bluuebunny/crossref_metadata_2025 huggingface dataset:
Genotype to phenotype mapping still needs underpinning by research in metabolism and enzymology
Authors: Fell David A.
Published: May 2018

The article ‘Evidence that the metabolite repair enzyme NAD(P)HX epimerase has a moonlighting function’ by Niehaus et al. published in this issue illustrates a number of the problems that still arise when attempting to translate genotypes to phenotypes, such as for interpreting mutant phenotypes or building genome-scale metabolic models. In this case, the mutation concerned appears to map to an enzyme in one of the little-known but essential metabolite repair pathways that have been discovered in recent years. However, the bioinformatic and experimental evidence presented suggests that the annotated enzyme activity of the mutated gene product, whilst correct, accounts neither for the phenotype nor for the chromosomal and transcriptional associations of the gene. The bioinformatic and metabolomic evidence presented points to an additional but important role for the gene product in pyridoxal phosphate homoeostasis, thus adding the enzyme to the expanding list of those with a ‘moonlighting function’.
Prorenin independently causes hypertension and renal and cardiac fibrosis in cyp1a1-prorenin transgenic rats
Authors: Zhou Guangyu , Wu Jie , Gu Chunyan , Wang Bin , Abel E. Dale , Cheung Alfred K. , Huang Yufeng
Published: May 2018

Plasma prorenin is commonly elevated in diabetic patients and appears to predict the development of diabetic nephropathy. However, the pathological role of prorenin is unclear. In the present study, a transgenic, inducible, hepatic prorenin-overexpressing rat model was generated and the effect of prorenin in organ injury was examined. Four groups of rats (cyp1a1 prorenin transgenic male and female rats and non-transgenic littermates) were assigned to receive a diet containing 0.3% of the transgene inducer indole-3-carbinol (I3C) for 4 weeks. Plasma prorenin concentration was increased and mean arterial pressure (MAP) increased from 80 ± 18 to 138 ± 17 (mmHg), whereas renal prorenin/renin protein expression was unchanged, in transgenic rats fed with I3C diet. The intact prorenin, not renin, in plasma and urine samples was further observed by Western blot analysis. Importantly, transgenic rats with high levels of prorenin developed albuminuria, glomerular and tubulointerstitial fibrosis associated with increased expression of transforming growth factor β (TGFβ) 1 (TGFβ1), plasminogen activator inhibitor-1 (PAI-1), collagen, and fibronectin (FN). These rats also exhibited cardiac hypertrophy determined by echocardiography, with elevated ratio of heart weight to body weight (HW/BW). Cardiac collagen in interstitial and perivascular regions was prominent, accompanied by the increase in mRNA contents of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), β-myosin heavy chain (β-MHC), TGFβ1, PAI-1, and collagen in the heart tissue. Furthermore, renal protein levels of p-NF-κB-p65 and monocyte chemoattractant protein-1 (MCP-1), NAPDH oxidases, malondialdehyde (MDA) and 8-isoprostane (8-IP), p-ERK, p-β-catenin, and p-Akt were dramatically increased in prorenin overexpressing rats. These results indicate that prorenin, without being converted into renin, causes hypertension, renal and cardiac fibrosis via the induction of inflammation, oxidative stress and the ERK, β-catenin, and Akt-mediated signals.
Submillimeter-wave emission of three Galactic red novae: cool molecular outflows produced by stellar mergers
Authors: Kamiński T. , Steffen W. , Tylenda R. , Young K. H. , Patel N. A. , Menten K. M.
Published: May 2018

Red novae are optical transients erupting at luminosities typically higher than those of classical novae. Their outbursts are believed to be caused by stellar mergers. We present millimeter/submillimeter-wave observations with the Atacama Large (sub)Millimeter Array (ALMA) and the Submillimeter Array (SMA) of the three best-known Galactic red novae, V4332 Sgr, V1309 Sco, and V838 Mon. The observations were taken 22, 8, and 14 yr after their respective eruptions and reveal the presence of molecular gas at excitation temperatures of 35–200 K. The gas displays molecular emission in rotational transitions with very broad lines (full width ~400 km s−1). We found emission of CO, SiO, SO, SO2 (in all three red novae), H2S (covered only in V838 Mon), and AlO (present in V4332 Sgr and V1309 Sco). No anomalies were found in the isotopic composition of the molecular material, and the chemical (molecular) compositions of the three red novae appear similar to those of oxygen-rich envelopes of classical evolved stars (RSGs, AGBs, post-AGBs). The minimum masses of the molecular material that was most likely dispersed in the red-nova eruptions are 0.05, 0.01, and 10−4 M⊙ for V838 Mon, V4332 Sgr, and V1309 Sco, respectively. The molecular outflows in V4332 Sgr and V1309 Sco are spatially resolved and appear bipolar. The kinematic distances to V1309 Sco and V4332 Sgr are 2.1 and 4.2 kpc, respectively. The kinetic energy stored in the ejecta of the two older red-nova remnants of V838 Mon and V4332 Sgr is of the order of 1046 erg, similar to values found for some post-AGB (pre-PN) objects whose bipolar ejecta were also formed in a short-duration eruption. Our observations strengthen the link between these post-AGB objects and red novae and support the hypothesis that some of the post-AGB objects were formed in a common-envelope ejection event or its most catastrophic outcome, a merger.
The WISSH quasars project
Authors: Bischetti M. , Piconcelli E. , Feruglio C. , Duras F. , Bongiorno A. , Carniani S. , Marconi A. , Pappalardo C. , Schneider R. , Travascio A. , Valiante R. , Vietri G. , Zappacosta L. , Fiore F.
Published: May 2018

We present an ALMA high-resolution (0.18″ × 0.21″) observation of the 840 μm continuum and [CII] λ157.74 μm line emission in the WISE-SDSS selected hyper-luminous (WISSH) quasi-stellar object (QSO) J1015+0020, at z ∼ 4.4. Our analysis reveals an exceptional overdensity of [CII]-emitting companions with a very small (<150 km s−1) velocity shift with respect to the QSO redshift. We report the discovery of the closest companion observed so far in submillimetre observations of high-z QSOs. It is only 2.2 kpc distant and merging with J1015+0020, while two other [CII] emitters are found at 8 and 17 kpc. Two strong continuum emitters are also detected at <3.5 arcsec from the QSO. They are likely associated with the same overdense structure of J1015+0020, as they exceed by a factor of 100 the number of expected sources, considering the log(N)–log(S) at 850 μm. The host galaxy of J1015+0020 shows a star formation rate (SFR) of about 100 M⊙ yr−1, while the total SFR of the QSO and its companion galaxies is a factor of ∼10 higher, indicating that substantial stellar mass assembly at early epochs may have taken place in the QSO satellites. For J1015+0020 we computed a black hole mass MBH ∼ 6 × 109 M⊙. As we resolve the [CII] emission of the QSO, we can compute a dynamical mass of Mdyn ∼ 4 × 1010 M⊙. This translates into an extreme ratio Mdyn/MBH ∼ 7, i.e. two orders of magnitude smaller than what is typically observed in local galaxies. The total stellar mass of the QSO host galaxy plus the [CII] emitters in the ALMA field of view already exceeds 1011 M⊙ at z ∼ 4.4. These sources will likely merge and develop into a giant galaxy of ∼1.3 × 1012 M⊙. Under the assumption of constant Ṁacc or λEdd equal to the observed values, we find that the growth timescale of the host galaxy of J1015+0020 is comparable or even shorter than that inferred for the SMBH.
Stationäre Therapie der komplexen PTBS in Folge körperlicher oder sexualisierter Gewalt in der Kindheit: Wirksamkeit und Prädiktoren des Behandlungsverlaufs
Authors: Kratzer Leonhard , Heinz Peter , Schennach Rebecca , Schiepek Günter , Padberg Frank , Jobst Andrea
Published: May 2018

Hintergrund Die Wirksamkeit stationärer traumafokussierter Psychotherapie ist bei PatientInnen mit komplexer posttraumatischer Belastungsstörung (PTBS) insbesondere unter klinischen Routinebedingungen unzureichend belegt. Ziel dieser Untersuchung war neben der Verlaufsanalyse die Identifikation von Prädiktoren des Behandlungserfolges.

Methode 150 PatientInnen der Abteilung für Psychotraumatologie der Klinik St. Irmingard mit komplexer PTBS in Folge körperlicher oder sexualisierter Gewalt in der Kindheit beantworteten Fragebögen zu PTBS, Kindheitstraumata, Achtsamkeit, Dissoziation und allgemeiner Psychopathologie. Die Unterschiede zwischen Prä- und Postmessung wurden regressionsanalytisch untersucht. Mittels konditionalem Klassifikationsbaum wurde untersucht, welche Parameter eine Response prädizieren.

Ergebnisse Die signifikante Verbesserung der PTBS-Symptomatik entsprach einem großen Effekt (d=1,8) und einer Responserate von 52% gemäß Reliable Change Index (p<0,05). Hinsichtlich anderer Symptombereiche waren Verbesserungen in der Größenordnung mittlerer bis großer Effekte (0,5<d<1,1) zu beobachten. Sowohl Abbrüche (7%) als auch Verschlechterungen (4%) waren selten. Somatoforme Beschwerden, das Vorliegen einer komplexen dissoziativen Störung sowie Achtsamkeitsdefizite erwiesen sich als negative Prädiktoren einer reliablen Besserung der PTBS-Belastung.

Diskussion und Schlussfolgerung Traumafokussierte Psychotherapie ist unter naturalistischen Bedingungen bei PatientInnen mit komplexer PTBS sicher und wirksam durchführbar. Zugleich zeigen sich hohe Nonresponseraten. Zukünftige Untersuchungen sollten die Bedeutung der identifizierten Prädiktoren für Nonresponse näher untersuchen. Mögliche Maßnahmen zur Reduktion von Nonresponse werden diskutiert.
A Pharmacological Update of Ellagic Acid
Authors: Ríos José-Luis , Giner Rosa , Marín Marta , Recio M.
Published: May 2018

Ellagic acid is a common metabolite present in many medicinal plants and vegetables. It is present either in free form or as part of more complex molecules (ellagitannins), which can be metabolized to liberate ellagic acid and several of its metabolites, including urolithins. While ellagic acidʼs antioxidant properties are doubtless responsible for many of its pharmacological activities, other mechanisms have also been implicated in its various effects, including its ability to reduce the lipidemic profile and lipid metabolism, alter pro-inflammatory mediators (tumor necrosis factor-α, interleukin-1β, interleukin-6), and decrease the activity of nuclear factor-κB while increasing nuclear factor erythroid 2-related factor 2 expression. These events play an important role in ellagic acidʼs anti-atherogenic, anti-inflammatory, and neuroprotective effects. Several of these activities, together with the effect of ellagic acid on insulin, glycogen, phosphatases, aldose reductase, sorbitol accumulation, advanced glycation end-product formation, and resistin secretion, may explain its effects on metabolic syndrome and diabetes. In addition, results from recent research have increased the interest in ellagic acid, both as a potential protective agent of the liver and skin and as a potential anticancer agent, due to the specific mechanisms affecting cell proliferation, apoptosis, DNA damage, and angiogenesis and its aforementioned anti-inflammatory properties. Taken together, these effects make ellagic acid a highly interesting compound that may contribute to different aspects of health; however, more studies are needed, especially on the compoundʼs pharmacokinetic profile. In this review, we selected papers published from 2005 to the present.
Vascular Permeability and Remodelling Coincide with Inflammatory and Reparative Processes after Joint Bleeding in Factor VIII-Deficient Mice
Authors: Cooke Esther , Zhou Jenny , Wyseure Tine , Joshi Shweta , Bhat Vikas , Durden Donald , Mosnier Laurent , von Drygalski Annette
Published: May 2018

Vascular remodelling is a prominent feature of haemophilic arthropathy (HA) that may underlie re-bleeding, yet the nature of vascular changes and underlying mechanisms remain largely unknown. Here, we aimed to characterize synovial vascular remodelling and vessel integrity after haemarthrosis, as well as temporal changes in inflammatory and tissue-reparative pathways. Thirty acutely painful joints in patients with haemophilia (PWH) were imaged by musculoskeletal ultrasound with Power Doppler (MSKUS/PD) to detect vascular abnormalities and bloody effusions. Nineteen out of 30 painful joint episodes in PWH were associated with haemarthrosis, and abnormal vascular perfusion was unique to bleeding joints. A model of induced haemarthrosis in factor VIII (FVIII)-deficient mice was used for histological assessment of vascular remodelling (α-smooth muscle actin [αSMA] expression), and monitoring of in vivo vascular perfusion and permeability by MSKUS/PD and albumin extravasation, respectively. Inflammatory (M1) and reparative (M2) macrophage markers were quantified in murine synovium over a 10-week time course by real-time polymerase chain reaction. The abnormal vascular perfusion observed in PWH was recapitulated in FVIII-deficient mice after induced haemarthrosis. Neovascularization and increased vessel permeability were apparent 2 weeks post-bleed in FVIII-deficient mice, after a transient elevation of inflammatory macrophage M1 markers. These vascular changes subsided by week 4, while vascular remodelling, evidenced by architectural changes and pronounced αSMA expression, persisted alongside a reparative macrophage M2 response. In conclusion, haemarthrosis leads to transient inflammation coupled with neovascularization and associated vascular permeability, while subsequent tissue repair mechanisms coincide with vascular remodelling. Together, these vascular changes may promote re-bleeding and HA progression.
Targeting von Willebrand Factor in Ischaemic Stroke: Focus on Clinical Evidence
Authors: Buchtele Nina , Schwameis Michael , Gilbert James , Schörgenhofer Christian , Jilma Bernd
Published: May 2018

Despite great efforts in stroke research, disability and recurrence rates in ischaemic stroke remain unacceptably high. To address this issue, one potential target for novel therapeutics is the glycoprotein von Willebrand factor (vWF), which increases in thrombogenicity especially under high shear rates as it bridges between vascular sub-endothelial collagen and platelets. The rationale for vWF as a potential target in stroke comes from four bodies of evidence. (1) Animal models which recapitulate the pathogenesis of stroke and validate the concept of targeting vWF for stroke prevention and the use of the vWF cleavage enzyme ADAMTS13 in acute stroke treatment. (2) Extensive epidemiologic data establishing the prognostic role of vWF in the clinical setting showing that high vWF levels are associated with an increased risk of first stroke, stroke recurrence or stroke-associated mortality. As such, vWF levels may be a suitable marker for further risk stratification to potentially fine-tune current risk prediction models which are mainly based on clinical and imaging data. (3) Genetic studies showing an association between vWF levels and stroke risk on genomic levels. Finally, (4) studies of patients with primary disorders of excess or deficiency of function in the vWF axis (e.g. thrombotic thrombocytopenic purpura and von Willebrand disease, respectively) which demonstrate the crucial role of vWF in atherothrombosis. Therapeutic inhibition of VWF by novel agents appears particularly promising for secondary prevention of stroke recurrence in specific sub-groups of patients such as those suffering from large artery atherosclerosis, as designated according to the TOAST classification.
Integrating Multimodal Radiation Therapy Data into i2b2
Authors: Zapletal Eric , Bibault Jean-Emmanuel , Giraud Philippe , Burgun Anita
Published: May 2018

Background Clinical data warehouses are now widely used to foster clinical and translational research and the Informatics for Integrating Biology and the Bedside (i2b2) platform has become a de facto standard for storing clinical data in many projects. However, to design predictive models and assist in personalized treatment planning in cancer or radiation oncology, all available patient data need to be integrated into i2b2, including radiation therapy data that are currently not addressed in many existing i2b2 sites.

Objective To use radiation therapy data in projects related to rectal cancer patients, we assessed the feasibility of integrating radiation oncology data into the i2b2 platform.

Methods The Georges Pompidou European Hospital, a hospital from the Assistance Publique – Hôpitaux de Paris group, has developed an i2b2-based clinical data warehouse of various structured and unstructured clinical data for research since 2008. To store and reuse various radiation therapy data—dose details, activities scheduling, and dose-volume histogram (DVH) curves—in this repository, we first extracted raw data by using some reverse engineering techniques and a vendor's application programming interface. Then, we implemented a hybrid storage approach by combining the standard i2b2 “Entity-Attribute-Value” storage mechanism with a “JavaScript Object Notation (JSON) document-based” storage mechanism without modifying the i2b2 core tables. Validation was performed using (1) the Business Objects framework for replicating vendor's application screens showing dose details and activities scheduling data and (2) the R software for displaying the DVH curves.

Results We developed a pipeline to integrate the radiation therapy data into the Georges Pompidou European Hospital i2b2 instance and evaluated it on a cohort of 262 patients. We were able to use the radiation therapy data on a preliminary use case by fetching the DVH curve data from the clinical data warehouse and displaying them in a R chart.

Conclusion By adding radiation therapy data into the clinical data warehouse, we were able to analyze radiation therapy response in cancer patients and we have leveraged the i2b2 platform to store radiation therapy data, including detailed information such as the DVH to create new ontology-based modules that provides research investigators with a wider spectrum of clinical data.
Student Perceptions of the Ophthalmology Curriculum in Medical School
Authors: Cobbs Lucy , Tsui Edmund , Haberman Ilyse , Kim Eleanore , Sperber Laurence , Wu Mengfei , Schuman Joel
Published: May 2018

Purpose There is no national standard for ophthalmology curricula in U.S. and Canadian medical schools. We aim to evaluate medical students' perceptions of the current ophthalmology curriculum without mandatory rotation at New York University School of Medicine (NYUSOM).

Design A cross-sectional Internet survey.

Methods A cross-sectional Internet survey was distributed to all NYUSOM students in March to May 2017. The main parameters measured in the study were students' self-reported confidence with ophthalmology skills and satisfaction with curriculum.

Results Response rate was 27.5% (166 of 604) of NYUSOM students. Many students reported they were not comfortable diagnosing eye emergencies (64%), using a direct ophthalmoscope (71%), or testing visual acuity (50%). The majority of students did not want ophthalmology to become a mandatory rotation, but reported additional in-person training would be most helpful, compared with videos, web-based didactics, lectures, or virtual training. Completion of an ophthalmology elective and more hours of ophthalmology training were associated with increased confidence with eye examination and greater satisfaction with the curriculum.

Conclusions It is critical for all physicians-in-training to have adequate skills in eye examination. Identifying areas of improvement and determining the best teaching modality will be important in updating the ophthalmology curriculum for medical students. The majority of medical students are not at all or only slightly confident with eye examinations. Increasing the amount of in-person ophthalmology training in medical school improves confidence with eye examination.
Prioritization of Candidate Genes for Congenital Diaphragmatic Hernia in a Critical Region on Chromosome 4p16 using a Machine-Learning Algorithm
Authors: Campbell Ian , Stover Samantha , Hernandez-Garcia Andres , Jhangiani Shalini , Punetha Jaya , Paine Ingrid , Posey Jennifer , Muzny Donna , Lally Kevin , Lupski James , Shaw Chad , Fernandes Caraciolo , Scott Daryl , Callaway Danielle
Published: May 2018

Wolf–Hirschhorn syndrome (WHS) is caused by partial deletion of the short arm of chromosome 4 and is characterized by dysmorphic facies, congenital heart defects, intellectual/developmental disability, and increased risk for congenital diaphragmatic hernia (CDH). In this report, we describe a stillborn girl with WHS and a large CDH. A literature review revealed 15 cases of WHS with CDH, which overlap a 2.3-Mb CDH critical region. We applied a machine-learning algorithm that integrates large-scale genomic knowledge to genes within the 4p16.3 CDH critical region and identified FGFRL1, CTBP1, NSD2, FGFR3, CPLX1, MAEA, CTBP1-AS2, and ZNF141 as genes whose haploinsufficiency may contribute to the development of CDH.
Investigation of the hydrodynamics and emission of a laser heated tamped high-Z target
Authors: Gray William J. , Foord Mark E. , Schneider Marilyn B. , Barrios Maria A. , Brown Greg V. , Heeter Robert F. , Jarrott L. Charlie , Liedahl Duane A. , Marley Ed V. , Mauche Chris W. , Widmann Klaus
Published: May 2018

We investigate the hydrodynamic expansion and x-ray emission of a laser-heated buried-layer target. This work is motivated by our interest in developing an experimental platform for probing plasma properties under relatively uniform conditions, such as ionization and equation of state. Targets consist of a few thousand angstrom-thick layer of material, embedded in a few microns of the tamper material (typically beryllium), which are irradiated on both sides by an intense few-nanosecond laser pulse. The expansion and emission of our target, composed of a homogeneous mixture of iron, vanadium, and gold, are simulated using the 2-D LASNEX code. Reasonable agreement is found with the time history of the x-ray emission traces (DANTE). Both experiments and simulations exhibit an interesting reduction in the radial size of the emission region with time, as measured using face-on imaging. This is shown to be due to the ablation of the beryllium tamper, which affects the radial confinement of the embedded target. Simulations using a larger diameter beryllium tamper are found to mitigate this effect, improving the one-dimensionality of the expansion.
A dual-polarized and reconfigurable reflectarray for generation of vortex radio waves
Authors: Li Chen-Chen , Wu Lin-Sheng , Yin Wen-Yan
Published: May 2018

Electromagnetic (EM) waves with orbital angular momentum (OAM) provide a new degree of freedom for channel multiplexing to improve the capacity of wireless communication. For OAM-based systems, it is important to design specific configurations to generate vortex radios. In this paper, a reconfigurable reflectarray antenna is proposed with independent control of dual polarizations. A reflective cell is proposed by properly assigning the variable capacitances of four varactors, which are placed between metal square rings of each unit. The varactors of each unit are divided into two groups and the capacitance value of each group controls the reflection phase for a single linear polarization. By using the equivalent circuit model, the reflective units and array can be designed efficiently. Smooth phase variation and good reflection efficiency are achieved. Then, the reflectarray is set into sectors and a simple phase-shifting surface model is used to generate vortex beam. Each sector is realized with reflective units satisfying desired reflection phases for different modes. This kind of OAM-generating method can reduce the required variation range of reflection phase and provide more choices for a specific OAM mode combination with dual polarization, which is helpful to reduce mutual coupling between the two linear polarizations. Finally, full-wave simulations show that the 0, ±1, ±2 modes of vortex beam are successfully generated at 3.5 GHz with arbitrary combination in dual-polarization, which is also supported by OAM modes purity and reflection efficiency analysis. Therefore, in our design, the reconfigurable OAM and spin angular momentum (SAM), related with polarization, can be utilized simultaneously and independently for high-capacity wireless communication.
Detection of core-periphery structure in networks based on 3-tuple motifs
Authors: Ma Chuang , Xiang Bing-Bing , Chen Han-Shuang , Small Michael , Zhang Hai-Feng
Published: May 2018

Detecting mesoscale structure, such as community structure, is of vital importance for analyzing complex networks. Recently, a new mesoscale structure, core-periphery (CP) structure, has been identified in many real-world systems. In this paper, we propose an effective algorithm for detecting CP structure based on a 3-tuple motif. In this algorithm, we first define a 3-tuple motif in terms of the patterns of edges as well as the property of nodes, and then a motif adjacency matrix is constructed based on the 3-tuple motif. Finally, the problem is converted to find a cluster that minimizes the smallest motif conductance. Our algorithm works well in different CP structures: including single or multiple CP structure, and local or global CP structures. Results on the synthetic and the empirical networks validate the high performance of our method.
Rapid micro fluorescence in situ hybridization in tissue sections
Authors: Huber D. , Kaigala G. V.
Published: May 2018

This paper describes a micro fluorescence in situ hybridization (μFISH)-based rapid detection of cytogenetic biomarkers on formalin-fixed paraffin embedded (FFPE) tissue sections. We demonstrated this method in the context of detecting human epidermal growth factor 2 (HER2) in breast tissue sections. This method uses a non-contact microfluidic scanning probe (MFP), which localizes FISH probes at the micrometer length-scale to selected cells of the tissue section. The scanning ability of the MFP allows for a versatile implementation of FISH on tissue sections. We demonstrated the use of oligonucleotide FISH probes in ethylene carbonate-based buffer enabling rapid hybridization within <1 min for chromosome enumeration and 10–15 min for assessment of the HER2 status in FFPE sections. We further demonstrated recycling of FISH probes for multiple sequential tests using a defined volume of probes by forming hierarchical hydrodynamic flow confinements. This microscale method is compatible with the standard FISH protocols and with the Instant Quality FISH assay and reduces the FISH probe consumption ∼100-fold and the hybridization time 4-fold, resulting in an assay turnaround time of <3 h. We believe that rapid μFISH has the potential of being used in pathology workflows as a standalone method or in combination with other molecular methods for diagnostic and prognostic analysis of FFPE sections.
Contact guidance is cell cycle-dependent
Authors: Esmaeili Pourfarhangi Kamyar , Cardenas De La Hoz Edgar , Cohen Andrew R. , Gligorijevic Bojana
Published: May 2018

Cancer cell migration is essential for metastasis, during which cancer cells move through the tumor and reach the blood vessels. In vivo, cancer cells are exposed to contact guidance and chemotactic cues. Depending on the strength of such cues, cells will migrate in a random or directed manner. While similar cues may also stimulate cell proliferation, it is not clear whether cell cycle progression affects migration of cancer cells and whether this effect is different in random versus directed migration. In this study, we tested the effect of cell cycle progression on contact guided migration in 2D and 3D environments, in the breast carcinoma cell line, FUCCI-MDA-MB-231. The results were quantified from live cell microscopy images using the open source lineage editing and validation image analysis tools (LEVER). In 2D, cells were placed inside 10 μm-wide microchannels to stimulate contact guidance, with or without an additional chemotactic gradient of the soluble epidermal growth factor. In 3D, contact guidance was modeled by aligned collagen fibers. In both 2D and 3D, contact guidance was cell cycle-dependent, while the addition of the chemoattractant gradient in 2D increased cell velocity and persistence in directionally migrating cells, regardless of their cell cycle phases. In both 2D and 3D contact guidance, cells in the G1 phase of the cell cycle outperformed cells in the S/G2 phase in terms of migration persistence and instantaneous velocity. These data suggest that in the presence of contact guidance cues in vivo, breast carcinoma cells in the G1 phase of the cell cycle may be more efficient in reaching the neighboring vasculature.
Structural analysis of peptides that fill sites near the active center of the two different enzyme molecules by artificial intelligence and computer simulations
Authors: Nishiyama Katsuhiko
Published: May 2018

Using artificial intelligence, the binding styles of 167 tetrapeptides were predicted in the active site of papain and cathepsin K. Five tetrapeptides (Asn–Leu–Lys–Trp, Asp–Gln–Trp–Gly, Cys–Gln–Leu–Arg, Gln–Leu–Trp–Thr and Arg–Ser–Glu–Arg) were found to bind sites near the active center of both papain and cathepsin K. These five tetrapeptides have the potential to also bind sites of other cysteine proteases, and structural characteristics of these tetrapeptides should aid the design of a common inhibitor of cysteine proteases. Smart application of artificial intelligence should accelerate data mining of important complex systems.
Nanoclusters of α-Fe naturally formed in twinned martensite after martensitic transformation
Authors: Liu X. , Ping D. H. , Xiang H. P. , Lu X. , Shen J.
Published: May 2018

Various Fe-C binary alloys with the carbon content from 0.05 to 2.0 (wt. %) have been prepared and water-quenched at austenitizing temperatures. The fine structure of the twinned martensite in the quenched samples has been investigated by means of transmission electron microscopy (TEM) in order to understand the initial products during the formation of the martensite structure. In the twinned structure (body-centered-cubic {112}⟨111⟩-type twin), TEM dark field observations have revealed that both matrix and twinned crystal regions are fully composed of ultra-fine particles (α-Fe nano-crystallites). The particles tend to have the same preferred direction (or texture) in the twinned martensite and the size is almost the same (1–2 nm). The ultra-fine particle structure has been commonly observed regardless of the carbon content; however, such a fine particle structure has been observed only in the martensite with the twinning structure. After in-situ TEM heating, recrystallization occurred and the fine particles merged into larger α-Fe grains; at the same time, the twinned relationship also disappeared.
Preface to Special Topic: Frontiers on THz photonic devices
Authors: Atakaramians Shaghik , Johnston Michael , Padilla Willie , Mendis Rajind
Published: May 2018

Terahertz (THz) photonic devices are now exploiting emerging materials systems, while novel device designs utilise plasmonic effects, nanophotinics, and metamaterials. The scope of this special topic highlights and reviews the recent cutting-edge THz photonic devices which have been revolutionised from the advances in the above research areas.
Singularities in vorticity-induced velocity field eliminated from linearized supersonic flow
Authors: Cockbill Louisa
Published: May 2018

The origin of singularities along the Mach cones in a horseshoe line-vortex distribution have been identified and eliminated.
Seasonal variations in the water quality of six tropical micro- and mesotidal estuaries along the central west coast of India
Authors: Fernandes Lina L. , Kessarkar Pratima M. , Suja Suresh , Ray Durbar , Bhat Mithila
Published: May 2018

Seasonal nutrient dynamics were investigated in four rivers with a microtidal range (Terekhol, Chapora, Sal and Talpona rivers) and were compared with those of two rivers with a mesotidal range (Zuari and Mandovi rivers) along the central west coast of India. Rainfall and freshwater discharge during the wet season led to salinity stratification of the water columns at the mouths of these rivers. Nutrient concentrations in all rivers were higher during the wet season than in the dry season due to considerable land run-off. Based on the estuarine mixing diagrams of the nutrients with regard to salinity, the mesotidal rivers showed greater flushing capacity and acted as corridors for the passage of nutrients between the estuary and open ocean. Conversely, of the microtidal rivers, the Terekhol and Chapora seemed to retain nutrients, whereas there was no indication of the presence of a nutrient sink or source in the Talpona River. The Sal River was eutrophic with high nutrient levels and acted as a source of phosphorus and nitrogen. Thus, the present study clearly illustrates the important role played by minor river estuaries in modifying nutrient concentrations during their transport from rivers to coastal waters and vice versa.
Insulin-like growth factor-1 (IGF-1) promotes primordial follicle growth and reduces DNA fragmentation through the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signalling pathway
Authors: Bezerra Maria É. S. , Barberino Ricássio S. , Menezes Vanúzia G. , Gouveia Bruna B. , Macedo Taís J. S. , Santos Jamile M. S. , Monte Alane P. O. , Barros Vanessa R. P. , Matos Maria H. T.
Published: May 2018

We investigated the effects of insulin-like growth factor 1 (IGF-1) on the morphology and follicular activation of ovine preantral follicles cultured in situ and whether the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway is involved in IGF-1 action in the sheep ovary. Ovine ovarian fragments were fixed for histological and terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) analyses (fresh control) or cultured in supplemented alpha-minimum essential medium (α-MEM+; control) or α-MEM+ with IGF-1 (1, 10, 50, 100 or 200 ng mL−1) for 7 days. Follicles were classified as normal or atretic, primordial or growing and the oocyte and follicle diameters were measured. DNA fragmentation was evaluated by TUNEL assay. Proliferating cell nuclear antigen (PCNA) immunohistochemistry was performed on the fresh control, α-MEM+ and 100 ng mL−1 IGF-1 samples. Inhibition of PI3K activity was performed through pretreatment with the PI3K inhibitor LY294002 and phosphorylated AKT (pAKT) expression was analysed after culture in the absence or presence of LY294002. IGF-1 at 100 ng mL−1 increased (P < 0.05) follicular activation compared with α-MEM+ and decreased TUNEL-positive cells (P < 0.05) compared with other treatments. PCNA-positive cells also increased (P < 0.05) in 100 ng mL−1 IGF-1. LY294002 significantly inhibited follicular activation stimulated by α-MEM+ and 100 ng mL−1 IGF-1 and reduced pAKT expression in follicles. Overall, IGF-1 at 100 ng mL−1 promoted primordial follicle activation, cell proliferation and reduced DNA fragmentation after in situ culture through the PI3K/AKT pathway.
A molecular perspective for global modeling of upper atmospheric NH
3
from freezing clouds
Authors: Ge Cui , Zhu Chongqin , Francisco Joseph S. , Zeng Xiao Cheng , Wang Jun
Published: May 2018

Significance

The retentions of gases upon freezing of water from available studies are conflicting. Using molecular dynamic simulations, we have revealed that the retention efficiency of NH
3
upon freezing cloud is close to 0 rather than 1 during deep convection. Our results further provide theoretical framework to explain the first-ever satellite-observed high concentration of NH
3
in the upper troposphere and lower stratosphere (UTLS). As NH
3
emission continues to increase, this study calls upon the emergent need to assess the role of NH
3
in UTLS chemistry especially in the deep convective regions. Methodologically, the molecular dynamics simulation is demonstrated as a tool for improving parameterization of interactions between trace gases and cloud (including ice) particles in global atmospheric models.
Navigation of brain networks
Authors: Seguin Caio , van den Heuvel Martijn P. , Zalesky Andrew
Published: May 2018

Significance

We show that the combination of topology and geometry in mammalian cortical networks allows for near-optimal decentralized communication under navigation routing. Following a simple propagation rule based on local knowledge of the distance between cortical regions, we demonstrate that brain networks can be successfully navigated with efficiency that is comparable to shortest paths routing. This finding helps to conciliate the major progress achieved over more than a decade of connectomics research, under the assumption of communication via shortest paths, with recent questions raised by the biologically unrealistic requirements involved in the computation of optimal routes. Our results reiterate the importance of the brain’s spatial embedding, suggesting a three-way relationship between connectome geometry, topology, and communication.
Involvement of ethylene signaling in Azospirillum sp. B510-induced disease resistance in rice
Authors: Kusajima Miyuki , Shima Shuhei , Fujita Moeka , Minamisawa Kiwamu , Che Fang-Sik , Yamakawa Hiromoto , Nakashita Hideo
Published: May 2018

A bacterial endophyte Azospirillum sp. B510 induces systemic disease resistance in the host without accompanying defense-related gene expression. To elucidate molecular mechanism of this induced systemic resistance (ISR), involvement of ethylene (ET) was examined using OsEIN2-knockdown mutant rice. Rice blast inoculation assay and gene expression analysis indicated that ET signaling is required for endophyte-mediated ISR in rice.

Abbreviations: ACC: 1-aminocyclopropane-1-carboxylic acid; EIN2: ethylene-insensitive protein 2; ET: ethylene; ISR: induced systemic resistance; JA: jasmonic acid; RNAi: RNA interference; SA: salicylic acid; SAR: systemic acquired resistance
An Afm Investigation of Thin Lubricious Coatings
Authors: Myshkin N. K. , Goryacheva I. G. , Kovalev A. V. , Dearnley P. A.
Published: May 2018

A multifunctional atomic force microscopy (AFM) instrument has been used to investigate the surface characteristics of two proprietary lubricious coatings applied to hardened and tempered low alloy steel substrates. The coating materials, MoST (MoS2-Ti) and carbon based Graphit-ic, were applied using magnetron sputter deposition technology. The short range roughness of the coatings (Ra and Rq) was in the range 4 - 7 nm. AFM phase contrast imaging revealed that the MoST coatings had a lateral grain size of 400 nm, whilst the Graphit-ic coatings had duplex lateral grain size of 400 and 600 nm. No second phase constituents were detected. The MoST coatings had a hardness of 33.2 ± 3.6 GPa, whilst the Graphit-ic coatings had a hardness of 16.4 ± 0.8 GPa. The MoST coatings were more scratch resistant than the Graphit-ic coatings and were probably also more resistant to abrasion.
Are the concepts of ‘social investment’ and ‘long-term care for the elderly’ compatible? Perceptions of long-term care stakeholders in Lithuania
Authors: Poškutė Virginija
Published: May 2018

Ageing of society and long-term care (LTC) for the elderly are becoming hot topics on most European countries’ social and economic policy agendas. Increasing demand for the financing of LTC raises the necessity for a search for social policy alternatives without further increasing pressure on national budgets. The social investment approach is seen as an argument in favour of interpreting social expenditure as a ‘productive factor’ (ILO. (2005). Social protection as a productive factor. GB.294/ESP/4. Geneva, p. 2). This approach to welfare systems argues that social expenditure might be seen as investment that produces economic and social returns in time. The perception of what social investment is in relation to the LTC for the elderly is not clear either in public or academic discussion. In responding to this lacuna, this article analyses the views of LTC stakeholders in Lithuania concerning: the system and its challenges; what factors they consider as most significant to successful LTC policies and their implementation; and how the concept of social investment should be understood.
Genetical control of B-cell responses. III. Requirement for functional mitogenicity of the antigen in thymus-independent specific responses.
Authors: Coutinho A , Gronowicz E
Published: May 2018

Spleen cells from C3H/HeJ mice fail to respond with polyclonal antibody synthesis to mitogenic concentrations of lipopolysaccharide (LPS) which are optimal for activating spleen cells from a high-responder strain (B10.5M). This unresponsiveness is selective for LPS, since C3H/HeJ cells respond as normals to another B-cell mitogen, purified protein derivative of tuberculin. Spleen cells from low-responder mice also fail to mount a specific anti-NNP plaque-forming cell (PFC) response, when challenged in vitro by NNP-LPS. However, C3H/HeJ cells develop normal responses to another thymus-independent hapten conjugate, DNP-AECM-Ficoll. C3H/HeJ mice fail to mount a specific anti-LPS antibody response, when challenged in vivo with doses of soluble LPS which are fully immunogenic for the high-responder strain. However, C3H/HeJ mice develop normal direct and indirect PFC responses to LPS, when challenged with a thymus-dependent form of the immunogen. These results are interpreted as indicating as absolute requirement for functional mitogenicity of the antigen, in the induction of specific thymus-independent antibody responses.
Evidence for the clonal abortion theory of B-lymphocyte tolerance.
Authors: Nossal G J , Pike B L
Published: May 2018

This paper deals with the behavior of adult mouse bone marrow cells placed in tissue culture with or without antigen, and subsequently assessed for immune competence after adoptive transfer into lethally X-irradiated, syngeneic hosts. Attention was focussed on B lymphocytes through using hapten human gamma globulin (HGG) preparations as putative tolerogens in tissue culture, the T-cell-independent antigens DNP-POL and NIP-POL as challenge injections in adoptive hosts, and numbers of hapten-specific PFC in host spleens for the quantitation of immune competence. It was found that the capacity of bone marrow cells to mount an adoptive immune response rose by a factor of about fivefold over 3 days in tissue culture. This rise was completely abolished by the presence in the culture of hapten-HGG conjugates with about one mole of hapten per carrier molecule. The prevention of the emergence of immune competence amongst maturing B cells was termed clonal abortion tolerogenesis. Dose-response studies showed the lowest effective antigen concentration to be between 2.5 times 10- minus 10 and 2.5 times 10- minus 9 M, and a standard concentration of 2.5 times 10- minus 8 M was chosen as producing near maximal effects. The tolerance was antigen-specific and time-dependent, being maximal only when antigen was present continuously as the cultured cells was maturing. It did not depend on the presence of T lymphocytes in marrow, and was not of an "infectious" type. In contrast to tolerogenesis of mature B lymphocytes by high antigen concentrations, it could not be abolished by lipopolysaccharide. We speculate that clonal abortion may be a tolerance mechanism of great physiological significance for self-recognition, and discuss the results in the framework of other recent tolerance models, including those involving receptor blockade and suppressor T cells.
Recognition by pregnancy serums of non-HL-A alloantigens selectively expressed on B lymphocytes.
Authors: Winchester R J , Wernet P , Kunkel H G , Dupont B , Jersild C , Fu S M
Published: May 2018

A group of alloantibodies are found in pregnancy sera which react with antigens present on B lymphocytes and monocytes but are not detectable on the vast majority of unstimulated T cells. This specificity distinguishes them from HL-A antibodies which react with both cell types. They were readily recognized through indirect fluorescent antibody analysis by employing the combination of B-cell lymphoid lines and normal peripheral blood T cells. Different sera gave a variety of patterns of reactivity with a panel of 11 lymphoid lines. Similar differential patterns were also observed with normal B cells from different individuals particularly after concentrating the B cells. The antibodies were also cytotoxic to B cells and this procedure gave parallel results to the fluorescence method. The pattern of reactions obtained indicated a very heterogeneous system similar to that for HL-A. Special study of certain of the sera provided evidence that the lymphocyte-defined determinants of the mixed lymphocyte reaction system were involved. For convenience the term HL-B has been employed for these antigens.
Cation Activation of the Basolateral Sodium-Potassium Pump in Turtle Colon
Authors: Halm D R , Dawson D C
Published: May 2018

The current generated by electrogenic sodium-potassium exchange at the basolateral membrane of the turtle colon can be measured directly in tissues that have been treated with serosal barium (to block the basolateral potassium conductance) and mucosal amphotericin B (to reduce the cation selectivity of the apical membrane). We studied the activation of this pump current by mucosal sodium and serosal potassium, rubidium, cesium, and ammonium. The kinetics of sodium activation were consistent with binding to three independent sites on the cytoplasmic side of the pump. The pump was not activated by cellular lithium ions. The kinetics of serosal cation activation were consistent with binding to two independent sites with the selectivity Rb > K > Cs > NH4. The properties and kinetics of the basolateral Na/K pump in the turtle colon are at least qualitatively similar to those ofthe well-characterized Na/K-ATPase of the human red blood cell .
Stability analysis of the phytoplankton effect model on changes in nitrogen concentration on integrated multi-trophic aquaculture systems
Authors: Widowati  , Putro S P , Silfiana
Published: May 2018

Integrated Multi-Trophic Aquaculture (IMTA) is a polyculture with several biotas maintained in it to optimize waste recycling as a food source. The interaction between phytoplankton and nitrogen as waste in fish cultivation including ammonia, nitrite, and nitrate studied in the form of mathematical models. The form model is non-linear systems of differential equations with the four variables. The analytical analysis was used to study the dynamic behavior of this model. Local stability analysis is performed at the equilibrium point with the first step linearized model by using Taylor series, then determined the Jacobian matrix. If all eigenvalues have negative real parts, then the equilibrium of the system is locally asymptotic stable. Some numerical simulations were also demonstrated to verify our analytical result.
Robust model predictive control for inventory system with uncertain demand using linear matrix inequalities
Authors: Widowati  , Tjahjana R. Heru , Sutrisno  , Saputra Aditya
Published: May 2018

In this paper, we develop an optimal control strategy on inventory systems with uncertain demand. To deal with these uncertainties we use a synthesis of robust model predictive control with linear matrix inequalities. The goal is to minimize the difference between the prediction and the reference trajectory subject to the objective function of each period, based on the input and output constraints. Using standard techniques, the optimization problem that minimizes the difference between the prediction and the reference trajectory, is reduced to a convex optimization problem involving linear matrix inequalities (LMIs). We provide numerical simulations on this system using MATLAB and then observe how robust predictive control models produce optimized strategy at the inventory level. In the simulation results, robust predictive control models provide an optimal strategy for controlling inventory levels with minimum total cost and inventory levels following inventory levels on issues.