bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of exhaled air for early-stage diagnosis of lung cancer: opportunities and challenges
Authors: Ganeev Aleksandr A. , Gubal Anna R. , Lukyanov Gennadij N. , Arseniev Andrey I. , Barchuk Anton A. , Jahatspanian Igor E. , Gorbunov Ilja S. , Rassadina Anna A. , Nemets Valerij M. , Nefedov Andrey O. , Korotetsky Boris A. , Solovyev Nikolay D. , Iakovleva Evgenia , Ivanenko Natalja B. , Kononov Aleksandr S. , Sillanpaa Mika , Seeger Thomas
Published: July 2018

Early detection of lung cancer usually markedly increases the efficiency of therapy. However, the currently employed diagnostic approaches are not sufficiently effective, resulting in late detection of the disease and high patient mortality. Therefore, development of a high-throughput and reliable diagnostic method is a priority task requiring fast solution. Analysis of exhaled air for a number of organic compounds recognized as lung cancer biomarkers seems to be a promising approach for early diagnosis of the disease. This issue attracts growing interest, as indicated by increasing number of publications on this topic. This review surveys contemporary analytical techniques for analysis of exhaled air, including various spectroscopic and mass spectral methods and also gas sensor-based methods. The key benefits and shortcomings of the techniques, sample injection and pre-concentration methods, and the potential applicability of the methods for lung cancer detection are discussed. The prospects of simultaneous application of several analytical techniques and approaches for the early diagnosis are demonstrated.

The bibliography includes 147 references.
Genetic structure of introduced American mink (Neovison vison) in Patagonia: colonisation insights and implications for control and management strategies
Authors: Mora Mónica , Medina-Vogel Gonzalo , Sepúlveda Maximiliano A. , Noll Daly , Álvarez-Varas Rocío , Vianna Juliana A.
Published: July 2018

Context Biological invasions have caused dramatic changes in native biodiversity and ecosystem function. Studies of genetic variation and evolutionary changes are useful for understanding population dynamics during biological invasions, and shed light on management, prevention and restoration strategies. Aims This study aimed to investigate the structure and genetic variability of American mink (Neovison vison), an invasive species in southern South America, introduced for fur farming in the 1930s. Methods Samples from 153 mink were obtained from 12 locations in southern Chile to sequence the mitochondrial DNA (mtDNA) control region and to genotype 11 polymorphic microsatellite loci. Key results The highest mtDNA diversity was detected in Puerto Cisnes, suggesting multiple introductions and/or the most probable area where mink was first introduced. The latter is also supported by microsatellite data, because a high percentage of individuals from different locations were assigned to this location. All other locations showed low or no mtDNA diversity, possibly due to founder effect. The results also indicate marked population structure, with three genetic clusters coincident with the main historical introduction points, with low dispersal among them. Conclusions The results suggest that control strategies for American mink in southern Chile should be concentrated on these three genetically differentiated management units, and particularly on source populations and locations with low effective population size and restricted connectivity. Implications Genetic approaches have been used for the management of numerous alien species worldwide. Recommendations delivered here for American mink control could also be implemented in other regions and for other invasive species with similar genetic diversity distribution and connectivity.
Efficient compression in color naming and its evolution
Authors: Zaslavsky Noga , Kemp Charles , Regier Terry , Tishby Naftali
Published: July 2018

Significance

Semantic typology documents and explains how languages vary in their structuring of meaning. Information theory provides a formal model of communication that includes a precise definition of efficient compression. We show that color-naming systems across languages achieve near-optimal compression and that this principle explains much of the variation across languages. These findings suggest a possible process for color category evolution that synthesizes continuous and discrete aspects of previous accounts. The generality of this principle suggests that it may also apply to other semantic domains.
Environmental limits of Rift Valley fever revealed using ecoepidemiological mechanistic models
Authors: Lo Iacono Giovanni , Cunningham Andrew A. , Bett Bernard , Grace Delia , Redding David W. , Wood James L. N.
Published: July 2018

Significance

Vector-borne diseases represent complex infection transmission systems; previous epidemiological models have been unable to formally capture the relationship between the ecological limits of vector species and the dynamics of pathogen transmission. By making this advance for the key disease, Rift Valley fever, we are able to show how seasonally varying availability of water bodies and ambient temperatures dictate when the mosquito vector populations will persist and importantly, those sets of conditions resulting in stable oscillations of disease transmission. Importantly, under the latter scenario, short-term health control measures will likely fail, as the system quickly returns to the original configuration after the intervention stops. Our model, therefore, offers an important tool to better understand vector-borne diseases and design effective eradication programs.
Scale Dependency and Downward Causation in Biology
Authors: Green Sara
Published: July 2018

This article argues that scale dependence of physical and biological processes offers resistance to reductionism and has implications that support a specific kind of downward causation. I demonstrate how insights from multiscale modeling can provide a concrete mathematical interpretation of downward causation as boundary conditions for models used to represent processes at lower scales. The autonomy and role of macroscale parameters and higher-level constraints are illustrated through examples of multiscale modeling in physics, developmental biology, and systems biology. Drawing on these examples, I defend the explanatory importance of constraining relations for understanding the behavior of biological systems.
Explanation of Molecular Processes without Tracking Mechanism Operation
Authors: Brigandt Ingo
Published: July 2018

Philosophical discussions of systems biology have enriched the notion of mechanistic explanation by pointing to the role of mathematical modeling. However, such accounts still focus on explanation in terms of tracking a mechanism’s operation across time (by means of mental or computational simulation). My contention is that there are explanations of molecular systems in which the explanatory understanding does not consist in tracking a mechanism’s operation and productive continuity. I make this case by a discussion of bifurcation analysis in dynamical systems, articulating the distinctive way in which explanatory understanding is provided, especially about the reversibility or irreversibility of molecular processes.
Pull-back components of the space of foliations of codimension ≥2
Authors: e Silva W. , Neto A.
Published: July 2018

We present a new list of irreducible components for the space of k-dimensional holomorphic foliations on

P

n

\mathbb P^{n}

,

n
≥
3

n\geq 3

,

k
≥
2

k\ge 2

. They are associated to pull-back of dimension one foliations on

P

n
−
k
+
1

\mathbb P^{n-k+1}

by non-linear rational maps.
On the estimation of the incidence and prevalence in two-phase longitudinal sampling design
Authors: Banerjee Prithish , Ghosh Samiran
Published: July 2018

Two-phase sampling design is a common practice in many medical studies. Generally, the first-phase classification is fallible but relatively cheap, while the accurate second phase state-of-the-art medical diagnosis is complex and rather expensive to perform. When constructed efficiently it offers great potential for higher true case detection as well as for higher precision at a limited cost. In this article, we consider epidemiological studies with two-phase sampling design. However, instead of a single two-phase study, we consider a scenario where a series of two-phase studies are done in a longitudinal fashion on a cohort of interest. Another major design issue is non-curable pattern of certain disease (e.g. Dementia, Alzheimer’s etc.). Thus often the identified disease positive subjects are removed from the original population under observation, as they require clinical attention, which is quite different from the yet unidentified group. In this article, we motivated our methodology development from two real-life studies. We consider efficient and simultaneous estimation of prevalence as well incidence at multiple time points from a sampling design-based approach. We have explicitly shown the benefit of our developed methodology for an elderly population with significant burden of home-health care usage and at the high risk of major depressive disorder.
Feeling Old, Body and Soul: The Effect of Aging Body Reminders on Age Identity
Authors: Barrett Anne E , Gumber Clayton
Published: July 2018

Objectives

Although changes in body functioning and appearance signal the aging process to ourselves and others, studies give limited attention to the effect of bodily experiences of aging on age identity. Our study examines the effect on age identity of 3 categories of aging body reminders: everyday body problems, body repairs, and body aids.

Methods

Hierarchical linear models are run using 5 waves of the National Health and Aging Trends Study (2011–2015). Models predict the effect on age identity of change in the count of everyday body problems (e.g., pain), body repairs (i.e., surgeries and medications), and body aids (e.g., hearing aids).

Results

Increases in everyday body problems and body repairs (in particular, medications) predict older identities, with the strongest average effect found for everyday body problems. These results are observed in models controlling on health, suggesting that body reminders exert independent effects.

Discussion

Our study reveals a realm of aging experiences—bodily experiences—that influence age identity. Avenues for further research include examinations of other aging body reminders, as well as variation across individuals.
Does health literacy mediate the relationship between socioeconomic status and health disparities? Integrative review
Authors: Stormacq Coraline , Van den Broucke Stephan , Wosinski Jacqueline
Published: July 2018

While socioeconomic disparities are among the most fundamental causes of health disparities, socioeconomic status (SES) does not impact health directly. One of the potential mediating factors that link SES and health is health literacy (HL). Yet although HL can be considered a modifiable risk factor of socioeconomic disparities in health, the relationship between SES, HL and health disparities is not well understood. This study reviewed the evidence regarding the mediating role of HL in the relationship between socioeconomic and health disparities. Medline, Cinahl, Embase, PsychInfo, Eric, Web of Science, Google, Google Scholar, Mednar, Doaj and Worldcat were used to retrieve studies that specifically addressed socioeconomic and socio-demographic factors related to low HL levels, as well as the mediating role of HL in the relationship between SES and disparities in health outcomes. Selected studies were assessed for methodological quality. Sixteen published studies were retained for inclusion and content analyzed using the constant comparison method. The review indicates that disadvantaged social and socioeconomic conditions contribute to low HL levels, whereby low SES, and particularly educational attainment, is the most important determinant of HL, and that HL mediates the relationship between SES and health status, quality of life, specific health-related outcomes, health behaviors and use of preventive services. HL can be considered as a modifiable risk factor of socioeconomic disparities in health. Enhancing the level of HL in the population or making health services more accessible to people with low HL may be a means to reach a greater equity in health.
Ibrutinib Therapy and Mycobacterium chelonae Skin and Soft Tissue Infection
Authors: Dousa Khalid M , Babiker Ahmed , Van Aartsen Daniel , Shah Neel , Bonomo Robert A , Johnson John L , Skalweit Marion J
Published: July 2018

Ibrutinib is an irreversible inhibitor of Bruton’s tyrosine kinase approved for the treatment of B-cell malignancies. There is growing concern about the risk of opportunistic infections following ibrutinib therapy. Herein, we describe the first case of Mycobacterium chelonae skin and soft tissue infection in a patient receiving ibrutinib and recount the challenges in treating this infection.
‘The Only Trouble is the Dam’ Heroin’: Addiction, Treatment and Punishment at the Fort Worth Narcotic Farm
Authors: Karibo Holly M
Published: July 2018

In 1929, the U.S. federal government approved two ground-breaking programs designed to treat drug addiction. Emerging at a time when many began to worry about a supposed rising tide of drug use across the country, the establishment of narcotic hospitals at Lexington, Kentucky and Fort Worth, Texas marked a watershed moment in the treatment of addiction. This article traces the institutional history of one of those facilities, the Fort Worth Narcotic Farm, and the experiences of the men who found themselves under its care. It argues that, on the surface, the creation of the farm model seemed like a hopeful alternative to strict incarceration models. Its creation reflected shifting notions of addiction: namely, that addiction is not simply a crime, but it is also a disease with serious public health implications. Yet, the establishment of the hospital as places to both treat and punish addicts was their inherent and fundamental flaw. Central to this was the concept of the “prisoner-patient,” a person forced to undergo treatment as a result of criminal charges. Not only did patients express their frustration with the prison-like setting at Fort Worth, but recidivism rates remained high throughout the facility’s operation. Ultimately, lawmakers and politicians would use these recidivism rates as part of a broader push for more punitive drug legislation in the post-World War II period. By placing the history of addiction into conversation with mass incarceration studies, this article shows that the roots of the punishment model employed in the last quarter of the twentieth century were interwoven into seemingly “progressive” treatment models dating back to at least the 1930s. Indeed, the very failures of early addiction treatment models that arose by mid-century helped to justify an expanding criminal justice model in the post-1960s era.
Uncommon Histopathological Variants of Malignant Melanoma: Part 1
Authors: Cota Carlo , Saggini Andrea , Lora Viviana , Kutzner Heinz , Rütten Arno , Sangüeza Omar , Requena Luis , Cerroni Lorenzo
Published: July 2018

Despite new horizons opened by recent advances in molecular pathology, histological evaluation still remains the diagnostic gold standard regarding cutaneous melanocytic neoplasms. Several histological variants of melanoma have been described, and their knowledge is crucial for accurate diagnosis and classification of cases with unusual clinicopathological features. Uncommon histological variants of melanoma have been described based on a broad constellation of features, including architectural pattern, stromal alterations, cytological attributes, and other morphological properties. This review is aimed at providing an extensive discussion of unusual but distinctive histopathological variants of melanoma.
The Extended Fetal Cardiac Examination: Is It Feasible in a High-Risk Practice?
Authors: McGahan John P. , Cheang Ellen C. , Sekhon Simran , Gerscovich Eugenio O. , James Gina , Boe Nina M. , Wilson Machelle D.
Published: July 2018

The aims of this study were to demonstrate the feasibility of obtaining additional cardiac views as proposed on an extended fetal cardiac examination and to see if there was any variation in individual components of that examination stratified by sonographer training, patient body habitus, or equipment. We retrospectively reviewed 200 consecutive detailed second-trimester high-risk fetal obstetric sonograms that included additional extended cardiac views. We analyzed the percentage of the time individual views were obtained, with variation based on (1) a sonographer with greater than 3 years of training compared with a group with 6 to 12 months of training, (2) 2 different ultrasound units, and (3) different body mass indices. Overall, the highest rate of visualization was achieved with the 4-chamber view (98.2%), whereas the 3-vessel tracheal view had the lowest percentage of visualization (40.2%), among the less experienced sonographers. Differences in successful completion of the extended cardiac views were not statistically different between the sonographer with a level of training greater than 3 years as compared with those with 6 to 12 months' training except for the 3-vessel tracheal view (P < 0.001). There is no statistically significant difference in our ultrasound equipment, when considering only inexperienced sonographers. Increasing body mass index had an inverse relationship with obtaining the components of the detailed cardiac examination. Using state-of-the-art ultrasound equipment and with focused additional training of obstetric sonographers, the majority of extended cardiac views can be obtained. There are exceptions.
Hepatitis C–Associated B-cell Non-Hodgkin Lymphoma
Authors: Iliescu Laura , Mercan-Stanciu Adriana , Ioanitescu Elena Simona , Toma Letitia
Published: July 2018

Background and Purpose

Hepatitis C virus (HCV) can induce both hepatic and extrahepatic malignancies. A strong association between HCV and non-Hodgkin lymphomas (NHLs) has been demonstrated. The purpose of this article is to give emphasis on the clinical and imagistic particularities of the hepatitis C–associated NHL, revealing the importance of ultrasonography in discovering and characterizing splenic masses.

Methods

We present the cases of 3 women (aged 72, 61, and 56 years, respectively), all of which had a history of chronic hepatitis C and were subsequently diagnosed with different forms of lymphoma. In all 3 cases, conventional ultrasound exploration showed inhomogeneous splenomegaly. Contrast-enhanced ultrasound and computerized tomography were performed soon after admission, both clinical and imaging findings leading to the suspicion of lymphoma. The bone marrow biopsy was relevant for the diagnosis lymphoma in 2 patients, whereas the third woman only presented age-related changes in cellularity. Splenectomy was later performed in this case, for both diagnostic and therapeutic purposes; histopathological examination and immunohistochemistry revealed malignant non-Hodgkin diffuse large B-cell lymphoma.

Conclusions

The cooccurrence of HCV infection and splenic lymphoma is a frequently encountered scenery. Ultrasonography, both conventional and contrast-enhanced, plays an important role in the exploration of the spleen, representing a first-line imagistic method and a valuable means of characterizing different types of splenic lesions.

Implications for Practice

This article states the importance of ultrasonographic evaluation regarding the splenic pathology, by revealing clinical and imagistic findings in 3 cases of hepatitis C–associated lymphoma.
Transient Elastography Identifies the Risk of Esophageal Varices and Bleeding in Patients With Hepatitis B Virus–Related Liver Cirrhosis
Authors: Zhu Qingjing , Wang Weijun , Zhao Jinfang , AL-Asbahi Afnan Ahmed Mohamed , Huang Ying , Du Fan , Zhou Jianning , Song Yuhu , Xu Keshu , Ye Jin , Yang Ling
Published: July 2018

This study aimed to analyze the diagnostic accuracy of liver stiffness for predicting esophageal variceal grading and the risk of esophageal variceal bleeding (EVB) in cases of cirrhosis. Hematological and biochemical parameters were measured and transient elastography was performed in 88 patients with hepatitis B–related cirrhosis undergoing endoscopy for esophageal varices. Esophageal varices grade was highly correlated with liver stiffness measurement (LSM) and the liver stiffness spleen diameter-to-platelet score in cirrhosis. Compared with those from endoscopy, the LSM and the liver stiffness spleen diameter-to-platelet score for the absence of esophageal varices were as follows: area under the receiver operating characteristic curve (AUROC), 0.894/0.926; sensitivity, 0.836/0.818; and specificity, 0.875/1.000, respectively. The AUROC and the sensitivity and specificity of LSM and the liver stiffness spleen diameter-to-platelet score for predicting grade III esophageal varices were 0.954 and 0.901, respectively. The AUROCs of LSM and the liver stiffness spleen diameter-to-platelet score for discriminating grades II and III from grade I or the absence of esophageal varices were 0.958 and 0.941, respectively. We also found that EVB was closely associated with LSM and spleen diameter. The AUROC, sensitivity, and specificity were 0.855/0.819, 0.857/0.875, and 0.747/0.780, respectively. Meanwhile, LSM and spleen diameter were 2 independent factors for predicting EVB. These data suggest that LSM and the liver stiffness spleen diameter-to-platelet score could accurately rule out cirrhosis without esophageal varices and differentiate high- and low-risk patients. Furthermore, LSM and spleen diameter had excellent abilities to predict EVB.
Effect of genetic drift on determinants of protein evolution
Authors: Subramanian Sankar
Published: July 2018

A number of previous studies reported that gene expression, tissue specificity, gene essentiality and the number of protein–protein interactions influence the rate of protein evolution. Here we investigated the influence of effective population size (Ne) on these determinants of protein evolution. For this purpose, we compared the ratio of non-synonymous-to-synonymous diversities (πN/πS) estimated for protein-coding genes ofMus musculus castaneusandMus musculus musculus: populations with high and lowNerespectively. Our results revealed that the difference betweenπN/πSestimated for genes with high and low expression levels was significantly smaller forM. m. musculuscompared to that observed forM. m. castaneus. The difference between theπN/πSof broadly expressed and tissue specific genes was much higher forM. m. castaneuscompared to that ofM. m. musculus.Furthermore, the difference between theπN/πScomputed for essential and non-essential genes was much smaller forM. m. musculusthanM. m. castaneus. A similar pattern was observed for genes involved in many protein–protein interactions versus those involved in one. These results suggest that the effects of the determinants on protein evolution were much reduced for the population with smallNedue to increased genetic drift.
Mechanically inferior constituents in spider silk result in mechanically superior fibres by adaptation to harsh hydration conditions: a molecular dynamics study
Authors: Kim Yoonjung , Lee Myeongsang , Baek Inchul , Yoon Taeyoung , Na Sungsoo
Published: July 2018

Spider silk exhibits mechanical properties such as high strength and toughness that are superior to those of any man-made fibre (Bourzac 2015
Nature
519
, S4–S6 (
doi:10.1038/519S4a
)). This high strength and toughness originates from a combination of the crystalline (exhibiting robust strength) and amorphous (exhibiting superb extensibility) regions present in the silk (Asakura
et al
. 2015
Macromolecules
48
, 2345–2357 (
doi:10.1021/acs.macromol.5b00160
)). The crystalline regions comprise a mixture of poly-alanine and poly-glycine-alanine. Poly-alanine is expected to be stronger than poly-glycine-alanine, because alanine exhibits greater interactions between the strands than glycine (Tokareva
et al
. 2014
Acta Biomater.
10
, 1612–1626 (
doi:10.1016/j.actbio.2013.08.020
)). We connect this characteristic sequence to the interactions observed upon the hydration of spider silk. Like most proteinaceous materials, spider silks become highly brittle upon dehydration, and thus water collection is crucial to maintaining its toughness (Gosline
et al
. 1986
Endeavour
10
, 37–43 (
doi:10.1016/0160-9327(86)90049-9
)). We report on the molecular dynamic simulations of spider silk structures with different sequences for the crystalline region of the silk structures, of wild-type (WT), poly-alanine, and poly-glycine-alanine. We reveal that the characteristic sequence of spider silk results in the β-sheets being maintained as the degree of hydration changes and that the high water collection capabilities of WT spider silk sequence prevent the silk from becoming brittle and weak in dry conditions. The characteristic crystalline sequence of spider dragline silk is therefore relevant not for maximizing the interactions between the strands but for adaption to changing hydration conditions to maintain an optimal performance even in harsh conditions.
Inference-based assessment of parameter identifiability in nonlinear biological models
Authors: Daly Aidan C. , Gavaghan David , Cooper Jonathan , Tavener Simon
Published: July 2018

As systems approaches to the development of biological models become more mature, attention is increasingly focusing on the problem of inferring parameter values within those models from experimental data. However, particularly for nonlinear models, it is not obvious, either from inspection of the model or from the experimental data, that the inverse problem of parameter fitting will have a unique solution, or even a non-unique solution that constrains the parameters to lie within a plausible physiological range. Where parameters cannot be constrained they are termed ‘unidentifiable’. We focus on gaining insight into the causes of unidentifiability using inference-based methods, and compare a recently developed measure-theoretic approach to inverse sensitivity analysis to the popular Markov chain Monte Carlo and approximate Bayesian computation techniques for Bayesian inference. All three approaches map the uncertainty in quantities of interest in the output space to the probability of sets of parameters in the input space. The geometry of these sets demonstrates how unidentifiability can be caused by parameter compensation and provides an intuitive approach to inference-based experimental design.
Separation of the main flavonoids and essential oil from seabuckthorn leaves by ultrasonic/microwave-assisted simultaneous distillation extraction
Authors: Li Chunying , Zhang Jingjing , Zhao Chunjian , Yang Lei , Zhao Wenyan , Jiang Hongwei , Ren Xueting , Su Weiran , Li Yuzheng , Guan Jiajing
Published: July 2018

Volatile essential oils (EOs), non-volatile rutin (RU), quercetin (QU), kaempferol (KA) and isorhamnetin (IS) were effectively extracted and isolated from seabuckthorn (
Hippophae rhamnoides
L.) leaves by ionic liquid-based ultrasound/microwave-assisted simultaneous distillation extraction (ILUMASDE). After optimization by response surface methodology, EOs, RU, QU, KA and IS were separated under the following optimum conditions: an ionic liquid of 1.0 M 1-butyl-3-methyl imidazole bromine salt ([C4mim]), liquid/solid ratio of 12 ml g
−1
, extraction time of 34 min, microwave power of 540 W and a fixed ultrasonic power of 50 W. Under the optimized conditions of ILUMASDE, the extraction yields of RU, QU, KA, IS and EOs were 9.18 ± 0.35, 5.52 ± 0.23, 3.03 ± 0.11, 5.64 ± 0.24 mg g
−1
and 0.095 ± 0.004%, respectively. The yield of EOs obtained using ILUMASDE was 1.07-fold higher than that obtained by conventional hydrodistillation extraction (HDE). In addition, the components of the EOs obtained using ILUMASDE and HDE were similar. The extraction yields of RU, QU, KA, IS obtained by ILUMASDE were 1.03–1.35-fold higher than that obtained by the ethanol ultrasonic-assisted extraction (EUAE), ionic liquid-based ultrasonic-assisted extraction (ILUAE) and ionic liquid-based microwave-assisted extraction (ILMAE). And the extraction time used by ILUMASDE was 34 min, which is 14.17%, 56.67%, 56.67% and 85.00% less than those used by HDE, EUAE, ILUAE and ILMAE, respectively. Therefore, ILUMASDE can be considered a rapid and efficient method for extracting flavonoids and EO from seabuckthorn (
Hippophae rhamnoids
L.) leaves.
Primary biocompatibility tests of poly(lactide-co-glycolide)-(poly-L-orithine/fucoidan) core–shell nanocarriers
Authors: Cai Duanhua , Fan Jingqian , Wang Shibin , Long Ruimin , Zhou Xia , Liu Yuangang
Published: July 2018

Layer-by-layer (LbL) self-assembly is the technology used in intermolecular static electricity, hydrogen bonds, covalent bonds and other polymer interactions during film assembling. This technology has been widely studied in the drug carrier field. Given their use in drug delivery systems, the biocompatibility of these potential compounds should be addressed. In this work, the primary biocompatibility of poly(lactide-co-glycolide)-(poly-L-orithine/fucoidan) [PLGA-(PLO/fucoidan)] core–shell nanoparticles (NPs) was investigated. Atomic force microscopy revealed the PLGA-(PLO/Fucoidan)
4
NPs to be spherical, with a uniform size distribution and a smooth surface, and the NPs were stable in physiological saline. The residual amount of methylene chloride was further determined by headspace gas chromatography, in which the organic solvent can be volatilized during preparation. Furthermore, cell viability, acridine orange/ethidium bromide staining, haemolysis and mouse systemic toxicity were all assessed to show that PLGA-(PLO/fucoidan)
4
NPs were biocompatible with cells and mice. Therefore, these NPs are expected to have potential applications in future drug delivery systems.
Determining cellular CTCF and cohesin abundances to constrain 3D genome models
Authors: Cattoglio Claudia , Pustova Iryna , Walther Nike , Ho Jaclyn J. , Hantsche-Grininger Merle , Inouye Carla J. , Hossain M. Julius , Dailey Gina M. , Ellenberg Jan , Darzacq Xavier , Tjian Robert , Hansen Anders S.
Published: July 2018

Achieving a quantitative and predictive understanding of 3D genome architecture remains a major challenge, as it requires quantitative measurements of the key proteins involved. Here we report the quantification of CTCF and cohesin, two causal regulators of topologically associating domains (TADs) in mammalian cells. Extending our previous imaging studies (Hansen et al., 2017), we estimate bounds on the density of putatively DNA loop-extruding cohesin complexes and CTCF binding site occupancy. Furthermore, co-immunoprecipitation studies of an endogenously tagged subunit (Rad21) suggest the presence of cohesin dimers and/or oligomers. Finally, based on our cell lines with accurately measured protein abundances, we report a method to conveniently determine the number of molecules of any Halo-tagged protein in the cell. We anticipate that our results and the established tool for measuring cellular protein abundances will advance a more quantitative understanding of 3D genome organization, and facilitate protein quantification, key to comprehend diverse biological processes.
Ultra-sensitive proteome profiling of FACS-isolated cell populations by data-independent acquisition-MS: Application to human hematopoietic stem and progenitor cells
Authors: Amon Sabine , Meier-Abt Fabienne , Gillet Ludovic C , Dimitrieva Slavica , Theocharides Alexandre PA , Manz Markus G , Aebersold Ruedi
Published: July 2018

Physiological processes in multicellular organisms depend on the function and interactions of a multitude of specialized cell types operating in context. Fluorescence-activated cell sorting (FACS) provides a powerful tool to determine the cell type composition of complex mixtures and to purify highly homogeneous cell populations using a small number of differentially expressed marker proteins. These populations can be further characterized, e.g. by phenotypic or molecular analyses.

We describe an ultra-sensitive mass spectrometric method for the robust quantitative and reproducible proteomic analysis of cohorts of FACS-isolated cell samples. It uses a minimum of post-sorting sample processing steps prior to data-independent acquisition MS on a current generation Orbitrap hybrid mass spectrometer. The method provides highly accurate and reproducible quantitative proteome profiles across the cohort with an average coefficient of variance <15% from as little as 150 ng of total peptide mass. We quantified the proteome of 25,000 sorted human hematopoietic stem/multipotent progenitor cell and three committed progenitor cell subpopulations (common myeloid progenitors, megakaryocyte-erythrocyte progenitors and granulocyte-macrophage progenitors) isolated from five healthy donors. On average, 5,851 protein groups were identified per sample. After stringent filtering, a subset of 4,131 protein groups (≥2 peptides) was used for differential comparison across the 20 samples, defining unique proteomic signatures for each cell type tested. A comparison of proteomic and transcriptomic profiles of the four cell types indicated hematopoietic stem/multipotent progenitor cell-specific divergent regulation of biochemical processes that are essential for maintaining stemness and were detected at the proteome rather than the transcriptome level.

The technology supports the generation of extensive and accurate quantitative proteomic profiles from low numbers of FACS-purified cells providing new information about the biochemical state of the analyzed cell types that is essential for basic and translational research.
Using GPUs to accelerate computational diffusion MRI: From microstructure estimation to tractography and connectomes
Authors: Hernandez-Fernandez Moises , Reguly Istvan , Jbabdi Saad , Giles Mike , Smith Stephen , Sotiropoulos Stamatios N.
Published: July 2018

The great potential of computational diffusion MRI (dMRI) relies on indirect inference of tissue microstructure and brain connections, since modelling and tractography frameworks map diffusion measurements to neuroanatomical features. This mapping however can be computationally highly expensive, particularly given the trend of increasing dataset sizes and the complexity in biophysical modelling. Limitations on computing resources can restrict data exploration and methodology development. A step forward is to take advantage of the computational power offered by recent parallel computing architectures, especially Graphics Processing Units (GPUs). GPUs are massive parallel processors that offer trillions of floating point operations per second, and have made possible the solution of computationally-intensive scientific problems that were intractable before. However, they are not inherently suited for all problems. Here, we present two different frameworks for accelerating dMRI computations using GPUs that cover the most typical dMRI applications: a framework for performing biophysical modelling and microstructure estimation, and a second framework for performing tractography and long-range connectivity estimation. The former provides a front-end and automatically generates a GPU executable file from a user-specified biophysical model, allowing accelerated non-linear model fitting in both deterministic and stochastic ways (Bayesian inference). The latter performs probabilistic tractography, it can generate whole-brain connectomes and supports new functionality for imposing anatomical constraints, such as inherent consideration of surface meshes (GIFTI files) along with volumetric images. We validate the frameworks against well-established CPU-based implementations and we show that despite the very different challenges for parallelising these problems, GPU-based designs can offer accelerations of more than two orders of magnitude in both cases.
Complementary topology of maintenance and manipulation brain networks in working memory
Authors: Davis S.W. , Crowell C.A. , Beynel L. , Deng L. , Lakhlani D. , Hilbig S.A. , Lim W. , Palmer H. , Nguyen D. , Peterchev A. V. , Luber B. , Lisanby S.H. , Appelbaum L.G. , Cabeza R.
Published: July 2018

Working memory (WM) is assumed to consist of a process that sustains memory representations in an active state (maintenance) and a process that operates on these activated representations (manipulation). Prior fMRI studies have examined maintenance and manipulation in separate task conditions, whereas in real life these processes operate simultaneously. In the current study, the neural mechanisms of maintenance and manipulation were disentangled during the same task by parametrically varying these processes. During fMRI, participants maintained consonant letters in WM while sorting them in alphabetical order. Maintenance was investigated by varying the number of letters held in WM and manipulation by varying the number of moves required to sort the list alphabetically. The study yielded three main findings. First, the degree of both maintenance and manipulation demand had significant effects on behavior that were associated with different cortical regions: maintenance was associated with bilateral prefrontal and left parietal cortex, and manipulation with right parietal activity, a link that is consistent with the role of parietal cortex in symbolic computations. Second, univariate fMRI and tractography based on diffusion-weighted imaging showed that maintenance and manipulation regions are supported by two dissociable structural networks. Finally, maintenance and manipulation functional networks became increasingly segregated with increasing demand, possibly reflecting the protection of information held in WM from interference generated by manipulation operations. These results represent a novel approach to study the brain as an adaptive system that coordinates multiple ongoing cognitive processes.

Significance Statement

Despite the importance of working memory (WM) in everyday life, little is known about how the brain is able to simultaneously maintain and manipulate information stored in short-term memory buffers. We examined evidence for two distinct, concurrent cognitive functions supporting maintenance and manipulation abilities by testing brain activity as participants performed a WM alphabetization task. We found behavioral and neural evidence in support of dissociable cognitive functions associated with these two operations. Furthermore, we found that connectivity between these networks was increasingly segregated as difficulty increased, and that this effect was positively related to individual WM ability. These results provide evidence that network segregation may act as a protective mechanism to enable successful performance under increasing WM demand.
A Matched-filter Based Algorithm for Subcellular Classification of T-system in Cardiac Tissues
Authors: Colli Dylan F , Blood Ryan , Sankarankutty Aparna C , Sachse Frank B , Frisk Michael , Louch William E , Kekenes-Huskey Peter M
Published: July 2018

In mammalian ventricular cardiomyocytes, invaginations of the surface membrane form the transverse tubular system (T-system) which consists of transverse tubules (TTs) that align with sarcomeres and Z-lines as well as longitudinal tubules (LTs) that are present between Z-lines in some species. In many cardiac disease etiologies the T-system is perturbed, which is believed to promote spatially heterogeneous, dyssynchronous Ca2+ release and inefficient contraction. In general, T-system characterization approaches have been directed primarily at isolated cells and do not detect subcellular T-system heterogeneity. Here we present MatchedMyo, a matched-filter based algorithm for subcellular T-system characterization in isolated cardiomyocytes and millimeter-scale myocardial sections. The algorithm utilizes "filters" representative of TTs, LTs, and T-system absence. Application of the algorithm to cardiomyocytes isolated from rat disease models of myocardial infarction (MI), dilated cardiomyopathy induced via aortic banding (AB), and sham surgery confirmed and quantified heterogeneous T-system structure and remodeling. Cardiomyocytes from post-MI hearts exhibited increasing T-system disarray as proximity to the infarct increased. We found significant (p<0.05, Welch's t-test) increases in LT density within cardiomyocytes proximal to the infarct (12±3%, data reported as mean ± SD, n=3) vs. sham (4±2%, n=5), but not distal to the infarct (7±1%, n=3). The algorithm also detected decreases in TTs within 5° of the myocyte minor axis for isolated AB (36±9%, n=3) and MI cardiomyocytes located intermediate (37±4%, n=3) and proximal (34±4%, n=3) to the infarct vs. sham (57±12%, n=5). Application of bootstrapping to rabbit MI tissue revealed distal sections comprised 18.9±1.0% TTs while proximal sections comprised 10.1±0.8% TTs (p<0.05), a 46.6% decrease. The matched filter approach therefore provides a robust and scalable technique for T-system characterization from isolated cells through millimeter-scale myocardial sections.
On the impact of competing intra- and intermolecular triplet-state quenching on photobleaching and photoswitching kinetics of organic fluorophores
Authors: Smit Jochem H. , van der Velde Jasper H. M. , Huang Jingyi , Trauschke Vanessa , Henrikus Sarah S. , Chen Si , Eleftheriadis Nikolaos , Warszawik Eliza M. , Herrmann Andreas , Cordes Thorben
Published: July 2018

While buffer cocktails remain the gold-standard for photostabilization and photoswitching of fluorescent markers, intramolecular triplet-state quenchers emerge as an alternative strategy to impart fluorophores with ‘self-healing’ or even functional properties such as photoswitching. In this contribution, we evaluated various combinations of both approaches and show that inter- and intramolecular triplet-state quenching processes compete with each other rather than being additive or even synergistic. Often intramolecular processes dominate the photophysical situation for combinations of covalently-linked and solution-based photostabilizers and photoswitching agents. In this context we identified a new function of intramolecular photostabilizers, i.e., protection of fluorophores from reversible off-switching events caused by solution-additives, which were previously misinterpreted as photobleaching. Our studies also provide practical guidance for usage of photostabilizer-dye conjugates for STORM-type super-resolution microscopy permitting the exploitation of their improved photophysics for increased spatio-temporal resolution. Finally, we provide evidence that the biochemical environment, e.g., proximity of aromatic amino-acids such as tryptophan, reduces the photostabilization efficiency of commonly used buffer cocktails. Not only have our results important implications for a deeper mechanistic understanding of self-healing dyes, but they will provide a general framework to select label positions for optimal and reproducible photostability or photoswitching kinetics.
A neuron-optimized CRISPR/dCas9 activation system for robust and specific gene regulation
Authors: Savell Katherine E. , Bach Svitlana V. , Zipperly Morgan E. , Revanna Jasmin S. , Goska Nicholas A. , Tuscher Jennifer J. , Duke Corey G. , Sultan Faraz A. , Burke Julia N. , Williams Derek , Ianov Lara , Day Jeremy J.
Published: July 2018

Recent developments in CRISPR-based gene editing have provided new avenues to interrogate gene function. However, application of these tools in the central nervous system has been delayed due to difficulties in transgene expression in post-mitotic neurons. Here, we present a highly efficient, neuron-optimized dual lentiviral CRISPR-based transcriptional activation (CRISPRa) system to drive gene expression in primary neuronal cultures and the adult brain of rodent model systems. We demonstrate robust, modular, and tunable induction of endogenous target genes as well as multiplexed gene regulation necessary for investigation of complex transcriptional programs. CRISPRa targeting unique promoters in the complex multi-transcript gene Brain-derived neurotrophic factor (Bdnf) revealed both transcript- and genome-level selectivity of this approach, in addition to highlighting downstream transcriptional and physiological consequences of Bdnf regulation. Finally, we illustrate that CRISPRa is highly efficient in vivo, resulting in increased protein levels of a target gene in diverse brain structures. Taken together, these results demonstrate that CRISPRa is an efficient and selective method to study gene expression programs in brain health and disease.
Alternative splicing and translation play important roles in parallel with transcriptional regulation during rice hypoxic germination
Authors: Chen Mo-Xian , Zhu Fu-Yuan , Wang Feng-Zhu , Ye Neng-Hui , Gao Bei , Chen Xi , Zhao Shan-Shan , Fan Tao , Cao Yun-Ying , Liu Tie-Yuan , Su Ze-Zhuo , Xie Li-Juan , Hu Qi-Juan , Wu Hui-Jie , Xiao Shi , Zhang Jianhua , Liu Ying-Gao
Published: July 2018

Post-transcriptional mechanisms, including alternative splicing (AS) and alternative translation initiation (ATI), have been used to explain the protein diversity involved in plant developmental processes and stress responses. Rice germination under hypoxia conditions is a classical model system for the study of low oxygen stress. It is known that there is transcriptional regulation during rice hypoxic germination, but the potential roles of AS and ATI in this process are not well understood. In this study, a proteogenomic approach was used to integrate the data from RNA sequencing, qualitative and quantitative proteomics to discover new players or pathways in the response to hypoxia stress. The improved analytical pipeline of proteogenomics led to the identification of 10,253 intron-containing genes, 1,729 of which were not present in the current annotation. Approximately 1,741 differentially expressed AS (DAS) events from 811 genes were identified in hypoxia-treated seeds in comparison to controls. Over 95% of these were not present in the list of differentially expressed genes (DEG). In particular, regulatory pathways such as spliceosome, ribosome, ER protein processing and export, proteasome, phagosome, oxidative phosphorylation and mRNA surveillance showed substantial AS changes under hypoxia, suggesting that AS responses are largely independent of traditional transcriptional regulation. Massive AS changes were identified, including the preference usage of certain non-conventional splice sites and enrichment of splicing factors in the DAS datasets. In addition, using self-constructed protein libraries by 6-frame translation, thousands of novel proteins/peptides contributed by ATI were identified. In summary, these results provide deeper insights towards understanding the underlying mechanisms of AS and ATI during rice hypoxic germination.
Comprehensive functional screening of taste sensation in vivo
Authors: Han Jisoo , Choi Myunghwan
Published: July 2018

The initial event in taste sensation is mediated by taste cells on the tongue that translate ingested chemicals into cellular signals. Current understanding on this cellular level taste encoding process has relied on ex vivo model systems that cannot fully recapitulate natural cellular microenvironment in vivo. To resolve this methodological limitation, we invented a microfluidics-on-a-tongue imaging chamber that has integrated multichannel microfluidics for auto-controlled tastant delivery. Using this system, we screened over 100 fungiform taste cells to the five basic taste qualities, and obtained comprehensive functional maps. We revealed that taste cells are composed of 70% of single-tuned and 30% of dual-tuned cells, and also discovered a novel population of dual-tuned taste cells encoding a positive valence. We believe that our novel screening platform will pave a way for the deeper understanding of taste coding logic.