda Kennosuke , Unno Mitsuaki , Horinouchi Takashi , Morokuma Seiichi , Saitoh Shinji , Iwata Osuke
Published: July 2019

Peripartum depression is a common, serious complication in mothers. To assess the influence of infant care, sleep and growth on the risk of peripartum depression, 1,271 mothers of healthy one-month-old infants completed comprehensive questionnaires including the Edinburgh Postnatal Depression Scale. Relationships between high depression scores and variables related to infants’ care, sleep and growth were assessed adjusting for other variables. High depression scores were found in 233 mothers, which were associated with variables related to infants’ care (poor satisfaction with infant care support, p < 0.001; mothers’ passive response to night-time fussing, p = 0.001), sleep (dim bedroom lighting, p < 0.05; short sleep duration, p < 0.05) and growth (poor weight gain, p < 0.05), as well as maternal variables (primiparas, p < 0.001; poor income satisfaction, p < 0.001; poor sleep satisfaction, p < 0.001; daytime sleepiness, p = 0.001). Considering the observed association between high depression scores and infants’ care, sleep and growth, a multidisciplinary approach accounting for infant care would be required to prevent peripartum depression.
Intrabody-based FRET probe to visualize endogenous histone acetylation
Authors: Chung Chan-I , Sato Yuko , Ohmuro-Matsuyama Yuki , Machida Shinichi , Kurumizaka Hitoshi , Kimura Hiroshi , Ueda Hiroshi
Published: July 2019

Post-translational histone modifications are major regulators of gene expression. However, conventional immunoassays do not provide sufficient information regarding their spatial and temporal dynamic changes. Fluorescence/Förster resonance energy transfer (FRET)-based probes are capable of monitoring the dynamic changes associated with histone modifications in real-time by measuring the balance between histone-modifying enzyme activities. Recently, a genetically encoded histone-modification fluorescent probe using a single-chain variable region (scFv) fragment of a specific antibody was developed. The probe, modification-specific intracellular antibody, is capable of monitoring histone-acetylation levels in both cultured cells and living organisms based on the ratio of fluorescence intensities between the cell nucleus and cytoplasm. In this study, we constructed a FRET probe composed of yellow fluorescent protein attached at the N-terminus of an acetyl H3K9-specific scFv, tethered to a cyan fluorescent protein. When the FRET probe was expressed in human cells, both FRET efficiency and fluorescence intensity in the nucleus increased following histone-deacetylase inhibitor treatment. Using these two parameters, endogenous histone-acetylation levels were quantified over a high dynamic range. This probe provides a simple approach to quantify spatial and temporal dynamic changes in histone acetylation.